Short-term soil bioassays may not reveal the full toxicity potential for nanomaterials; bioavailability and toxicity of silver ions (AgNO₃) and silver nanoparticles to earthworm Eisenia fetida in long-term aged soils.

PubMed

Diez-Ortiz, Maria; Lahive, Elma; George, Suzanne; Ter Schure, Anneke; Van Gestel, Cornelis A M; Jurkschat, Kerstin; Svendsen, Claus; Spurgeon, David J

2015-08-01

This study investigated if standard risk assessment hazard tests are long enough to adequately provide the worst case exposure for nanomaterials. This study therefore determined the comparative effects of the aging on the bioavailability and toxicity to earthworms of soils dosed with silver ions and silver nanoparticles (Ag NP) for 1, 9, 30 & 52 weeks, and related this to the total Ag in the soil, Ag in soil pore water and earthworm tissue Ag concentrations. For ionic Ag, a classical pattern of reduced bioavailability and toxicity with time aged in the soil was observed. For the Ag NP, toxicity increased with time apparently driven by Ag ion dissolution from the added Ag NPs. Internal Ag in the earthworms did not always explain toxicity and suggested the presence of an internalised, low-toxicity Ag fraction (as intact or transformed NPs) after shorter aging times. Our results indicate that short-term exposures, without long-term soil aging, are not able to properly assess the environmental risk of Ag NPs and that ultimately, with aging time, Ag ion and Ag NP effect will merge to a common value. Copyright © 2015 Elsevier Ltd. All rights reserved.

Apparent respiration rate of the human corneal epithelium with tetracaine HCl and benoxinate HCl.

PubMed

Bentley, C R; Larke, J R

1983-12-01

Local anesthetics may have a cytotoxic effect which causes a depression in the apparent epithelial oxygen uptake rate (AEOR) of the cornea. We measured the AEOR of human corneas in vivo before and after applying 1% tetracaine (amethocaine) HCl and 0.4% benoxinate HCl. These drugs had no effect on AEOR. In human corneas that had been subjected to a period of hypoxia, AEOR was slightly higher after administration of benoxinate, a result in the opposite direction to that expected on the grounds of toxicity. The increase was not statistically significant. We conclude that clinical doses of tetracaine HCl and benoxinate HCl normally have a minimal cytotoxic effect, and that this is similarly true when benoxinate is applied to the cornea after contact lens wear.

Treatment-related toxicities in tumor-bearing cats treated with temozolomide alone or in combination with doxorubicin: a pilot assessment.

PubMed

Gagnon, Jerome; Dervisis, Nikolaos G; Kitchell, Barbara E

2012-08-01

A retrospective study assessing treatment-related toxicities in tumor-bearing cats treated with temozolomide (TMZ) alone or in combination with doxorubicin was conducted. TMZ was administered orally once a day for 5 days every 3 weeks at a dose of 20 mg/cat. Tumor response was evaluated with standard World Health Organization criteria and toxicity was monitored using veterinary co-operative oncology group-common terminology criteria for adverse events (VCOG--CTCAE) criteria. Ten tumor-bearing cats with various types of malignancies were treated with TMZ-based chemotherapy. Eight cats were evaluable for response. Two cats achieved a complete response, one achieved stable disease and five achieved a partial response. Four grade III and one grade IV hematological toxicities, and one grade IV gastrointestinal toxicity were observed. Four cats were euthanased as a result of apparent toxicity. One cat was euthanased as a result of severe and prolonged myelosuppression with fever. Three were euthanased for grade III pleural and pericardial effusions. Effusion was seen in cats treated with higher cumulative dose of TMZ (P = 0.0046). Planned additional case accrual was discontinued because of unacceptable levels of toxicity despite evidence of efficacy in some of the cats. Additional investigation is needed to elucidate this unexpected apparent cumulative toxicity.

The Poisoning of America's Children: Lead Exposure, Children's Brains, and the Ability To Learn. National Health/Education Consortium Occasional Paper #6.

ERIC Educational Resources Information Center

Needleman, Herbert L.

Despite years of concern about the toxic effects of high lead exposure and recent knowledge about the less apparent effects of exposure to low doses of lead, a total of 3 to 4 million children in the United States are still being exposed to concentrations of lead that could compromise their cognitive and social development. This paper discusses:…

Inhibition of Acetoclastic Methanogenesis in Crude Oil- and Creosote-Contaminated Groundwater

USGS Publications Warehouse

Warren, E.; Bekins, B.A.; Godsy, E.M.; Smith, V.K.

2003-01-01

The inhibition of acetoclastic methanogenesis in crude oil- and creosote-contaminated groundwater was studied. The crude oil and water-soluble components of creosote contributed to the inhibition of acetoclastic methanogens. Acetoclastic methanogenesis was much more susceptible to the toxic inhibition of crude oil and creosote than either hydrogen- or formate-utilizing methanogenesis. The effect of this toxic inhibition was apparent in the population of the methanogenic trophic groups near nonaqueous crude oil at the Bemidji, MN, site. At a crude oil-contaminated site, numbers of acetoclastic methanogens found close to crude oil were 100 times fewer than those of hydrogen- and formate-utilizing methanogens. In laboratory toxicity assays, crude oil collected from the site inhibited methane production from acetate but not from formate or hydrogen. Toxicity assays with aqueous creosote extract completely inhibited acetate utilization over the range of tested dilutions but only mildly affected formate and hydrogen utilization. Wastewater reactor studies indicated that this toxicity would result in a decrease in the biodegradation rate of contaminants at sites where toxic compounds are present.

Development and evaluation of consensus-based sediment effect concentrations for polychlorinated biphenyls

USGS Publications Warehouse

MacDonald, Donald D.; Dipinto, Lisa M.; Field, Jay; Ingersoll, Christopher G.; Long, Edward R.; Swartz, Richard C.

2000-01-01

Sediment-quality guidelines (SQGs) have been published for polychlorinated biphenyls (PCBs) using both empirical and theoretical approaches. Empirically based guidelines have been developed using the screening-level concentration, effects range, effects level, and apparent effects threshold approaches. Theoretically based guidelines have been developed using the equilibrium-partitioning approach. Empirically-based guidelines were classified into three general categories, in accordance with their original narrative intents, and used to develop three consensus-based sediment effect concentrations (SECs) for total PCBs (tPCBs), including a threshold effect concentration, a midrange effect concentration, and an extreme effect concentration. Consensus-based SECs were derived because they estimate the central tendency of the published SQGs and, thus, reconcile the guidance values that have been derived using various approaches. Initially, consensus-based SECs for tPCBs were developed separately for freshwater sediments and for marine and estuarine sediments. Because the respective SECs were statistically similar, the underlying SQGs were subsequently merged and used to formulate more generally applicable SECs. The three consensus-based SECs were then evaluated for reliability using matching sediment chemistry and toxicity data from field studies, dose-response data from spiked-sediment toxicity tests, and SQGs derived from the equilibrium-partitioning approach. The results of this evaluation demonstrated that the consensus-based SECs can accurately predict both the presence and absence of toxicity in field-collected sediments. Importantly, the incidence of toxicity increases incrementally with increasing concentrations of tPCBs. Moreover, the consensus-based SECs are comparable to the chronic toxicity thresholds that have been estimated from dose-response data and equilibrium-partitioning models. Therefore, consensus-based SECs provide a unifying synthesis of existing SQGs, reflect causal rather than correlative effects, and accurately predict sediment toxicity in PCB-contaminated sediments.

Influence of complexation with chloride on the responses of a lux-marked bacteria bioassay to cadmium, copper, lead, and mercury

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sarin, C.; Hall, J.M.; Cotter-Howells, J.

2000-02-01

The toxicity of a heavy metal in solution to a microorganism depends not only on its concentration but also on pH and the concentrations of any aqueous complexing ligands in the microorganism's environment. This paper reports on the use of different inorganic resuscitation media and effect of the chloride ion, Cl{sup {minus}}, on the bioluminescence response of a bacterial biosensor, Escherichia coli HB101 (pUCD607), to four metals: Cd, Cu, Hg, and Pb. The toxicity tests were conducted at pH 4, using 0.1 M KNO{sub 3} as resuscitation medium and adding KCl to investigate effect of Cl{sup {minus}} concentration. The speciesmore » distributions of metals as a function of Cl{sup {minus}} concentration were calculated using GeoChem-PC. Resuscitation in 0.1 M KCl gave significantly higher light output than that in 0.1 M KNO{sub 3}, demonstrating that Cl{sup {minus}} ions increased the toxicity of Hg, apparently because of the formation of HgCl{sub 3}{sup {minus}}, and increased the toxicity of Pb because of PbCl{sup +} formation. The toxicity of Cu decreased at high Cl{sup {minus}} concentrations as free Cu{sup 2+} decreased, in accordance with the free ion model. Concentrations of Cl{sup {minus}} had no significant effect on the toxicity of Cd. This study clearly demonstrates that the chloro-complexes of some heavy metals can be toxic and, for Pb and Hg, more toxic than the free ion.« less

Acute oral toxicity of colchicine in rats: effects of gender, vehicle matrix and pre-exposure to lipopolysaccharide.

PubMed

Wiesenfeld, Paddy L; Garthoff, Larry H; Sobotka, Thomas J; Suagee, Jessica K; Barton, Curtis N

2007-01-01

The oral toxicity of a single administration by gavage (10, 20 or 30 mg kg(-1) body weight) of colchicine (COL) was determined in young, mature male and female Sprague-Dawley rats. The effect of COL was evaluated in the presence or absence of additional treatment variables that included vehicle and lipopolysaccharide (LPS) pre-exposure. The vehicle for COL was either Half and Half cream (H & H) or saline, and each group included pretreatment with either saline or a low, minimally toxic dose (83 microg kg(-1) body weight) of LPS. Colchicine toxicity in both male and female age-matched rats was characterized by progressively more severe dose-related clinical signs of toxicity. These included mortality, decreased body weight and feed intake during the first several days after dosing, with recovery thereafter in surviving animals. There were differences in the severity of the toxic response to COL between male and female rats. The most notable sex-related difference was in COL lethality. Female rats were two times more susceptible to the lethal effects of COL than male rats. Saline or H & H delivery vehicles did not result in any apparent qualitative or quantitative differences in COL toxicity. LPS pretreatment significantly potentiated COL lethality in both males and females, although the potentiation in males was greater than in females. LPS pretreatment modestly increased the COL induced anorexic effect in surviving males, but not in surviving female animals. LPS did not appear to modulate either the body weights or clinical signs of COL induced toxicity in surviving males or females. (c) 2007 John Wiley & Sons, Ltd.

Diet composition modifies the toxicity of repeated soman exposure in rats.

PubMed

Langston, Jeffrey L; Myers, Todd M

2011-12-01

It was previously demonstrated that diet potently modulates the toxic effects of an acute lethal dose of the nerve agent soman. The current investigation was undertaken to examine the influence of diet on the cumulative toxicity of repeated soman administration. Rats were fed one of four distinct diets (standard, choline-enriched, glucose-enriched, or ketogenic) for four weeks prior to and throughout a repeated soman dosing and recovery regimen. Each diet group included animals exposed to an equivalent volume of saline that served as negative controls. In exposure Week 1, animals received three consecutive daily doses of 0.4 LD(50) soman. In exposure Week 2, animals received four consecutive daily doses of 0.5 LD(50) soman. In exposure Week 3, animals received five consecutive daily doses of 0.5 LD(50) soman. Week 4 constituted a post-exposure recovery evaluation. Throughout the experiment, behavioral function was assessed by a discriminated avoidance test that required intact sensory and motor function. Survival and body weight changes were recorded daily. Differences in toxicity as a function of diet composition became apparent during the first week. Specifically, rats fed the glucose-enriched diet showed pronounced intoxication during Week 1, resulting in imperfect survival, weight loss, and deteriorated avoidance performance relative to all other groups. All rats fed the glucose-enriched diet died by the end of exposure Week 2. In contrast, only 10% of animals fed the standard diet died by the end of Week 2. Also in Week 2, weight loss and disrupted avoidance performance were apparent for all groups except for those fed the ketogenic diet. This differential effect of diet composition became even more striking in Week 3 when survival in the standard and choline diet groups approximated 50%, whereas survival equaled 90% in the ketogenic diet group. Avoidance performance and weight loss measures corroborated the differential toxicity observed across diet groups. Upon cessation of soman exposure during the final week, recovery of weight and avoidance performance in survivors was comparable across diet groups. These results systematically replicate previous findings demonstrating that diet composition exacerbates or attenuates toxicity in rodents exposed acutely to organophosphorus compounds. Published by Elsevier B.V.

Predicting adult fish acute lethality with the zebrafish embryo: relevance of test duration, endpoints, compound properties, and exposure concentration analysis.

PubMed

Knöbel, Melanie; Busser, Frans J M; Rico-Rico, Angeles; Kramer, Nynke I; Hermens, Joop L M; Hafner, Christoph; Tanneberger, Katrin; Schirmer, Kristin; Scholz, Stefan

2012-09-04

The zebrafish embryo toxicity test has been proposed as an alternative for the acute fish toxicity test, which is required by various regulations for environmental risk assessment of chemicals. We investigated the reliability of the embryo test by probing organic industrial chemicals with a wide range of physicochemical properties, toxicities, and modes of toxic action. Moreover, the relevance of using measured versus nominal (intended) exposure concentrations, inclusion of sublethal endpoints, and different exposure durations for the comparability with reported fish acute toxicity was explored. Our results confirm a very strong correlation of zebrafish embryo to fish acute toxicity. When toxicity values were calculated based on measured exposure concentrations, the slope of the type II regression line was 1 and nearly passed through the origin (1 to 1 correlation). Measured concentrations also explained several apparent outliers. Neither prolonged exposure (up to 120 h) nor consideration of sublethal effects led to a reduced number of outliers. Yet, two types of compounds were less lethal to embryos than to adult fish: a neurotoxic compound acting via sodium channels (permethrin) and a compound requiring metabolic activation (allyl alcohol).

In vitro biopharmaceutical evaluation of ciprofloxacin/metal cation complexes for pulmonary administration.

PubMed

Brillault, J; Tewes, F; Couet, W; Olivier, J C

2017-01-15

Pulmonary delivery of fluoroquinolones (FQs) is an interesting approach to treat lung infections as it may lead to high local concentrations while minimizing systemic exposure. However, FQs have a rapid diffusion through the lung epithelium giving the pulmonary route no advantage compared to the oral route. Interactions between FQs and metal cations form complexes which limit the diffusion through the epithelial barrier and would reduce the absorption of FQs and maintain high concentrations in the lung. The effects of this complexation depend on the FQ and the metal cations and optimum partners should be selected through in vitro experiments prior to aerosol drug formulation. In this study, CIP was chosen as a representative FQ and 5 cations (Ca 2+ , Mg 2+ , Zn 2+ , Al 3+ , Cu 2+ ) were selected to study the complexation and its effects on permeability, antimicrobial efficacy and cell toxicity. The results showed that the apparent association constants between CIP and cations ranked with the descending order: Cu 2+ >Al 3+ >Zn 2+ >Mg 2+ >Ca 2+ . When a target of 80% complexation was reached with the adequate concentrations of cations, the CIP permeability through the Calu-3 lung epithelial cells was decreased of 50%. Toxicity of the CIP on the Calu-3 cells, with an EC50 evaluated at 7μM, was not significantly affected by the presence of the cations. The minimum inhibitory concentration of CIP for Pseudomonas aeruginosa was not affected or slightly increased in the range of cation concentrations tested, except for Mg 2+ . In conclusion, permeability was the main parameter that was affected by the metal cation complexation while cell toxicity and antimicrobial activity were not or slightly modified. Cu 2+ , with the highest apparent constant of association and with no effect on cell toxicity and antimicrobial activity of the CIP, appeared as a promising cation for the development of a controlled-permeability formulation of CIP for lung treatment. Copyright © 2016 Elsevier B.V. All rights reserved.

Effects of calcium, magnesium, and sodium on alleviating cadmium toxicity to Hyalella azteca

USGS Publications Warehouse

Jackson, B.P.; Lasier, P.J.; Miller, W.P.; Winger, P.V.

2000-01-01

Toxicity of trace metal ions to aquatic organisms, arising through either anthropogenic inputs or acidification of surface waters, continues to be both a regulatory and environmental problem. It is generally accepted that the free metal ion is the major toxic species (Florence et a1.,1992) and that inorganic or organic complexation renders the metal ion non-bioavailable (Meador, 1991, Galvez and Wood, 1997). However, water chemistry parameters such as alkalinity, hardness, dissolved organic carbon and pH influence metal ion toxicity either directly by lowering free metal ion concentration or indirectly through synergistic or antagonistic effects. Alkalinity and salinity can affect the speciation of metal ions by increasing ion-pair formation, thus decreasing free metal ion concentration. For example, Cu was found to be less toxic to rainbow trout in waters of high alkalinity (Miller and Mackay, 1980), due to formation of CuCO3 ion pair, and corresponding reduction in free Cu2+ concentration. The influence of salinity on the toxicity of cadmium to various organisms has been demonstrated in a number of studies (Bervoets et al., 1995, Hall et al., 1995, Lin and Dunson, 1993, Blust et al., 1992). In all these studies the apparent toxicity of cadmium was lowered as salinity was increased due to increased formation of CdC1+ and CDCl2 aqueous complexes that are non-toxic or of much lower toxicity than the free Cd2+ ion. Changes in pH exert both a biological and chemical effect on metal ion toxicity (Campbell and Stokes, 1985). Low pH favors greater metal ion solubility, and, in the absence of complexing ions, reduced speciation of the metal ion, which tends to increase toxicity compared to higher pH. However, Iow pH also enhances competition between H+ and metal ion for cell surface binding sites, which tends to decrease metal ion toxicity.

Lead, Arsenic, and Manganese Metal Mixture Exposures: Focus on Biomarkers of Effect.

PubMed

Andrade, V M; Mateus, M L; Batoréu, M C; Aschner, M; Marreilha dos Santos, A P

2015-07-01

The increasing exposure of human populations to excessive levels of metals continues to represent a matter of public health concern. Several biomarkers have been studied and proposed for the detection of adverse health effects induced by lead (Pb), arsenic (As), and manganese (Mn); however, these studies have relied on exposures to each single metal, which fails to replicate real-life exposure scenarios. These three metals are commonly detected in different environmental, occupational, and food contexts and they share common neurotoxic effects, which are progressive and once clinically apparent may be irreversible. Thus, chronic exposure to low levels of a mixture of these metals may represent an additive risk of toxicity. Building upon their shared mechanisms of toxicity, such as oxidative stress, interference with neurotransmitters, and effects on the hematopoietic system, we address putative biomarkers, which may assist in assessing the onset of neurological diseases associated with exposure to this metal mixture.

Emerging contaminants in Belgian marine waters: single toxicant and mixture risks of pharmaceuticals.

PubMed

Claessens, Michiel; Vanhaecke, Lynn; Wille, Klaas; Janssen, Colin R

2013-06-15

Knowledge on the effects of pharmaceuticals on aquatic marine ecosystems is limited. The aim of this study was therefore to establish the effect thresholds of pharmaceutical compounds occurring in the Belgian marine environment for the marine diatom Phaeodactylum tricornutum, and subsequently perform an environmental risk assessment for these substances. Additionally, a screening-level risk assessment was performed for the pharmaceutical mixtures. No immediate risk for acute toxic effects of these compounds on P. tricornutum were apparent at the concentrations observed in the Belgian marine environment. In two Belgian coastal harbours however, a potential chronic risk was observed for the β-blocker propranolol. No additional risks arising from the exposure to mixtures of pharmaceuticals present in the sampling area could be detected. However, as risk characterization ratios for mixtures of up to 0.5 were observed, mixture effects could emerge should more compounds be taken into account. Copyright © 2013 Elsevier Ltd. All rights reserved.

Lead, arsenic and manganese metal mixture exposures: focus on biomarkers of effect

PubMed Central

Andrade, VL; Mateus, ML; Batoréu, MC; Aschner, M; Marreilha dos Santos, AP

2015-01-01

Summary The increasing exposure of human populations to excessive levels of metals continues to represent a matter of public health concern. Several biomarkers have been studied and proposed for the detection of adverse health effects induced by lead (Pb), arsenic (As) and manganese (Mn); however, these studies have relied on exposures to each single metal, which fails to replicate real-life exposure scenarios. These 3 metals are commonly detected in different environmental, occupational and food contexts and they share common neurotoxic effects, which are progressive and once clinically apparent may be irreversible. Thus, chronic exposure to low levels of a mixture of these metals represents an additive risk of toxicity. Building upon their shared mechanisms of toxicity, such as oxidative stress, interference with neurotransmitters and effects on hematopoietic system, we address putative biomarkers, which may be assist in assessing onset of neurological diseases associated with exposure to this metal mixture. PMID:25693681

Disruption of Phosphatidylcholine Monolayers and Bilayers by Perfluorobutane Sulfonate

PubMed Central

Oldham, E. Davis; Xie, Wei; Farnoud, Amir M.; Fiegel, Jennifer; Lehmler, Hans-Joachim

2012-01-01

Perfluoroalkyl acids (PFAAs) are persistent environmental contaminants resistant to biological and chemical degradation due to the presence of carbon-fluorine bonds. These compounds exhibit developmental toxicity in vitro and in vivo. The mechanisms of toxicity may involve partitioning into lipid bilayers. We investigated the interaction between perfluorobutane sulfonate (PFBS), an emerging PFAA, and model phosphatidylcholine (PC) lipid assemblies (i.e., dimyristoyl-, dipalmitoyl- and distearylphosphatidylcholine) using fluorescence anisotropy and Langmuir monolayer techniques. PFBS decreased the transition temperature and transition width of PC bilayers. The apparent membrane partition coefficients ranged from 4.9 × 102 to 8.2 × 102. The effects on each PC were comparable. The limiting molecular area of PC monolayers increased and the surface pressure at collapse decreased in a concentration-dependent manner. The compressibility of all three PCs was decreased by PFBS. In summary, PFBS disrupted different model lipid assemblies indicating potential for PFBS to be a human toxicant. However the effects of PFBS are not as pronounced as those seen with longer chain PFAAs. PMID:22834732

Non-toxic engineered carbon nanodiamond concentrations induce oxidative/nitrosative stress, imbalance of energy metabolism, and mitochondrial dysfunction in microglial and alveolar basal epithelial cells.

PubMed

Fresta, Claudia G; Chakraborty, Aishik; Wijesinghe, Manjula B; Amorini, Angela M; Lazzarino, Giacomo; Lazzarino, Giuseppe; Tavazzi, Barbara; Lunte, Susan M; Caraci, Filippo; Dhar, Prajnaparamita; Caruso, Giuseppe

2018-02-14

Engineered nanoparticles are finding a wide spectrum of biomedical applications, including drug delivery and capacity to trigger cytotoxic phenomena, potentially useful against tumor cells. The full understanding of their biosafety and interactions with cell processes is mandatory. Using microglial (BV-2) and alveolar basal epithelial (A549) cells, in this study we determined the effects of engineered carbon nanodiamonds (ECNs) on cell viability, nitric oxide (NO) and reactive oxygen species (ROS) production, as well as on energy metabolism. Particularly, we initially measured decrease in cell viability as a function of increasing ECNs doses, finding similar cytotoxic ECN effects in the two cell lines. Subsequently, using apparently non-cytotoxic ECN concentrations (2 µg/mL causing decrease in cell number < 5%) we determined NO and ROS production, and measured the concentrations of compounds related to energy metabolism, mitochondrial functions, oxido-reductive reactions, and antioxidant defences. We found that in both cell lines non-cytotoxic ECN concentrations increased NO and ROS production with sustained oxidative/nitrosative stress, and caused energy metabolism imbalance (decrease in high energy phosphates and nicotinic coenzymes) and mitochondrial malfunctioning (decrease in ATP/ADP ratio).These results underline the importance to deeply investigate the molecular and biochemical changes occurring upon the interaction of ECNs (and nanoparticles in general) with living cells, even at apparently non-toxic concentration. Since the use of ECNs in biomedical field is attracting increasing attention the complete evaluation of their biosafety, toxicity and/or possible side effects both in vitro and in vivo is mandatory before these highly promising tools might find the correct application.

Acute and Cumulative Effects of Unmodified 50-nm Nano-ZnO on Mice.

PubMed

Kong, Tao; Zhang, Shu-Hui; Zhang, Ji-Liang; Hao, Xue-Qin; Yang, Fan; Zhang, Cai; Yang, Zi-Jun; Zhang, Meng-Yu; Wang, Jie

2018-01-02

Nanometer zinc oxide (nano-ZnO) is widely used in diverse industrial and agricultural fields. Due to the extensive contact humans have with these particles, it is crucial to understand the potential effects that nano-ZnO have on human health. Currently, information related to the toxicity and mechanisms of nano-ZnO is limited. The aim of the present study was to investigate acute and cumulative toxic effects of 50-nm unmodified ZnO in mice. This investigation will seek to establish median lethal dose (LD50), a cumulative coefficient, and target organs. The acute and cumulative toxicity was investigated by Karber's method and via a dose-increasing method, respectively. During the experiment, clinical signs, mortality, body weights, hematology, serum biochemistry, gross pathology, organ weight, and histopathology were examined. The LD50 was 5177-mg/kg·bw; the 95% confidence limits for the LD50 were 5116-5238-mg/kg·bw. It could be concluded that the liver, kidney, lung, and gastrointestinal tract were target organs for the 50-nm nano-ZnO acute oral treatment. The cumulative coefficient (K) was 1.9 which indicated that the cumulative toxicity was apparent. The results also indicated that the liver, kidney, lung, and pancrea were target organs for 50-nm nano-ZnO cumulative oral exposure and might be target organs for subchronic and chronic toxicity of oral administered 50-nm ZnO.

Oxidation of diclofenac by potassium ferrate (VI): reaction kinetics and toxicity evaluation.

PubMed

Wang, Yingling; Liu, Haijin; Liu, Guoguang; Xie, Youhai; Gao, Shuyan

2015-02-15

The reaction kinetics and toxicity of diclofenac (DCF) oxidation by ferrate (VI) under simulated water disinfection conditions were investigated. Experimental results indicated that the reaction between DCF and Fe(VI) followed first-order kinetics with respect to each reactant. Furthermore, the effects of pH and temperature on DCF oxidation by Fe(VI) were elucidated using a systematic examination. The apparent second-order rate constants (kapp) increased significantly from 2.54 to 11.6M(-1)s(-1), as the pH of the solution decreased from 11.0 to 7.0, and the acid-base equilibriums of Fe(VI) and DCF were proposed to explain the pH dependence of kapp. The acute toxicity of DCF solution during Fe(VI) oxidation was evaluated using a Microtox bioassay. Overall, the DCF degradation process resulted in a rapid increase of the inhibition rate of luminescent bacteria. These toxicity tests suggest that the formation of enhanced toxic intermediates during the Fe(VI) disinfection process may pose potential health risk to consumers. Copyright © 2014 Elsevier B.V. All rights reserved.

Neurotoxic effects of ecstasy on the thalamus.

PubMed

de Win, Maartje M L; Jager, Gerry; Booij, Jan; Reneman, Liesbeth; Schilt, Thelma; Lavini, Cristina; Olabarriaga, Sílvia D; Ramsey, Nick F; Heeten, Gerard J den; van den Brink, Wim

2008-10-01

Neurotoxic effects of ecstasy have been reported, although it remains unclear whether effects can be attributed to ecstasy, other recreational drugs or a combination of these. To assess specific/independent neurotoxic effects of heavy ecstasy use and contributions of amphetamine, cocaine and cannabis as part of The Netherlands XTC Toxicity (NeXT) study. Effects of ecstasy and other substances were assessed with (1)H-magnetic resonance spectroscopy, diffusion tensor imaging, perfusion weighted imaging and [(123)I]2beta-carbomethoxy-3beta-(4-iodophenyl)-tropane ([(123)I]beta-CIT) single photon emission computed tomography (serotonin transporters) in a sample (n=71) with broad variation in drug use, using multiple regression analyses. Ecstasy showed specific effects in the thalamus with decreased [(123)I]beta-CIT binding, suggesting serotonergic axonal damage; decreased fractional anisotropy, suggesting axonal loss; and increased cerebral blood volume probably caused by serotonin depletion. Ecstasy had no effect on brain metabolites and apparent diffusion coefficients. Converging evidence was found for a specific toxic effect of ecstasy on serotonergic axons in the thalamus.

High-resolution magic angle spinning 1H-NMR spectroscopy studies on the renal biochemistry in the bank vole (Clethrionomys glareolus) and the effects of arsenic (As3+) toxicity.

PubMed

Griffin, J L; Walker, L; Shore, R F; Nicholson, J K

2001-06-01

1. High-resolution magic angle spinning (MAS) 1H-NMR spectroscopy was used to study renal metabolism and the toxicity of As3+, a common environmental contaminant, in the bank vole (Clethrionomys glareolus), a wild species of rodent. 2. Following a 14-day exposure to an environmentally relevant dose of As2O3 (28 mg kg(-1) feed), voles displayed tissue damage at autopsy. MAS 1H spectra indicated abnormal lipid profiles in these samples. 3. Tissue necrosis was also evident from measurements of the apparent diffusion coefficient of water in the intact tissue using MAS 1H diffusion-weighted spectroscopy, its first application to toxicology. 4. Comparison of renal tissue from the wood mouse (Apodemus sylvaticus) exposed to identical exposure levels of As3+ suggested that the bank vole is particularly vulnerable to As3+ toxicity.

Sensitivity and toxic mode of action of dietary organic and inorganic selenium in Atlantic salmon (Salmo salar).

PubMed

Berntssen, M H G; Sundal, T K; Olsvik, P A; Amlund, H; Rasinger, J D; Sele, V; Hamre, K; Hillestad, M; Buttle, L; Ørnsrud, R

2017-11-01

Depending on its chemical form, selenium (Se) is a trace element with a narrow range between requirement and toxicity for most vertebrates. Traditional endpoints of Se toxicity include reduced growth, feed intake, and oxidative stress, while more recent finding describe disturbance in fatty acid synthesis as underlying toxic mechanism. To investigate overall metabolic mode of toxic action, with emphasis on lipid metabolism, a wide scope metabolomics pathway profiling was performed on Atlantic salmon (Salmo salar) (572±7g) that were fed organic and inorganic Se fortified diets. Atlantic salmon were fed a low natural background organic Se diet (0.35mg Se kg -1 , wet weight (WW)) fortified with inorganic sodium selenite or organic selenomethionine-yeast (SeMet-yeast) at two levels (∼1-2 or 15mgkg -1 , WW), in triplicate for 3 months. Apparent adverse effects were assessed by growth, feed intake, oxidative stress as production of thiobarbituric acid-reactive substances (TBARS) and levels of tocopherols, as well as an overall metabolomic pathway assessment. Fish fed 15mgkg -1 selenite, but not 15mgkg -1 SeMet-yeast, showed reduced feed intake, reduced growth, increased liver TBARS and reduced liver tocopherol. Main metabolic pathways significantly affected by 15mgkg -1 selenite, and to a lesser extent 15mgkg -1 SeMet-yeast, were lipid catabolism, endocannabinoids synthesis, and oxidant/glutathione metabolism. Disturbance in lipid metabolism was reflected by depressed levels of free fatty acids, monoacylglycerols and diacylglycerols as well as endocannabinoids. Specific for selenite was the significant reduction of metabolites in the S-Adenosylmethionine (SAM) pathway, indicating a use of methyl donors that could be allied with excess Se excretion. Dietary Se levels to respectively 1.1 and 2.1mgkg -1 selenite and SeMet-yeast did not affect any of the above mentioned parameters. Apparent toxic mechanisms at higher Se levels (15mgkg -1 ) included oxidative stress and altered lipid metabolism for both inorganic and organic Se, with higher toxicity for inorganic Se. Copyright © 2017 Elsevier B.V. All rights reserved.

Haloacetonitriles: metabolism and toxicity.

PubMed

Lipscomb, John C; El-Demerdash, Ebtehal; Ahmed, Ahmed E

2009-01-01

The haloacetonitriles (HANs) exist in drinking water exclusively as byproducts of disinfection. HANs are found in drinking water more often, and in higher concentrations, when surface water is treated by chloramination. Human exposure occurs through consumption of finished drinking water; oral and dermal contact also occurs, and results from showering, swimming and other activities. HANs are reactive and are toxic to gastrointestinal tissues following oral administration. Such toxicity is characterized by GSH depletion, increased lipid peroxidation, and covalent binding of HAN-associated radioactivity to gut tissues. The presence of GSH in cells is an important protective mechanism against HAN toxicity; depletion of cellular GSH results in increased toxicity. Some studies have demonstrated an apparently synergistic effect between ROS and HAN administration, that may help explain effects observed in GI tissues. ROS are produced in gut tissues, and in vitro evidence indicates that ROS may contribute to the degradation and formation of reactive intermediates from HANs. The rationale for ROS involvement may involve HAN-induced depletion of GSH and the role of GSH in scavenging ROS. In addition to effects on GI tissues, studies show that HAN-derived radiolabel is found covalently bound to proteins and DNA in several organs and tissues. The addition of antioxidants to biologic systems protects against HAN-induced DNA damage. The protection offered by antioxidants supports the role of oxidative stress and the potential for a threshold in han-induced toxicity. However, additional data are needed to substantiate evidence for such a threshold. HANs are readily absorbed from the GI tract and are extensively metabolized. Elimination occurs primarily in urine, as unconjugated one-carbon metabolites. Evidence supports the involvement of mixed function oxidases, the cytochrome P450 enzyme family and GST, in HAN metabolism. Metabolism represents either a detoxification or bioactivation process, depending on the particular HAN and the enzyme involved. HANs can inhibit CYP2E1-mediated metabolism, an effect which may be dependent on a covalent interaction with the enzyme. In addition, HAN compounds inhibit GST-mediated conjugation, but this effect is reversible upon dialysis, indicating that the interaction does not represent covalent binding. No subchronic studies of HAN toxicity are available in the literature. However, studies show that HANs produce developmental toxicity in experimental animals. The nature of developmental toxicity is affected by the type of administration vehicle, which renders interpretation of results more difficult. Skin tumors have been found following dermal application of HANs, but oral studies for carcinogenicity are negative. Pulmonary adenomas were increased following oral administration of HANs, but the A/J strain of mice employed has a characteristically high background rate of such tumors. HANs interact with DNA to produce unscheduled DNA repair, SCE and reverse mutations in Salmonella. HANs did not induce micronuclei or cause alterations in sperm head morphology in mice, but did induce micronuclei in newts. Thus, there is concern for the potential carcinogenicity of HANs. It would be valuable to delineate any relationship between the apparent threshold for micronuclei formation in newts and the potential mechanism of toxicity involving HAN-induced oxidative stress. Dose-response studies in rodents may provide useful information on toxicity mechanisms and dose selection for longer term toxicity studies. Additional studies are warranted before drawing firm conclusions on the hazards of HAN exposure. Moreover, additional studies on HAN-DNA and HAN-protein interaction mechanisms, are needed. Such studies can better characterize the role of metabolism in toxicity of individual HANs, and delineate the role of oxidative stress, both of which enhance the capacity to predict risk. Most needed, now, are new subchronic (and chronic) toxicity studies; the results of such well-planned, controlled, conducted, interpreted and published investigations would be valuable in establishing margins of safety for HANs in human health risk assessment.

Influence of salinity and organic carbon on the chronic toxicity of silver to mysids (Americamysis bahia) and silversides (Menidia beryllina).

PubMed

Ward, Timothy J; Boeri, Robert L; Hogstrand, Christer; Kramer, James R; Lussier, Suzanne M; Stubblefield, William A; Wyskiel, Derek C; Gorsuch, Joseph W

2006-07-01

Tests were conducted with mysids (Americamysis bahia) and silversides (Menidia beryllina) to evaluate the influence of salinity and organic carbon on the chronic toxicity of silver. During 7- and 28-d tests conducted at 10, 20, and 30% per hundred salinity, higher concentrations of dissolved silver generally were required to cause a chronic effect as the salinity of the seawater was increased. The 28-d mysid and silverside 20%-effective concentration values (expressed as dissolved silver) ranged from 3.9 to 60 and from 38 to 170 microg/L, respectively, over the salinity range. This pattern was not observed when the same test results were evaluated against the concentrations of free ionic silver (measured directly during toxicity tests), as predicted by the free-ion activity model. Increasing the concentration of dissolved organic carbon from 1 mg/L to the apparent maximum achievable concentration of 6 mg/L in seawater caused a slight decrease in chronic toxicity to silversides but had no effect on the chronic toxicity to mysids. The possible additive toxicity of silver in both food and water also was investigated. Even at the maximum achievable foodborne concentration, the chronic toxicity of silver added to the water was not affected when silver was also added to the food, based on the most sensitive endpoint (growth). However, although fecundity was unaffected at all five tested concentrations during the test with silver in water only, it was significantly reduced at the two highest waterborne silver concentrations (12 and 24 microg/L) during the test with silver dosed into food and water.

Optimization of extraction procedures for ecotoxicity analyses: Use of TNT contaminated soil as a model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sunahara, G.I.; Renoux, A.Y.; Dodard, S.

1995-12-31

The environmental impact of energetic substances (TNT, RDX, GAP, NC) in soil is being examined using ecotoxicity bioassays. An extraction method was characterized to optimize bioassay assessment of TNT toxicity in different soil types. Using the Microtox{trademark} (Photobacterium phosphoreum) assay and non-extracted samples, TNT was most acutely toxic (IC{sub 50} = 1--9 PPM) followed by RDX and GAP; NC did not show obvious toxicity (probably due to solubility limitations). TNT (in 0.25% DMSO) yielded an IC{sub 50} 0.98 + 0.10 (SD) ppm. The 96h-EC{sub 50} (Selenastrum capricornutum growth inhibition) of TNT (1. 1 ppm) was higher than GAP and RDX;more » NC was not apparently toxic (probably due to solubility limitations). Soil samples (sand or a silt-sand mix) were spiked with either 2,000 or 20,000 mg TNT/kg soil, and were adjusted to 20% moisture. Samples were later mixed with acetonitrile, sonicated, and then treated with CaCl{sub 2} before filtration, HPLC and ecotoxicity analyses. Results indicated that: the recovery of TNT from soil (97.51% {+-} 2.78) was independent of the type of soil or moisture content; CaCl{sub 2} interfered with TNT toxicity and acetonitrile extracts could not be used directly for algal testing. When TNT extracts were diluted to fixed concentrations, similar TNT-induced ecotoxicities were generally observed and suggested that, apart from the expected effects of TNT concentrations in the soil, the soil texture and the moisture effects were minimal. The extraction procedure permits HPLC analyses as well as ecotoxicity testing and minimizes secondary soil matrix effects. Studies will be conducted to study the toxic effects of other energetic substances present in soil using this approach.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sawyer, Thomas W., E-mail: Thomas.Sawyer@drdc-rddc.gc.ca; Nelson, Peggy; Bjarnason, Stephen

The effect of ionic environment on sulphur mustard (bis 2-chloroethyl sulphide; HD) toxicity was examined in CHO-K1 cells. Cultures were treated with HD in different ionic environments at constant osmolar conditions (320 mOsM, pH 7.4). The cultures were refed with fresh culture medium 1 h after HD exposure, and viability was assessed. Little toxicity was apparent when HD exposures were carried out in ion-free sucrose buffer compared to LC{sub 50} values of {approx} 100-150 {mu}M when the cultures were treated with HD in culture medium. Addition of NaCl to the buffer increased HD toxicity in a salt concentration-dependent manner tomore » values similar to those obtained in culture medium. HD toxicity was dependent on both cationic and anionic species with anionic environment playing a much larger role in determining toxicity. Substitution of NaI for NaCl in the treatment buffers increased HD toxicity by over 1000%. The activity of the sodium hydrogen exchanger (NHE) in recovering from cytosolic acidification in salt-free and in different chloride salts did not correlate with the HD-induced toxicity in these buffers. However, the inhibition by HD of intracellular pH regulation correlated with its toxicity in NaCl, NaI and sucrose buffers. Analytical chemical studies and the toxicity of the iodine mustard derivative ruled out the role of chemical reactions yielding differentially toxic species as being responsible for the differences in HD toxicity observed. This work demonstrates that the early events that HD sets into motion to cause toxicity are dependent on ionic environment, possibly due to intracellular pH deregulation.« less

Effects of boron derivatives on extracellular matrix formation.

PubMed

Benderdour, M; Van Bui, T; Hess, K; Dicko, A; Belleville, F; Dousset, B

2000-10-01

Boric acid solution (3%) dramatically improves wound healing through action on the extracellular matrix, a finding that has been obtained in vitro. Consequently, investigations are presently underway to produce boronated compounds having a therapeutical effectiveness similar to that of boric acid. On the basis of experimental results obtained with boric acid, we examined the effects of boron derivatives on extracellular matrix formation and degradation and analyzed their potential toxicity by using two biological models (chick embryo cartilage and human fibroblasts). The four boron derivatives tested in this study (triethanolamine borate; N-diethyl-phosphoramidate-propylboronique acid; 2,2 dimethylhexyl-1,3-propanediol-aminopropylboronate and 1,2 propanediol-aminopropylboronate) mimicked the effects of boric acid. They induced a decrease of intracellular concentrations in extracellular matrix macromolecules (proteoglycans, proteins)-associated with an increase of their release in culture medium and stimulated the activity of intra- and extracellular proteases. Similarly to boric acid, these actions occurred after exposure of the cells to concentrations of all boron derivatives without apparent toxic effects. The compounds were found to be more toxic than boric acid itself when concentrations were calculated according to their molecular weight. Nevertheless, these in vitro preliminary results demonstrate effects of boron derivatives that may be of therapeutic benefit in wound repair.

Toxic effects of endrin and toxaphene on the southern leopard frog Rana sphenocephala

USGS Publications Warehouse

Hall, R.J.; Swineford, D.

1980-01-01

Eggs, larvae and sub-adults of the southern leopard frog Rana sphenocephala were exposed to endrin and toxaphene. Exposure was in water by a continuous-flow technique, following standards that have been used successfully in the study of fish and invertebrates. R. sphenocephala is more sensitive to both pesticides than are higher vertebrates but is slightly less sensitive than fish. Eggs seem to be resistant to the effects of both pesticides and are probably poor indicators of environmental hazard. The toxic level of endrin is about equal in larvae and transformed frogs (LC50, 0?005-0?015 ppm). Toxaphene is less toxic to sub-adults (LC50, 0?37-0?790 ppm) than to larvae (LC50, 0?032-0?054 ppm). Delayed mortality, behavioural aberrations and effects on growth have been seen in toxaphene-dosed larvae observed over 30-day periods. Behavioural effects are more severe than those reported in other groups of animals. Effects on growth resulting from a 96-h exposure begin in the 0?013-0?018 ppm range. The maximum accumulation of residues observed for each chemical represented bioconcentration factors of about 100. Endrin residues are apparently lost more readily than toxaphene residues; relative depuration rates correlate well with the time course of toxic action in each chemical. Although less sensitive to these pesticides than fish, amphibians may not be protected in their natural habitats. Future studies of the effects of toxicants on amphibians should employ larvae if only one stage can be tested, should expose subjects for at least 96 h and should continue observations for a total of at least 30 days.

Curcumin reduces the toxic effects of iron loading in rat liver epithelial cells

PubMed Central

Messner, Donald J.; Sivam, Gowsala; Kowdley, Kris V.

2008-01-01

Background/aims Iron overload can cause liver toxicity and increase the risk of liver failure or hepatocellular carcinoma in humans. Curcumin (diferuloylmethane), a component of the food spice turmeric, has antioxidant, iron binding, and hepatoprotective properties. The aim of this study was to quantify its effects on iron overload and resulting downstream toxic effects in cultured T51B rat liver epithelial cells. Methods T51B cells were loaded with ferric ammonium citrate (FAC) with or without the iron delivery agent 8-hydroxyquinoline. Cytotoxicity was measured by MTT assay. Iron uptake and iron bioavailability were documented by chemical assay, quench of calcein fluorescence, and ferritin induction. Reactive oxygen species (ROS) were measured by fluorescence assay using 2′,7′-dichlorodihydrofluorescein diacetate. Oxidative stress signaling to jnk, c-jun, and p38 was measured by western blot with phospho-specific antibodies. Results Curcumin bound iron, but did not block iron uptake or bioavailability in T51B cells given FAC. However, it reduced cytotoxicity, blocked generation of ROS, and eliminated signaling to cellular stress pathways caused by iron. Inhibition was observed over a wide range of FAC concentrations (50 – 500 μM), with an apparent IC50 in all cases between 5 and 10 μM curcumin. In contrast, desferoxamine blocked both iron uptake and toxic effects of iron at concentrations that depended on the FAC concentration. Effects of curcumin also differed from those of α-tocopherol, which did not bind iron and was less effective at blocking iron-stimulated ROS generation. Conclusions Curcumin reduced iron-dependent oxidative stress and iron toxicity in T51B cells without blocking iron uptake. PMID:18492020

Synthesis of a Series of Caffeic Acid Phenethyl Amide (CAPA) Fluorinated Derivatives: Comparison of Cytoprotective Effects to Caffeic Acid Phenethyl Ester (CAPE)

DTIC Science & Technology

2010-06-11

the cinnamic acid phenyl ring. Although compound 4c proved to be very cytotoxic in HUVEC over a 24 h period, the toxicity is less apparent over a 5 h...drug development process, as it determines how much of the initial dose actually reaches the target site. Cinnamic acid -derived amides are known to...Synthesis of a series of caffeic acid phenethyl amide (CAPA) fluorinated derivatives: Comparison of cytoprotective effects to caffeic acid phenethyl

ICRF-187 in clinical oncology.

PubMed

Poster, D S; Penta, J S; Bruno, S; Macdonald, J S

1981-01-01

Although the mechanism of action of ICRF-159 and 187 has not been clearly defined, it is evident from both preclinical and early clinical studies that these compounds are of interest. There are three distinct characteristics of these ICRF compounds that deserve careful clinical evaluation. First, these drugs are apparently alkylating agents with modest, predictable and noncumulative bone marrow toxicity that makes them good potential candidates for combination chemotherapy regimens. The second characteristic that should be investigated is the suggestion that combination of ICRF-187 with an anthracycline may ameliorate the cardiac toxicity of the latter. The third factor in the preclinical evaluation of the bis-diketopiperazines that may have clinical application is the evidence that suggests that these drugs have an antimetastatic effect.

Biosafety assessment of Gd@C82(OH)22 nanoparticles on Caenorhabditis elegans

NASA Astrophysics Data System (ADS)

Zhang, Wendi; Sun, Baoyun; Zhang, Longze; Zhao, Baolu; Nie, Guangjun; Zhao, Yuliang

2011-06-01

Gd@C82(OH)22, a water-soluble endohedral metallofullerene derivative, has been proven to possess significant antineoplastic activity in mice. Toxicity studies of the nanoparticle have shown some evidence of low or non toxicity in mice and cell models. Here we employed Caenorhabditis elegans (C. elegans) as a model organism to further evaluate the short- and long-term toxicity of Gd@C82(OH)22 and possible behavior changes under normal and stress culture conditions. With treatment of Gd@C82(OH)22 at 0.01, 0.1, 1.0 and 10 μg ml-1 within one generation (short-term), C. elegans showed no significant decrease in longevity or thermotolerance compared to the controls. Furthermore, when Gd@C82(OH)22 treatment was extended up to six generations (long-term), non-toxic effects to the nematodes were found. In addition, data from body length measurement, feeding rate and egg-laying assays with short-term treatment demonstrated that the nanoparticles have no significant impact on the individual growth, feeding behavior and reproductive ability, respectively. In summary, this work has shown that Gd@C82(OH)22 is tolerated well by worms and it has no apparent toxic effects on longevity, stress resistance, growth and behaviors that were observed in both adult and young worms. Our work lays the foundations for further developments of this anti-neoplastic agent for clinical applications.

Fate and toxicity of aircraft deicing fluid additives through anaerobic digestion.

PubMed

Gruden, C L; Dow, S M; Hernandez, M T

2001-01-01

Benzotriazole derivatives are widely used corrosion inhibitors and their fate during wastewater treatment processes is unknown. The purpose of this research was to study the toxic effects and fate of the two commercially significant benzotriazole isomers used in aircraft deicing fluids (4-, and 5-, methylbenzotriazole [MeBT]) during anaerobic digestion. Experiments were executed in microcosms using mesophilic anaerobic biomass co-digesting wastewater sludge and propylene glycol. Sorption of MeBT to digesting solids could be approximated with a Freundlich model, and no anaerobic breakdown of either MeBT isomer was detected. Digesters fed more than 300 mg/L MeBT responded with a significant decrease in methanogenic microbial activity and volatile solids production and a concomitant increase in accumulation of volatile fatty acids. Direct microscopic measurements using fluorescent phylogenetic probes applied to digesting biomass revealed that members of both Archaea and Bacteria domains were sensitive to MeBT. Granular activated carbon (GAC) (volatile solids: GAC = 10%) reduced the apparent toxic effects of MeBT; GAC addition nearly restored the baseline activity of digesters fed MeBT (500 to 1000 mg/L).

Cytotoxic responses of selected insecticides in chick ganglia cultures.

PubMed Central

Sharma, R P; Obersteiner, E J

1981-01-01

Various agricultural chemicals, e.g. pesticides, are known to cause different toxic effects in man and animals. Some of these produce responses involving the nervous tissue. Total of 52 such chemicals, representing organophosphates, carbamates and other miscellaneous insecticides were evaluated to determine their relative cytotoxic effects in avian dorsal root ganglia cultures. Many of these chemicals caused a slight stimulation of cellular growth at very low concentrations. At toxic concentrations, a dose-related but nonspecific inhibition of cell growth occurred. The cytotoxic changes included the decreased migration of cells from the culture implant, varicosities in and shortening of various cells and vacuolization and rounding of neuroglial cells. At high concentrations, pigmentary degeneration and complete abolition of cell growth were observed. The toxic effects were numerically scored in a random blind fashion and the concentrations of individual chemicals to produce a half maximal effect (IC50) in culture were determined from the dose-response curves. The IC50 values for various chemicals ranged from approximately 10(-6) M for compounds like methylparathion, diazinon, paraoxon and Vendex to greater than 10(-2) M for chlorpyriphos and methylchlorpyriphos. No significant correlations of nerve fiber or glial cell cytotoxicity were apparent with other toxic or physico-chemical properties such as lethal dose in animals, cholinesterase inhibition, lipophilicity or water solubility of chemicals. Clinically neurotoxic and nonneurotoxic compounds caused similar cytotoxic effects in ganglia cultures. Images Fig. 3. Fig. 4. Fig. 5. Fig. 6. PMID:7272842

Food-chain contamination evaluations in ecological risk assessments

DOE Office of Scientific and Technical Information (OSTI.GOV)

Linder, G.

Food-chain models have become increasingly important within the ecological risk assessment process. This is the case particularly when acute effects are not readily apparent, or the contaminants of concern are not readily detoxified, have a high likelihood for partitioning into lipids, or have specific target organs or tissues that may increase their significance in evaluating their potential adverse effects. An overview of food-chain models -- conceptual, theoretical, and empirical -- will be considered through a series of papers that will focus on their application within the ecological risk assessment process. Whether a food-chain evaluation is being developed to address relativelymore » simple questions related to chronic effects of toxicants on target populations, or whether a more complex food-web model is being developed to address questions related to multiple-trophic level transfers of toxicants, the elements within the food chain contamination evaluation can be generalized to address the mechanisms of toxicant accumulation in individual organisms. This can then be incorporated into more elaborate models that consider these organismal-level processes within the context of a species life-history or community-level responses that may be associated with long-term exposures.« less

[Ideas and methods on efficient screening of traditional medicines for anti-osteoporosis activity based on M-Act/Tox integrated evaluation using zebrafish].

PubMed

Wang, Mo; Ling, Jie; Chen, Ying; Song, Jie; Sun, E; Shi, Zi-Qi; Feng, Liang; Jia, Xiao-Bin; Wei, Ying-Jie

2017-11-01

The increasingly apparent liver injury problems of bone strengthening Chinese medicines have brought challenges for clinical application, and it is necessary to consider both effectiveness and safety in screening anti-osteoporosis Chinese medicines. Metabolic transformation is closely related to drug efficacy and toxicity, so it is significant to comprehensively consider metabolism-action/toxicity(M-Act/Tox) for screening anti-osteoporosis Chinese medicines. The current evaluation models and the number of compounds(including metabolites) severely restrict efficient screening in vivo. By referring to previous relevant research and domestic and abroad literature, zebrafish M-Act/Tox integrative method was put forward for efficiently screening anti-osteoporosis herb medicines, which has organically integrated zebrafish metabolism model, osteoporosis model and toxicity evaluation method. This method can break through the bottleneck and blind spots that trace compositions can't achieve efficient and integrated in vivo evaluation, and realize both efficient and comprehensive screening on anti-osteoporosis traditional medicines based on in vivo process taking both safety and effectiveness into account, which is significant to accelerate discovery of effective and safe innovative traditional Chinese medicines for osteoporosis. Copyright© by the Chinese Pharmaceutical Association.

A field experiment to assess impact of chemically dispersed oil on Arabian Gulf corals

DOE Office of Scientific and Technical Information (OSTI.GOV)

Le Gore, R.S.; Cuddeback, J.E.; Hofmann, J.E.

1983-03-01

Field experiments were conducted on a coral reef at Jurayd Island (Saudi Arabia) in the Arabian Gulf to study the effects of chemically dispersed oil on local corals. Portions of the reef were exposed to predetermined concentrations of oil alone, dispersant alone, and oil-plus-dispersant mixtures. Areas of the reef not exposed to any of the toxicants were used as controls. Arabian Light Crude and Corexit 9527 dispersant were the test toxicants. Two series of experiments were conducted beginning in September 1981, one with a 24-hour exposure period and the other with a 5-day (120-hour) exposure period. Corals were stained formore » growth rate studies and extensively photographed to document any observed effects. Corals were examined for biological impacts immediately after the exposures, and then at 3-month intervals for 1 year. Water temperature, salinity, dissolved oxygen, and hydrocarbon content were recorded during the exposure periods. Coral growth appeared unaffected by exposure to the toxicants. Some Acropora species corals exposed to dispersed oil for 5 days exhibited delayed effects, which became apparent during the relatively cold winter season.« less

Database Assessment of the Health and Environmental Effects of Munition Production Waste Products

DTIC Science & Technology

1984-08-01

manufacture heavy metals are apparently leached P from the nitrating vessels as a result of the action of the nitrating acid mixture. Attempts to remove...characterize these inorganic pollu- tants, but two reports (Chen et al. 1981 and Ribaudo et al. 1981) iden- tify heavy metals and inorganic ions present...in wastewater effluents from munition plants. Three of the heavy metals (cadmium, chromium, and copper) are of concern because of their known toxic

An Annotated Bibliography of the Literature Dealing With the Hazardous Chemicals Used in the Chemistry Laboratory.

ERIC Educational Resources Information Center

Chaney, Donna J.

On the premise that many laboratory instructors lack knowledge about chemical toxicity, this study investigated three areas: (1) chemicals used in the academic laboratory which pose a health hazard; (2) ways of reducing toxicity in the laboratory (with attention to the apparent lack of teacher training which contributes to the cause of the problem…

Comparison of methods for conducting marine and estuarine sediment porewater toxicity tests—extraction, storage, and handling techniques

USGS Publications Warehouse

Carr, R.S.; Chapman, D.C.

1995-01-01

A series of studies was conducted to compare different porewater extraction techniques and to evaluate the effects of sediment and porewater storage conditions on the toxicity of pore water, using assays with the sea urchin Arbacia punctulata. If care is taken in the selection of materials, several different porewater extraction techniques (pressurized squeezing, centrifugation, vacuum) yield samples with similar toxicity. Where the primary contaminants of concern are highly hydrophobic organic compounds, centrifugation is the method of choice for minimizing the loss of contaminants during the extraction procedure. No difference was found in the toxicity of pore water obtained with the Teflon® and polyvinyl chloride pressurized extraction devices. Different types of filters in the squeeze extraction devices apparently adsorbed soluble contaminants to varying degrees. The amount of fine suspended particulate material remaining in the pore water after the initial extraction varied among the methods. For most of the sediments tested, freezing and thawing did not affect the toxicity of porewater samples obtained by the pressurized squeeze extraction method. Pore water obtained by other methods (centrifugation, vacuum) and frozen without additional removal of suspended particulates by centrifugation may exhibit increased toxicity compared with the unfrozen sample.The toxicity of pore water extracted from refrigerated (4°C) sediments exhibited substantial short-term (days, weeks) changes. Similarly, sediment pore water extracted over time from a simulated amphipod solid-phase toxicity test changed substantially in toxicity. For the sediments tested, the direction and magnitude of change in toxicity of pore water extracted from both refrigerated and solid-phase test sediments was unpredictable.

Size effect of SnO2 nanoparticles on bacteria toxicity and their membrane damage.

PubMed

Chávez-Calderón, Adriana; Paraguay-Delgado, Francisco; Orrantia-Borunda, Erasmo; Luna-Velasco, Antonia

2016-12-01

Semiconductor SnO 2 nanoparticles (NPs) are being exploited for various applications, including those in the environmental context. However, toxicity studies of SnO 2 NPs are very limited. This study evaluated the toxic effect of two sizes of spherical SnO 2 NPs (2 and 40 nm) and one size of flower-like SnO 2 NPs (800 nm) towards the environmental bacteria E. coli and B. subtilis. SnO 2 NPs were synthesized using a hydrothermal or calcination method and they were well characterized prior to toxicity assessment. To evaluate toxicity, cell viability and membrane damage were determined in cells (1 × 10 9  CFU mL -1 ) exposed to up to 1000 mg L -1 of NPs, using the plate counting method and confocal laser scanning microscopy. Spherical NPs of smaller primary size (E2) had the lowest hydrodynamic size (226 ± 96 nm) and highest negative charge (-30.3 ± 10.1 mV). Smaller spherical NPs also showed greatest effect on viability (IC 50  > 500 mg L -1 ) and membrane damage of B. subtilis, whereas E. coli was unaffected. Scanning electron microscopy confirmed the membrane damage of exposed B. subtilis and also exhibited the attachment of E2 NPs to the cell surface, as well as the elongation of cells. It was also apparent that toxicity was caused solely by NPs, as released Sn 4+ was not toxic to B. subtilis. Thus, surface charge interaction between negatively charged SnO 2 NPs and positively charged molecules on the membrane of the Gram positive B. subtilis was indicated as the key mechanism related to toxicity of NPs. Copyright © 2016 Elsevier Ltd. All rights reserved.

Health effects and toxicity mechanisms of rare earth elements-Knowledge gaps and research prospects.

PubMed

Pagano, Giovanni; Guida, Marco; Tommasi, Franca; Oral, Rahime

2015-05-01

In the recent decades, rare earth elements (REE) have undergone a steady spread in several industrial and medical applications, and in agriculture. Relatively scarce information has been acquired to date on REE-associated biological effects, from studies of bioaccumulation and of bioassays on animal, plant and models; a few case reports have focused on human health effects following occupational REE exposures, in the present lack of epidemiological studies of occupationally exposed groups. The literature is mostly confined to reports on few REE, namely cerium and lanthanum, whereas substantial information gaps persist on the health effects of other REE. An established action mechanism in REE-associated health effects relates to modulating oxidative stress, analogous to the recognized redox mechanisms observed for other transition elements. Adverse outcomes of REE exposures include a number of endpoints, such as growth inhibition, cytogenetic effects, and organ-specific toxicity. An apparent controversy regarding REE-associated health effects relates to opposed data pointing to either favorable or adverse effects of REE exposures. Several studies have demonstrated that REE, like a number of other xenobiotics, follow hormetic concentration-related trends, implying stimulatory or protective effects at low levels, then adverse effects at higher concentrations. Another major role for REE-associated effects should be focused on pH-dependent REE speciation and hence toxicity. Few reports have demonstrated that environmental acidification enhances REE toxicity; these data may assume particular relevance in REE-polluted acidic soils and in REE mining areas characterized by concomitant REE and acid pollution. The likely environmental threats arising from REE exposures deserve a new line of research efforts. Copyright © 2015 Elsevier Inc. All rights reserved.

Ketoconazole modulates the infectivity of Ichthyophonus sp. (Mesomycetozoa) in vivo in experimentally injected European sea bass.

PubMed

Hontoria, Francisco; González, Ma Angeles; Sitjà-Bobadilla, Ariadna; Palenzuela, Oswaldo; Alvarez-Pellitero, Pilar

2013-09-03

In vitro studies have confirmed the inhibitory effect of the azol-derivative ketoconazole (KZ) on the growth of Ichthyophonus, an important pathogen causing epizootics in wild and cultured fish. We evaluated the effect of KZ in vivo in European sea bass Dicentrarchus labrax experimentally infected with the same Ichthyophonus isolate. Liposomes were used to vehiculate different doses of KZ to increase the effect on Ichthyophonus and lower the toxicity of the drug, and KZ toxicity was assessed in cultured sea bass juveniles. We also studied the effect of liposome-vehiculated KZ included in medicated food on ichthyophoniasis. KZ causes clear toxic effects in D. labrax juveniles at doses >80 mg kg-1, apparent in the reduced survival of fish and histological alterations to livers, kidneys and spleens. Fish injected with Ichthyophonus and treated with KZ dosages of ≤80 mg kg-1 d-1 presented lower ichthyophoniasis prevalence, fewer organs infected per fish, and fewer spores in the affected organs than the untreated fish. KZ seems to delay the onset of infection, but cannot stop further progression once established. However, this behaviour is not clearly reflected in the biometric and haematological data collected from these fish. We hypothesise that KZ's delaying effect would increase, if lower infective doses (more similar to natural situations) were used. The drug administration vehicle (liposomes vs. emulsions) did not affect the results. Our data confirm the potential utility of KZ in treating ichthyophoniasis and reveal its low toxicity for sea bass. Nevertheless, the optimal dose and appropriate application protocol remain to be determined.

Thermal stability and haemolytic effects of depolymerized guar gum derivatives.

PubMed

Hussain, Majid; Zahoor, Tahir; Akhtar, Saeed; Ismail, Amir; Hameed, Aneela

2018-03-01

The purpose of current study was to purify and partially depolymerize guar gum by β-mannanase, HCl, Ba(OH) 2 actions and subjected to inspect compositional, thermogravimetric analysis (TGA) and haemolytic activity. Chemical composition revealed mannose and galactose ratio remained un-altered even after process of purification and hydrolysis. TGA thermograms affirmed initial and final decomposition temperature in various zones. Major decomposition stages apparently revealed partially hydrolyzed guar gum (PHGG) exhibited better heat stable properties having more zones of degradation than crude one. Furthermore, all guar fractions (2.5-250 mg/mL) were subjected to haemolysis to evaluate toxic effects during process of hydrolysis. The crude and hydrolyzed guar galactomannans exhibited minor haemolytic activity (1.9 ± 0.03-7.24 ± 0.02%) when compared to 0.1% Triton-X 100 (100% haemolysis) showing no toxic effects to human RBC's. Conclusively, hydrolyzed guar-galactomannans are safe and can be used in food products with improved heat stability.

Relative toxicity of the pyrolysis products from some thermoplastic and thermoset polymers

NASA Technical Reports Server (NTRS)

Kourtides, D. A.; Gilwee, W. J., Jr.; Hilado, C. J.

1978-01-01

Relative toxicity data on the pyrolysis products of a variety of thermoplastic and thermoset polymers are presented. The data are presented in terms of time to incapacitation and time to death with a fixed sample weight of 1.0 g, and in terms of the apparent lethal concentration required to produce 50 percent mortality within a fixed exposure period of 30 min.

Multivariate analysis of the impacts of the turbine fuel JP-4 in a microcosm toxicity test with implications for the evaluation of ecosystem dynamics and risk assessment.

PubMed

Landis, W G; Matthews, R A; Markiewicz, A J; Matthews, G B

1993-12-01

Turbine fuels are often the only aviation fuel available in most of the world. Turbine fuels consist of numerous constituents with varying water solubilities, volatilities and toxicities. This study investigates the toxicity of the water soluble fraction (WSF) of JP-4 using the Standard Aquatic Microcosm (SAM). Multivariate analysis of the complex data, including the relatively new method of nonmetric clustering, was used and compared to more traditional analyses. Particular emphasis is placed on ecosystem dynamics in multivariate space.The WSF is prepared by vigorously mixing the fuel and the SAM microcosm media in a separatory funnel. The water phase, which contains the water-soluble fraction of JP-4 is then collected. The SAM experiment was conducted using concentrations of 0.0, 1.5 and 15% WSF. The WSF is added on day 7 of the experiments by removing 450 ml from each microcosm including the controls, then adding the appropriate amount of toxicant solution and finally bringing the final volume to 3 L with microcosm media. Analysis of the WSF was performed by purge and trap gas chromatography. The organic constituents of the WSF were not recoverable from the water column within several days of the addition of the toxicant. However, the impact of the WSF on the microcosm was apparent. In the highest initial concentration treatment group an algal bloom ensued, generated by the apparent toxicity of the WSF of JP-4 to the daphnids. As the daphnid populations recovered the algal populations decreased to control values. Multivariate methods clearly demonstrated this initial impact along with an additional oscillation seperating the four treatment groups in the latter segment of the experiment. Apparent recovery may be an artifact of the projections used to describe the multivariate data. The variables that were most important in distinguishing the four groups shifted during the course of the 63 day experiment. Even this simple microcosm exhibited a variety of dynamics, with implications for biomonitoring schemes and ecological risk assessments.

Use of intravenous lipid emulsion to reverse central nervous system toxicity of an iatrogenic local anesthetic overdose in a patient on peritoneal dialysis.

PubMed

Lange, D Bruce; Schwartz, Daniel; DaRoza, Gerald; Gair, Robert

2012-12-01

To describe a case of severe central nervous system toxicity after an overdose of lidocaine by local infiltration in a peritoneal dialysis patient and subsequent treatment of the toxicity with lipid emulsion. A 31-year-old male received an iatrogenic overdose of 1600 mg of lidocaine 2% by infiltration during an attempt to remove and replace a peritoneal dialysis catheter. Within 10 minutes after the last lidocaine injection, the patient exhibited features of local anesthetic toxicity, which included tachycardia, hypertension, shortness of breath, dizziness, and a choking sensation that progressed to hallucinations, dysarthria, and uncoordinated, weak limb movement. Within 10 minutes after administration of a single 1.5-mg/kg intravenous bolus of 1.5 mL/kg [corrected], the patient improved dramatically. After observation overnight in a monitored care setting, the patient was discharged home with no apparent neurologic sequelae. Systemic toxicity due to regional anesthesia with local anesthetic agents such as lidocaine has been well described in the medical literature. The use of lipid emulsion as an antidote to the toxicity of local anesthetics and other lipophilic drugs has been suggested as a valuable intervention in both early, rapidly progressive toxicity, as well as toxicity that is refractory to standard treatment. Patients with advanced chronic kidney disease may be more susceptible to systemic effects of lidocaine due to decreased drug elimination. Central nervous system toxicity due to an overdose of lidocaine was quickly reversed by intravenous lipid emulsion in our patient.

Acylcarnitine Profiles in Acetaminophen Toxicity in the Mouse: Comparison to Toxicity, Metabolism and Hepatocyte Regeneration

PubMed Central

Bhattacharyya, Sudeepa; Pence, Lisa; Beger, Richard; Chaudhuri, Shubhra; McCullough, Sandra; Yan, Ke; Simpson, Pippa; Hennings, Leah; Hinson, Jack; James, Laura

2013-01-01

High doses of acetaminophen (APAP) result in hepatotoxicity that involves metabolic activation of the parent compound, covalent binding of the reactive intermediate N-acetyl-p-benzoquinone imine (NAPQI) to liver proteins, and depletion of hepatic glutathione. Impaired fatty acid β-oxidation has been implicated in previous studies of APAP-induced hepatotoxicity. To better understand relationships between toxicity and fatty acid β-oxidation in the liver in APAP toxicity, metabolomic assays for long chain acylcarnitines were examined in relationship to established markers of liver toxicity, oxidative metabolism, and liver regeneration in a time course study in mice. Male B6C3F1 mice were treated with APAP (200 mg/kg IP) or saline and sacrificed at 1, 2, 4, 8, 24 or 48 h after APAP. At 1 h, hepatic glutathione was depleted and APAP protein adducts were markedly increased. Alanine aminotransferase (ALT) levels were elevated at 4 and 8 h, while proliferating cell nuclear antigen (PCNA) expression, indicative of hepatocyte regeneration, was apparent at 24 h and 48 h. Elevations of palmitoyl, oleoyl and myristoyl carnitine were apparent by 2–4 h, concurrent with the onset of Oil Red O staining in liver sections. By 8 h, acylcarnitine levels were below baseline levels and remained low at 24 and 48 h. A partial least squares (PLS) model suggested a direct association of acylcarnitine accumulation in serum to APAP protein adduct and hepatic glutathione levels in mice. Overall, the kinetics of serum acylcarnitines in APAP toxicity in mice followed a biphasic pattern involving early elevation after the metabolism phases of toxicity and later depletion of acylcarnitines. PMID:24958141

VORICONAZOLE TOXICITY IN MULTIPLE PENGUIN SPECIES.

PubMed

Hyatt, Michael W; Georoff, Timothy A; Nollens, Hendrik H; Wells, Rebecca L; Clauss, Tonya M; Ialeggio, Donna M; Harms, Craig A; Wack, Allison N

2015-12-01

Aspergillosis is a common respiratory fungal disease in penguins managed under human care. Triazole antifungal drugs, including itraconazole, are most commonly used for treatment; however, itraconazole treatment failures from drug resistance are becoming more common, requiring newer treatment options. Voriconazole, a newer triazole, is being used more often. Until recently, no voriconazole pharmacokinetic studies had been performed in penguins, leading to empiric dosing based on other avian studies. This has led to increased anecdotal reporting of apparent voriconazole toxicity in penguins. This report describes 18 probable and 6 suspected cases of voriconazole toxicity in six penguin species from nine institutions: 12 African penguins (Spheniscus demersus), 5 Humboldt penguins (Spheniscus humboldti), 3 Magellanic penguins (Spheniscus magellanicus), 2 gentoo penguins (Pygoscelis papua papua), 1 macaroni penguin (Eudyptes chrysolophus), and 1 emperor penguin (Aptenodytes forsteri). Observed clinical signs of toxicity included anorexia, lethargy, weakness, ataxia, paresis, apparent vision changes, seizure-like activity, and generalized seizures. Similar signs of toxicity have also been reported in humans, in whom voriconazole therapeutic plasma concentration for Aspergillus spp. infections is 2-6 μg/ml. Plasma voriconazole concentrations were measured in 18 samples from penguins showing clinical signs suggestive of voriconazole toxicity. The concentrations ranged from 8.12 to 64.17 μg/ml, with penguins having plasma concentrations above 30 μg/ml exhibiting moderate to severe neurologic signs, including ataxia, paresis, and seizures. These concentrations were well above those known to result in central nervous system toxicity, including encephalopathy, in humans. This case series highlights the importance of species-specific dosing of voriconazole in penguins and plasma therapeutic drug monitoring. Further investigation, including pharmacokinetic studies, is warranted. The authors recommend caution in determining voriconazole dosages for use in penguin species.

Evaluation of water treatment sludges toxicity using the Daphnia bioassay.

PubMed

Sotero-Santos, Rosana B; Rocha, Odete; Povinelli, Jurandyr

2005-10-01

Alum and ferric chloride sludges from two water treatment plants (WTPs) were analyzed regarding their physicochemical characteristics and toxicity to Daphnia similis. Experiments were carried out in the dry and rainy seasons. Acute and chronic toxicity was measured using survival and reproduction as measurement endpoints. No acute toxicity of the sludge was observed in 48 h exposure. Ferric chloride sludge caused chronic toxicity, demonstrated by low fecundity and some mortality, while alum sludge caused chronic toxicity characterized by low fecundity. Some sludge characteristics varied between samplings, including turbidity, solids contents, N, P and metal (Al and Fe) concentrations. These variables and the increase of chemical oxygen demand (COD) were identified as the main cause of degradation of the receiving waters. However, no relationship was observed between these variables and degree of toxicity. It is apparent from these results that water treatment sludges may be toxic and therefore may impair receiving waters. Alum sludge was less toxic than ferric chloride sludge.

Combining web-based tools for transparent evaluation of data for risk assessment: developmental effects of bisphenol A on the mammary gland as a case study.

PubMed

Molander, Linda; Hanberg, Annika; Rudén, Christina; Ågerstrand, Marlene; Beronius, Anna

2017-03-01

Different tools have been developed that facilitate systematic and transparent evaluation and handling of toxicity data in the risk assessment process. The present paper sets out to explore the combined use of two web-based tools for study evaluation and identification of reliable data relevant to health risk assessment. For this purpose, a case study was performed using in vivo toxicity studies investigating low-dose effects of bisphenol A on mammary gland development. The reliability of the mammary gland studies was evaluated using the Science in Risk Assessment and Policy (SciRAP) criteria for toxicity studies. The Health Assessment Workspace Collaborative (HAWC) was used for characterizing and visualizing the mammary gland data in terms of type of effects investigated and reported, and the distribution of these effects within the dose interval. It was then investigated whether there was any relationship between study reliability and the type of effects reported and/or their distribution in the dose interval. The combination of the SciRAP and HAWC tools allowed for transparent evaluation and visualization of the studies investigating developmental effects of BPA on the mammary gland. The use of these tools showed that there were no apparent differences in the type of effects and their distribution in the dose interval between the five studies assessed as most reliable and the whole data set. Combining the SciRAP and HAWC tools was found to be a useful approach for evaluating in vivo toxicity studies and identifying reliable and sensitive information relevant to regulatory risk assessment of chemicals. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Fluoride effects: the two faces of janus.

PubMed

Gazzano, E; Bergandi, L; Riganti, C; Aldieri, E; Doublier, S; Costamagna, C; Bosia, A; Ghigo, D

2010-01-01

The behavior of fluoride ions in the human organism is a classic example of double-edged sword. On the one hand the daily supplementation with fluoride is undoubtedly an important preventing factor in protecting teeth from caries, and, as an important mitogenic stimulus for osteoblasts, it may enhance mineral deposition in bone, but on the other hand fluoride, above a threshold concentration, has been demonstrated to be toxic. We present here a brief review of fluoride metabolism and exposure, its use in caries prevention and its effects on bone, followed by an updating about the main hypotheses concerning its mechanism of action and toxicity. The effects of fluoride have been related mainly to its ability to evoke the activation of G proteins and the inhibition of phosphotyrosine phosphatases, leading to an intracellular increase of tyrosine phosphorylation and activation of the mitogen-activated protein kinase pathway, and its capacity to cause generation of reactive oxygen species. We present also a unifying hypothesis accounting for these apparently different effects, although the available experimental models and conditions are highly variable in the literature. A lot of experiments still need to be performed to clarify the positive and negative effects of fluoride. Finding the mechanisms accounting for fluoride toxicity is an important point: indeed, the use of fluoride has been proposed in the preparation of new biomaterials to be inserted in the bone, in order to improve their stable and safe integration.

Membrane Alterations Following Toxic Chemical Insult.

DTIC Science & Technology

1988-03-10

GROUP in vitro toxicology, perfluorinated fatty acids, mycoplasmas, membranes 3. asS T tAC .Cocry M r reverse if necessary and identify by black...cells were used as the target organism. The toxic action of the perfluorinated fatty acids apparently involves some interaction with the me,-,brane...the eucarvotir or proc~ryctic cytoplasmic membrine. Ceil waii-iess micobes known as mycoplasmas were used. In this current study, two perfluorinated

Comparing rat and rabbit embryo-fetal developmental toxicity ...

EPA Pesticide Factsheets

A database of embryo-fetal developmental toxicity (EFDT) studies of 379 pharmaceutical compounds in rat and rabbit was analyzed for species differences based on toxicokinetic parameters of area under the curve (AUC) and maximum concentration (Cmax) at the developmental adverse effect level (dLOAEL). For the vast majority of cases (83% based on AUC of n=283), dLOAELs in rats and rabbits were within the same order of magnitude (less than 10-fold different) when compared based on available data on AUC and Cmax exposures. For 13.5% of the compounds the rabbit was more sensitive and for 3.5% of compounds the rat was more sensitive when compared based on AUC exposures. For 12% of the compounds the rabbit was more sensitive and for 1.3% of compounds the rat was more sensitive based on Cmax exposures. When evaluated based on human equivalent dose (HED) conversion using standard factors, the rat and rabbit were equally sensitive. The relative extent of embryo-fetal toxicity in the presence of maternal toxicity was not different between species. Overall effect severity incidences were distributed similarly in rat and rabbit studies. Individual rat and rabbit strains did not show a different general distribution of systemic exposure LOAELs as compared to all strains combined for each species. There were no apparent species differences in the occurrence of embryo-fetal variations. Based on power of detection and given differences in the nature of developmental effects betwe

EFFECT OF DEUTERIUM OXIDE ON LOCAL ANESTHETIC ACTIVITY OF PROCAINE

DOE Office of Scientific and Technical Information (OSTI.GOV)

Susina, S.V.; Hiter, F.D.; Siegel, F.P.

1962-12-01

Since it appears that D/sub 2/O is toxic in animals only when the concentration in the body fluids reaches high levels (> 20%), and since D/sub 2/O resembles the common solvent protium oxide more closely than any other, possible pharmaceutical applications of this solvent were explored. In studies in mice, D/ sub 2/O was used as a solvent for procaine and the effect on the stability and local anesthetic activity was noted. The ED/sub 50/ was determined by the method using corneal sensitivity, and comparison was made with procaine solutions in H/ sub 2/O. In H/sub 2/O the ED/sub 50/more » was 1.8% while in D/sub 2/O it was 1.0%. The LD/sub 50/was determined by intraperitoneal injection in mice. There appeared to be no significant difference in the toxicity of procaine in either solvent. Stability studies indicate that procaine is more stable in D/sub 2/O than H/sub 2/O at apparent pH values of 8.0, 8.5, and 9.0. Hence, the increased local anesthetic activity of procaine in D/sub 2/O may be accounted for by the fact that procaine free base is more stable in D/sub 2/O solutions, or that at the same apparent pH a D/sub 2/O solution of procaine will contain more free base than in the corresponding aqueous solution. (H.H.D.)« less

Anaerobic digestion of aircraft deicing fluid wastes: interactions and toxicity of corrosion inhibitors and surfactants.

PubMed

Gruden, Cyndee L; Hernandez, Mark

2002-01-01

Corrosion inhibitors and surfactants are present in aircraft deicing fluids (ADFs) at significant concentrations (> 1% w/w). The purpose of this research was to study the interactions of a common nonionic surfactant with the commercially significant corrosion inhibitors used in modern ADF (4- and 5-methylbenzotriazole [MeBT]), and to determine the effects of their mixture on the conventional anaerobic digestion process. In mesophilic anaerobic microcosms codigesting wastewater solids, propylene glycol, and MeBT, increasing surfactant levels resulted in enhanced MeBT sorption on digester solids. As judged by anaerobic toxicity assays, responses from digesters containing surfactant concentrations below their critical micelle concentration (CMC) suggested that low nonionic surfactant concentrations could facilitate a reduction in the apparent toxicity of MeBT. In microcosms exposed to surfactant concentrations above their CMC, no increase in MeBT solubility was observed, and the anaerobic toxicity response corresponded to control systems not containing surfactant. Direct microscopic measurements of digesting biomass using fluorescent phylogenetic probes (fluorescent in situ hybridization) revealed that members of the domain Bacteria were more sensitive to MeBT in the presence of surfactant than were members of the domain Archaea.

Understanding the toxicological potential of aerosol organic compounds using informatics based screening

NASA Astrophysics Data System (ADS)

Topping, David; Decesari, Stefano; Bassan, Arianna; Pavan, Manuela; Ciacci, Andrea

2016-04-01

Exposure to atmospheric particulate matter is responsible for both short-term and long-term adverse health effects. So far, all efforts spent in achieving a systematic epidemiological evidence of specific aerosol compounds determining the overall aerosol toxicity were unsuccessful. The results of the epidemiological studies apparently conflict with the laboratory toxicological analyses which have highlighted very different chemical and toxicological potentials for speciated aerosol compounds. Speciation remains a problem, especially for organic compounds: it is impossible to conduct screening on all possible molecular species. At the same time, research on toxic compounds risks to be biased towards the already known compounds, such as PAHs and dioxins. In this study we present results from an initial assessment of the use of in silico methods (i.e. (Q)SAR, read-across) to predict toxicity of atmospheric organic compounds including evaluation of applicability of a variety of popular tools (e.g. OECD QSAR Toolbox) for selected endpoints (e.g. genotoxicity). Compounds are categorised based on the need of new experimental data for the development of in silico approaches for toxicity prediction covering this specific chemical space, namely the atmospheric aerosols. Whilst only an initial investigation, we present recommendations for continuation of this work.

Mechanisms of redox interactions of bilirubin with copper and the effects of penicillamine.

PubMed

Božić, Bojana; Korać, Jelena; Stanković, Dalibor M; Stanić, Marina; Popović-Bijelić, Ana; Bogdanović Pristov, Jelena; Spasojević, Ivan; Bajčetić, Milica

2017-12-25

Toxic effects of unconjugated bilirubin (BR) in neonatal hyperbilirubinemia have been related to redox and/or coordinate interactions with Cu 2+ . However, the development and mechanisms of such interactions at physiological pH have not been resolved. This study shows that BR reduces Cu 2+ to Cu 1+ in 1:1 stoichiometry. Apparently, BR undergoes degradation, i.e. BR and Cu 2+ do not form stable complexes. The binding of Cu 2+ to inorganic phosphates, liposomal phosphate groups, or to chelating drug penicillamine, impedes redox interactions with BR. Cu 1+ undergoes spontaneous oxidation by O 2 resulting in hydrogen peroxide accumulation and hydroxyl radical production. In relation to this, copper and BR induced synergistic oxidative/damaging effects on erythrocytes membrane, which were alleviated by penicillamine. The production of reactive oxygen species by BR and copper represents a plausible cause of BR toxic effects and cell damage in hyperbilirubinemia. Further examination of therapeutic potentials of copper chelators in the treatment of severe neonatal hyperbilirubinemia is needed. Copyright © 2017 Elsevier B.V. All rights reserved.

Toxicity and Bioavailability of Metals in the Missouri River Adjacent to a Lead Refinery

DTIC Science & Technology

2001-12-01

Missouri River adjacent to the facility. Groundwater was also collected from the facility. Waters and sediments were analyzed for inorganic...highly elevated in the groundwater , but not in river sediment pore waters . Lead concentrations were moderately elevated in whole sediment at one site...but lead concentrations in pore waters were low due to apparent sequestration by acid-volatile sulfides. The groundwater sample was highly toxic to

The toxicity of selected gasoline components to glucose methanogenesis by aquifer microorganisms

USGS Publications Warehouse

Mormile, Melanie R.; Suflita, Joseph M.

1996-01-01

Six model hydrocarbons, representing various classes of chemicals found in gasoline, and methyl ethyl ketone, were assayed for their inhibitory effect on glucose methanogenesis in slurries prepared from aquifer sediments and ground water. Biogas (CH4and CO2) production was monitored with an automated pressure transducer system. Benzene, 1-methyl naphthalene, and methyltert-butyl ether (MTBE) were found to have no inhibitory influence on biogas production rates at concentrations up to 71·7 mg/L. Similarly, octane, cyclohexane, indan, and methyl ethyl ketone (MEK) were found to have only marginal negative effects on the rate of biogas production in aquifer slurries, at concentrations ranging from 51·7 to 72·1 mg/L. Thus, gasoline components had low apparent toxicities to microorganisms responsible for glucose methanogenesis in aquifier slurries. As the concentrations of the assayed hydrocarbons are about 100 times those typically reported after an aquifer has been contaminated with gasoline, it is unlikely that individual hydrocarbons will substantially impact anaerobic metabolic processes.

Toxicity of DEGDN (Diethyleneglycol Dinitrate), Synthetic-HC Smoke Combustion Products, Solvent Yellow 33 and Solvent Green 3 to Freshwater Aquatic Organisms. Phase 2

DTIC Science & Technology

1987-01-15

algicidal effect on the * alga. LC50 values for the rainbow trout and the water flea were 2.2% and 9.3% of the stock solution, respectively. Additional...significantly from the initial inoculum level. " Algicidal concentration. This is the lowest concentration tested which causes an apparent algistatic...86.9 - 335.5 mg/L). The minimum algicidal concentration was greater than 542.4 mg/L, the highest concentration tested. When algal cultures from this

Human skin penetration and local effects of topical nano zinc oxide after occlusion and barrier impairment.

PubMed

Leite-Silva, V R; Sanchez, W Y; Studier, H; Liu, D C; Mohammed, Y H; Holmes, A M; Ryan, E M; Haridass, I N; Chandrasekaran, N C; Becker, W; Grice, J E; Benson, H A E; Roberts, M S

2016-07-01

Public health concerns continue to exist over the safety of zinc oxide nanoparticles that are commonly used in sunscreen formulations. In this work, we assessed the effects of two conditions which may be encountered in everyday sunscreen use, occlusion and a compromised skin barrier, on the penetration and local toxicity of two topically applied zinc oxide nanoparticle products. Caprylic/capric triglyceride (CCT) suspensions of commercially used zinc oxide nanoparticles, either uncoated or with a silane coating, were applied to intact and barrier impaired skin of volunteers, without and with occlusion for a period of six hours. The exposure time was chosen to simulate normal in-use conditions. Multiphoton tomography with fluorescence lifetime imaging was used to noninvasively assess zinc oxide penetration and cellular metabolic changes that could be indicative of toxicity. We found that zinc oxide nanoparticles did not penetrate into the viable epidermis of intact or barrier impaired skin of volunteers, without or with occlusion. We also observed no apparent toxicity in the viable epidermis below the application sites. These findings were validated by ex vivo human skin studies in which zinc penetration was assessed by multiphoton tomography with fluorescence lifetime imaging as well as Zinpyr-1 staining and toxicity was assessed by MTS assays in zinc oxide treated skin cryosections. In conclusion, applications of zinc oxide nanoparticles under occlusive in-use conditions to volunteers are not associated with any measurable zinc oxide penetration into, or local toxicity in the viable epidermis below the application site. Copyright © 2016 Elsevier B.V. All rights reserved.

Preliminary assessment of the relative toxicity of 1,5-diazido-3-nitrazapentane 90-day dermal application male and female rabbits study number 75-51-y809-90, May 1990 - June 1992. Phase 2. Final report, May 1990-June 1992

DOE Office of Scientific and Technical Information (OSTI.GOV)

Haight, E.A.; Harvey, J.G.; Beall, P.

1992-06-01

A 90-day application of DANPE has the potential to cause testicular hypospermatogenesis in male rabbits and an apparent inhibition of mature ovarian follicles formation in female rabbits. A no-observed-adverse-effect-level was not achieved in the male rabbits but was achieved in female rabbits at 27.3 mg/kg dose level.... 1,5-Diazido-3-Nitrazapentane, Dermal, Approximate Lethal Dose (ALD), Testicular hypospermatogenesis, Ovarian follicle No-observed-adverse-effect-level (NOAEL).

Toxic phytoplankton in San Francisco Bay

USGS Publications Warehouse

Rodgers, Kristine M.; Garrison, David L.; Cloern, James E.

1996-01-01

The Regional Monitoring Program (RMP) was conceived and designed to document the changing distribution and effects of trace substances in San Francisco Bay, with focus on toxic contaminants that have become enriched by human inputs. However, coastal ecosystems like San Francisco Bay also have potential sources of naturally-produced toxic substances that can disrupt food webs and, under extreme circumstances, become threats to public health. The most prevalent source of natural toxins is from blooms of algal species that can synthesize metabolites that are toxic to invertebrates or vertebrates. Although San Francisco Bay is nutrient-rich, it has so far apparently been immune from the epidemic of harmful algal blooms in the world’s nutrient-enriched coastal waters. This absence of acute harmful blooms does not imply that San Francisco Bay has unique features that preclude toxic blooms. No sampling program has been implemented to document the occurrence of toxin-producing algae in San Francisco Bay, so it is difficult to judge the likelihood of such events in the future. This issue is directly relevant to the goals of RMP because harmful species of phytoplankton have the potential to disrupt ecosystem processes that support animal populations, cause severe illness or death in humans, and confound the outcomes of toxicity bioassays such as those included in the RMP. Our purpose here is to utilize existing data on the phytoplankton community of San Francisco Bay to provide a provisional statement about the occurrence, distribution, and potential threats of harmful algae in this Estuary.

Nickel

USDA-ARS?s Scientific Manuscript database

The agricultural significance of nickel (Ni) is becoming increasingly apparent; yet, relative few farmers, growers, specialists or researchers know much about its function in crops, nor symptoms of deficiency or toxicity. The body of knowledge is reviewed regarding Ni’s background, uptake, transloc...

Hydrostatic pressure and temperature affect the tolerance of the free-living marine nematode Halomonhystera disjuncta to acute copper exposure.

PubMed

Mevenkamp, Lisa; Brown, Alastair; Hauton, Chris; Kordas, Anna; Thatje, Sven; Vanreusel, Ann

2017-11-01

Potential deep-sea mineral extraction poses new challenges for ecotoxicological research since little is known about effects of abiotic conditions present in the deep sea on the toxicity of heavy metals. Due to the difficulty of collecting and maintaining deep-sea organisms alive, a first step would be to understand the effects of high hydrostatic pressure and low temperatures on heavy metal toxicity using shallow-water relatives of deep-sea species. Here, we present the results of acute copper toxicity tests on the free-living shallow-water marine nematode Halomonhystera disjuncta, which has close phylogenetic and ecological links to the bathyal species Halomonhystera hermesi. Copper toxicity was assessed using a semi-liquid gellan gum medium at two levels of hydrostatic pressure (0.1MPa and 10MPa) and temperature (10°C and 20°C) in a fully crossed design. Mortality of nematodes in each treatment was assessed at 4 time intervals (24 and 48h for all experiments and additionally 72 and 96h for experiments run at 10°C). LC 50 values ranged between 0.561 and 1.864mg Cu 2+ L -1 and showed a decreasing trend with incubation time. Exposure to high hydrostatic pressure significantly increased sensitivity of nematodes to copper, whereas lower temperature resulted in an apparently increased copper tolerance, possibly as a result of a slower metabolism under low temperatures. These results indicate that hydrostatic pressure and temperature significantly affect metal toxicity and therefore need to be considered in toxicity assessments for deep-sea species. Any application of pollution limits derived from studies of shallow-water species to the deep-sea mining context must be done cautiously, with consideration of the effects of both stressors. Copyright © 2017 Elsevier B.V. All rights reserved.

Preclinical development of a non-toxic oral formulation of monoethanolamine, a lipid precursor, for prostate cancer treatment

PubMed Central

Saxena, Roopali; Yang, Chunhua; Rao, Mukkavilli; Turaga, Ravi Chakra; Garlapati, Chakravarthy; Gundala, Sushma Reddy; Myers, Kimberly; Ghareeb, Ahmed; Bhattarai, Shristi; Kamilinia, Golnaz; Bristi, Sangina; Su, Dan; Gadda, Giovanni; Rida, Padmashree C. G.; Cantuaria, Guilherme H.; Aneja, Ritu

2018-01-01

Purpose Most currently-available chemotherapeutic agents target rampant cell division in cancer cells, thereby affecting rapidly-dividing normal cells resulting in toxic side-effects. This non-specificity necessitates identification of novel cellular pathways that are reprogrammed selectively in cancer cells and can be exploited to develop pharmacologically superior and less-toxic therapeutics. Despite growing awareness on dysregulation of lipid metabolism in cancer cells, targeting lipid biosynthesis is still largely uncharted territory. Herein, we report development of a novel non-toxic orally-deliverable anticancer formulation of monoethanolamine (Etn), for prostate cancer by targeting the Kennedy pathway of phosphatidylethanolamine (PE) lipid biosynthesis. Experimental Design We first evaluated GI-tract stability, drug-drug interaction liability, pharmacokinetic and toxicokinetic properties of Etn to evaluate its suitability as a non-toxic orally-deliverable agent. We next performed in vitro and in vivo experiments to investigate efficacy and mechanism of action. Results Our data demonstrate that Etn exhibits excellent bioavailability, GI-tract stability, and no drug-drug interaction liability. Remarkably, orally-fed Etn inhibited tumor growth in four weeks by ~67% in mice bearing human prostate cancer PC-3 xenografts without any apparent toxicity. Mechanistically, Etn exploits selective overexpression of choline kinase in cancer cells, resulting in accumulation of phosphoethanolamine (PhosE), accompanied by downregulation of HIF-1α that induces metabolic stress culminating into cell death. Conclusions Our study provides first evidence for the superior anticancer activity of Etn, a simple lipid precursor formulation, whose non-toxicity conforms to FDA-approved standards, compelling its clinical development for prostate cancer management. PMID:28167510

Safety of inadvertent administration of overdose of intrathecal Cytarabine in a pediatric patient.

PubMed

Al Omar, Suha; Amayiri, Nisreen; Madanat, Faris

2015-10-01

To describe a medication error of intrathecal Cytarabine overdose that was managed conservatively with no apparent toxicities. An 11-year-old girl was diagnosed with bone marrow relapsed precursor B-cell acute lymphoblastic leukemia. According to her chemotherapy protocol, she was started on triple intrathecal chemotherapy consisting of Methotrexate, Cytarabine and Hydrocortisone on day 1 of the protocol. After the intrathecal therapy being administered to the patient, the pharmacist who checked the medication realized that the wrong formulation of Cytarabine was used to prepare the intrathecal therapy; this error resulted in five times overdose of Cytarabine. The patient was then managed conservatively without cerebrospinal fluid exchange. Our patient remained clinically and neurologically stable without apparent toxicities and was discharged safely from hospital. Supportive care without the need for invasive procedures such as cerebrospinal fluid exchange may be adequate for managing intrathecal Cytarabine overdose. © The Author(s) 2014.

Inhalation toxicology of diesel fuel obscurant aerosol in Sprague-Dawley rats. Final report, Phase 3, subchronic exposures

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lock, S.; Dalbey, W.; Schmoyer, R.

1984-12-01

Inhalation exposures were performed twice per week, for 13 weeks, to determine whether there was any potential toxicity to rats of comparatively low concentrations of a condensation aerosol from diesel fuel. Changes in breathing frequency and the response of animals to a loud sharp sound (startle response) were measured in selected animals prior to the start of the exposures, at various time points during the thirteen week exposure period, and at monthly intervals during the recovery period. Assays were performed on selected animals at the end of the exposure period, and again after the two month recovery period. Endpoints includedmore » pulmonary function tests, numbers of alveolar free cells, clinical chemistry, hematology, organ weights and histopathology. No mortalities were recorded during the exposure or recovery periods. Slight toxicity occurred at these low aerosol concentrations with the loss in body weight of all treated animals during the exposure period. During the exposure period there were also some slight changes in startle reflex, however, these were apparently acute effects, and there appeared to be no permanent CNS involvement as measured by this endpoint. Immediately post-exposure, the numbers of lavaged alveolar macrophages were slightly elevated in all aerosol exposed animals. Pulmonary function tests, pulmonary gas exchange and dynamic lung tests were all apparently unaffected by these low diesel fuel aerosol exposures. Changes in tissue weights in aerosol exposed animals were minor and the few histopathological lesions were randomly scattered amongst all groups included in this study and were more attributable to the age of the animals than any specific treatment group. No significant cumulative toxicity may be attributed to these diesel fuel aerosol exposures. 14 references, 1 figure, 42 tables.« less

Role of selenium toxicity and oxidative stress in aquatic birds

USGS Publications Warehouse

Hoffman, D.J.

2002-01-01

Adverse effects of selenium (Se) in wild aquatic birds have been documented as a consequence of pollution of the aquatic environment by subsurface agricultural drainwater and other sources. These effects include mortality, impaired reproduction with teratogenesis, reduced growth, histopathological lesions and alterations in hepatic glutathione metabolism. A review is provided, relating adverse biological effects of Se in aquatic birds to altered glutathione metabolism and oxidative stress. Laboratory studies, mainly with an organic form of Se, selenomethionine, have revealed oxidative stress in different stages of the mallard (Anas platyrhynchos) life cycle. As dietary and tissue concentrations of Se increase, increases in plasma and hepatic GSH peroxidase activities occur, followed by dose-dependent increases in the ratio of hepatic oxidized to reduced glutathione (GSSG:GSH) and ultimately hepatic lipid peroxidation measured as an increase in thiobarbituric acid reactive substances (TBARS). One or more of these oxidative effects were associated with teratogenesis (4.6 ppm wet weight Se in eggs), reduced growth in ducklings (15 ppm Se in liver), diminished immune function (5 ppm Se in liver) and histopathological lesions (29 ppm Se in liver) in adults. Manifestations of Serelated effects on glutathione metabolism were also apparent in field studies in seven species of aquatic birds. Reduced growth and possibly immune function but increased liver:body weight and hepatic GSSG:GSH ratios were apparent in American avocet (Recurvirostra americana) hatchlings from eggs containing 9 ppm Se. In blacknecked stilts (Himantopus mexicanus), which contained somewhat lower Se concentrations, a decrease in hepatic GSH was apparent with few other effects. In adult American coots (Fulica americana), signs of Se toxicosis included emaciation, abnormal feather loss and histopathological lesions. Mean liver concentrations of 28 ppm Se (ww) in the coots were associated with elevated hepatic GSH peroxidase, depletion of hepatic protein bound thiols and total thiols, but a small increase in GSH. Diving ducks in the San Francisco Bay area exhibited a positive correlation between hepatic Se concentration and GSH peroxidase activity (r=0.63, P<0.05), but a negative correlation between hepatic Se and GSH concentration (r=0.740, P<0.05). In willets (Catoptrophorus semipalmatus) from the San Diego area, positive correlations occurred between hepatic Se concentration and GSSG (r=0.70, P<0.001), GSSG:GSH ratio, and TBARS. In emperor geese (Chen canagica) from western Alaska, blood levels of up to 9.4 ppm occurred and were associated with increased plasma GSH peroxidase activity (r=0.62, P<0.001), but with decreased plasma GSSG reductase activity. When evaluating Se toxicity, interactive nutritional factors, including other elements and dietary protein, should also be taken into consideration. Further studies are needed to examine the relationship between different forms of environmentally occurring selenium, arsenic and mercury on reproduction, hepatotoxicity and immune function of aquatic birds. Further selenium nutritional interaction studies may also help to illucidate the mechanism of selenium induced teratogenesis, by optimizing GSH and other antioxidant defense mechanisms in a manner that would stabilize or raise the cell's threshold for susceptibility to toxic attack from excess selenium. It is concluded that Se-related manifestations of oxidative stress may serve as useful bioindicators of Se exposure and toxicity in wild aquatic birds.

Infant botulism following honey ingestion

PubMed Central

Abdulla, C O; Ayubi, A; Zulfiquer, F; Santhanam, G; Ahmed, M A S; Deeb, J

2012-01-01

An apparently well baby girl born at term was presented with signs and symptoms suggestive of acute onset of generalised floppiness at the age of 3 months. Clinically, the baby had lower motor neuron type of muscle weakness; detailed investigation lead to the diagnosis of neuromuscular junction disorder secondary to botulism toxicity. Further tests confirmed the botulism toxicity secondary to honey ingestion. The baby was treated with specific anticlostridium antibodies; she recovered remarkably, now growing and developing normally. PMID:22962382

Mammalian Toxicological Evaluation of TNT Wastewaters. Volume II. Acute and Subacute Mammalian Toxicity of TNT and LAP Mixture

DTIC Science & Technology

1979-06-01

different species of fish and four Invertebrate species. 17 Irradiated mixtures (with >50% TNT degradation) were invariably less toxic than the...statistically. Moreover, a marked lymphocytosis was apparent at this level. Some parameters, especially the RBC, Hgb, and/or Hct, were significantly...on treatment after 13 weeks had lymphocytosis , the males that continued on study but were allowed 4 weeks of recovery had a slight granulocytosis

The Bacterial (Vibrio alginolyticus) Production of Tetrodotoxin in the Ribbon Worm Lineus longissimus—Just a False Positive?

PubMed Central

Strand, Malin; Hedström, Martin; Seth, Henrik; McEvoy, Eric G.; Jacobsson, Erik; Göransson, Ulf; Andersson, Håkan S.; Sundberg, Per

2016-01-01

We test previous claims that the bacteria Vibrio alginolyticus produces tetrodotoxin (TTX) when living in symbiosis with the nemertean Lineus longissimus by a setup with bacteria cultivation for TTX production. Toxicity experiments on the shore crab, Carcinus maenas, demonstrated the presence of a paralytic toxin, but evidence from LC-MS and electrophysiological measurements of voltage-gated sodium channel–dependent nerve conductance in male Wistar rat tissue showed conclusively that this effect did not originate from TTX. However, a compound of similar molecular weight was found, albeit apparently non-toxic, and with different LC retention time and MS/MS fragmentation pattern than those of TTX. We conclude that C. maenas paralysis and death likely emanate from a compound <5 kDa, and via a different mechanism of action than that of TTX. The similarity in mass between TTX and the Vibrio-produced low-molecular-weight, non-toxic compound invokes that thorough analysis is required when assessing TTX production. Based on our findings, we suggest that re-examination of some published claims of TTX production may be warranted. PMID:27023570

Prediction of paraquat exposure and toxicity in clinically ill poisoned patients: a model based approach.

PubMed

Wunnapuk, Klintean; Mohammed, Fahim; Gawarammana, Indika; Liu, Xin; Verbeeck, Roger K; Buckley, Nicholas A; Roberts, Michael S; Musuamba, Flora T

2014-10-01

Paraquat poisoning is a medical problem in many parts of Asia and the Pacific. The mortality rate is extremely high as there is no effective treatment. We analyzed data collected during an ongoing cohort study on self-poisoning and from a randomized controlled trial assessing the efficacy of immunosuppressive therapy in hospitalized paraquat-intoxicated patients. The aim of this analysis was to characterize the toxicokinetics and toxicodynamics of paraquat in this population. A non-linear mixed effects approach was used to perform a toxicokinetic/toxicodynamic population analysis in a cohort of 78 patients. The paraquat plasma concentrations were best fitted by a two compartment toxicokinetic structural model with first order absorption and first order elimination. Changes in renal function were used for the assessment of paraquat toxicodynamics. The estimates of toxicokinetic parameters for the apparent clearance, the apparent volume of distribution and elimination half-life were 1.17 l h(-1) , 2.4 l kg(-1) and 87 h, respectively. Renal function, namely creatinine clearance, was the most significant covariate to explain between patient variability in paraquat clearance.This model suggested that a reduction in paraquat clearance occurred within 24 to 48 h after poison ingestion, and afterwards the clearance was constant over time. The model estimated that a paraquat concentration of 429 μg l(-1) caused 50% of maximum renal toxicity. The immunosuppressive therapy tested during this study was associated with only 8% improvement of renal function. The developed models may be useful as prognostic tools to predict patient outcome based on patient characteristics on admission and to assess drug effectiveness during antidote drug development. © 2014 The British Pharmacological Society.

Comparative Toxicities of Salts on Microbial Processes in Soil

PubMed Central

Maheshwari, Arpita; Bengtson, Per; Rousk, Johannes

2016-01-01

Soil salinization is a growing threat to global agriculture and carbon sequestration, but to date it remains unclear how microbial processes will respond. We studied the acute response to salt exposure of a range of anabolic and catabolic microbial processes, including bacterial (leucine incorporation) and fungal (acetate incorporation into ergosterol) growth rates, respiration, and gross N mineralization and nitrification rates. To distinguish effects of specific ions from those of overall ionic strength, we compared the addition of four salts frequently associated with soil salinization (NaCl, KCl, Na2SO4, and K2SO4) to a nonsaline soil. To compare the tolerance of different microbial processes to salt and to interrelate the toxicity of different salts, concentration-response relationships were established. Growth-based measurements revealed that fungi were more resistant to salt exposure than bacteria. Effects by salt on C and N mineralization were indistinguishable, and in contrast to previous studies, nitrification was not found to be more sensitive to salt exposure than other microbial processes. The ion-specific toxicity of certain salts could be observed only for respiration, which was less inhibited by salts containing SO42− than Cl− salts, in contrast to the microbial growth assessments. This suggested that the inhibition of microbial growth was explained solely by total ionic strength, while ion-specific toxicity also should be considered for effects on microbial decomposition. This difference resulted in an apparent reduction of microbial growth efficiency in response to exposure to SO42− salts but not to Cl− salts; no evidence was found to distinguish K+ and Na+ salts. PMID:26801570

Metabonomics study of the effects of pretreatment with glycyrrhetinic acid on mesaconitine-induced toxicity in rats.

PubMed

Sun, Bo; Zhang, Ming; Zhang, Qi; Ma, Kunpeng; Li, Haijing; Li, Famei; Dong, Fangting; Yan, Xianzhong

2014-07-03

Aconitum carmichaelii Debx. (Fuzi), a commonly use traditional Chinese medicine (TCM), has often been used in combination with Rhizoma Glycyrrhizae (Gancao) to reduce its toxicity due to diester diterpenoid alkaloids aconitine, mesaconitine, and hypaconitine. However, the mechanism of detoxication is still unclear. Glycyrrhetinic acid (GA) is the metabolite of glycyrrhizinic acid (GL), the major component of Gancao. In present study, the effect of GA on the changes of metabolic profiles induced by mesaconitine was investigated using NMR-based metabolomic approaches. Fifteen male Wistar rats were divided into a control group, a group administered mesaconitine alone, and a group administered mesaconitine with one pretreatment with GA. Their urine samples were used for NMR spectroscopic metabolic profiling. Statistical analyses such as orthogonal projections to latent structures-discriminant analysis (OPLS-DA), t-test, hierarchical cluster, and pathway analysis were used to detect the effects of pretreatment with GA on mesaconitine-induced toxicity. The OPLS-DA score plots showed the metabolic profiles of GA-pretreated rats apparently approach to those of normal rats compared to mesaconitine-induced rats. From the t-test and boxplot results, the concentrations of leucine/isoleucine, lactate, acetate, succinate, trimethylamine (TMA), dimethylglycine (DMG), 2-oxo-glutarate, creatinine/creatine, glycine, hippurate, tyrosine and benzoate were significantly changed in metabolic profiles of mesaconitine-induced rats. The disturbed metabolic pathways include amino acid biosynthesis and metabolism. GA-pretreatment can mitigate the metabolic changes caused by mesaconitine-treatment on rats, indicating that prophylaxis with GA could reduce the toxicity of mesaconitine at the metabolic level. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Comparison of Toxicity of Benzene Metabolite Hydroquinone in Hematopoietic Stem Cells Derived from Murine Embryonic Yolk Sac and Adult Bone Marrow

PubMed Central

Zhu, Jie; Wang, Hong; Yang, Shuo; Guo, Liqiao; Li, Zhen; Wang, Wei; Wang, Suhan; Huang, Wenting; Wang, Liping; Yang, Tan; Ma, Qiang; Bi, Yongyi

2013-01-01

Benzene is an occupational toxicant and an environmental pollutant that potentially causes hematotoxicity and leukemia in exposed populations. Epidemiological studies suggest an association between an increased incidence of childhood leukemia and benzene exposure during the early stages of pregnancy. However, experimental evidence supporting the association is lacking at the present time. It is believed that benzene and its metabolites target hematopoietic stem cells (HSCs) to cause toxicity and cancer in the hematopoietic system. In the current study, we compared the effects of hydroquinone (HQ), a major metabolite of benzene in humans and animals, on mouse embryonic yolk sac hematopoietic stem cells (YS-HSCs) and adult bone marrow hematopoietic stem cells (BM-HSCs). YS-HSCs and BM-HSCs were isolated and enriched, and were exposed to HQ at increasing concentrations. HQ reduced the proliferation and the differentiation and colony formation, but increased the apoptosis of both YS-HSCs and BM-HSCs. However, the cytotoxic and apoptotic effects of HQ were more apparent and reduction of colony formation by HQ was more severe in YS-HSCs than in BM-HSCs. Differences in gene expression profiles were observed in HQ-treated YS-HSCs and BM-HSCs. Cyp4f18 was induced by HQ both in YS-HSCs and BM-HSCs, whereas DNA-PKcs was induced in BM-HSCs only. The results revealed differential effects of benzene metabolites on embryonic and adult HSCs. The study established an experimental system for comparison of the hematopoietic toxicity and leukemogenicity of benzene and metabolites during mouse embryonic development and adulthood. PMID:23940708

THE CANNABINOID RECEPTOR ANTAGONIST AM251 INCREASES PARAOXON AND CHLORPYRIFOS OXON TOXICITY IN RATS

PubMed Central

Liu, Jing; Pope, Carey

2014-01-01

Organophosphorus anticholinesterases (OPs) elicit acute toxicity by inhibiting acetylcholinesterase (AChE), leading to acetylcholine accumulation and overstimulation of cholinergic receptors. Endocannabinoids (eCBs, e.g., arachidonoyl ethanolamide [AEA] and 2-arachidonoyl glycerol [2-AG]) are neuromodulators that regulate neurotransmission by reducing neurotransmitter release. The eCBs are degraded by the enzymes fatty acid amide hydrolase (FAAH, primarily involved in hydrolysis of AEA) and monoacylglycerol lipase (MAGL, primarily responsible for metabolism of 2-AG). We previously reported that the cannabinoid receptor agonist WIN 55,212-2 reduced cholinergic toxicity after paraoxon exposure. This study compared the effects of the cannabinoid receptor antagonist AM251 on acute toxicity following either paraoxon (PO) or chlorpyrifos oxon (CPO). CPO was more potent in vitro than PO at inhibiting AChE (≈ 2 fold), FAAH (≈ 8 fold), and MAGL (≈ 19 fold). Rats were treated with vehicle, PO (0.3 and 0.6 mg/kg, sc.) or CPO (6 and 12 mg/kg, sc.) and subsets treated with AM251 (3 mg/kg, ip; 30 min after OP). Signs of toxicity were recorded for four hours and rats were then sacrificed. OP-treated rats showed dose-related involuntary movements, with AM251 increasing signs of toxicity with the lower dosages. PO and CPO elicited excessive secretions, but AM251 had no apparent effect with either OP. Lethality was increased by AM251 with the higher dosage of PO, but no lethality was noted with either dosage of CPO, with or without AM251. Both OPs caused extensive inhibition of hippocampal AChE and FAAH (>80–90%), but only CPO inhibited MAGL (37–50%). These results provide further evidence that eCB signaling can influence acute OP toxicity. The selective in vivo inhibition of MAGL by CPO may be important in the differential lethality noted between PO and CPO with AM251 co-administration. PMID:25447325

Zinc oxide nanoparticles decrease the expression and activity of plasma membrane calcium ATPase, disrupt the intracellular calcium homeostasis in rat retinal ganglion cells.

PubMed

Guo, Dadong; Bi, Hongsheng; Wang, Daoguang; Wu, Qiuxin

2013-08-01

Zinc oxide nanoparticle is one of the most important materials with diverse applications. However, it has been reported that zinc oxide nanoparticles are toxic to organisms, and that oxidative stress is often hypothesized to be an important factor in cytotoxicity mediated by zinc oxide nanoparticles. Nevertheless, the mechanism of toxicity of zinc oxide nanoparticles has not been completely understood. In this study, we investigated the cytotoxic effect of zinc oxide nanoparticles and the possible molecular mechanism involved in calcium homeostasis mediated by plasma membrane calcium ATPase in rat retinal ganglion cells. Real-time cell electronic sensing assay showed that zinc oxide nanoparticles could exert cytotoxic effect on rat retinal ganglion cells in a concentration-dependent manner; flow cytometric analysis indicated that zinc oxide nanoparticles could lead to cell damage by inducing the overproduction of reactive oxygen species. Furthermore, zinc oxide nanoparticles could also apparently decrease the expression level and their activity of plasma membrane calcium ATPase, which finally disrupt the intracellular calcium homeostasis and result in cell death. Taken together, zinc oxide nanoparticles could apparently decrease the plasma membrane calcium ATPase expression, inhibit their activity, cause the elevated intracellular calcium ion level and disrupt the intracellular calcium homeostasis. Further, the disrupted calcium homeostasis will trigger mitochondrial dysfunction, generate excessive reactive oxygen species, and finally initiate cell death. Thus, the disrupted calcium homeostasis is involved in the zinc oxide nanoparticle-induced rat retinal ganglion cell death. Copyright © 2013 Elsevier Ltd. All rights reserved.

Novel toxic effects associated with a tropical Limnothrix/Geitlerinema-like cyanobacterium.

PubMed

Bernard, Catherine; Froscio, Suzanne; Campbell, Rebecca; Monis, Paul; Humpage, Andrew; Fabbro, Larelle

2011-06-01

The presence of a toxic strain of a fine filamentous cyanobacterium belonging to the Oscillatorialean family Pseudanabaenacea was detected during a survey of cyanobacterial taxa associated with the presence of cylindrospermopsin in dams in Central Queensland (Australia). The strain, AC0243, was isolated and cultured, its genomic DNA extracted and 16S RNA gene sequenced. Phylogenetic analysis placed AC0243 with Limnothrix species, although this genus appears polyphyletic. Moreover, not all morphological characters are consistent with this genus but more closely fit the description of Geitlerinema unigranulatum (R.N. Singh) Komárek and Azevedo. The potential toxic effects of AC0243 extract were assessed chemically and biologically. Cell free protein synthesis was inhibited by the extract. Exposure of Vero cells to the extract resulted in a significant reduction in cellular ATP levels following 24-72 h incubation. The presence of cylindrospermopsin was excluded based on the nature of responses obtained in cell and cell-free assays; in addition, (i) it could not be detected by HPLC, LC-MS, or immunological assay, and (ii) no genes currently associated with the production of cylindrospermopsin were found in the genome. Other known cyanobacterial toxins were not detected. The apparent novelty of this toxin is discussed. Copyright © 2009 Wiley Periodicals, Inc.

Size dependent biodistribution and toxicokinetics of iron oxide magnetic nanoparticles in mice

NASA Astrophysics Data System (ADS)

Yang, Lin; Kuang, Huijuan; Zhang, Wanyi; Aguilar, Zoraida P.; Xiong, Yonghua; Lai, Weihua; Xu, Hengyi; Wei, Hua

2014-12-01

In spite of the immense benefits from iron oxide magnetic nanoparticles (IOMNs), there is scanty information regarding their metabolic activities and toxicity in vivo. In this study, we investigated the size dependent in vivo biodistribution, toxicokinetics, and toxicity and gene expression changes of various sizes of carboxyl coated IOMNs (diameters of 10, 20, 30, and 40 nm). Our findings demonstrated that the various sizes of IOMNs accumulated primarily in the liver and spleen on the first day post-injection. Interestingly, size dependent biodistribution and transport were observed: the smallest IOMNs (10 nm) showed the highest uptake by the liver, whereas the largest IOMNs (40 nm) showed the highest uptake by the spleen. Moreover, the IOMNs with the smallest size (10 nm) were cleared faster from the liver and kidneys, but more readily entered the brain and the uterus. IOMNs with the largest size (40 nm) accumulated more readily but were easily eliminated in the spleen. However, the level of iron in the heart decreased in all IOMN exposed groups. In addition, blood biochemistry, hematological analyses and histological examination demonstrated that there was no apparent acute toxicity caused by IOMNs in mice. However, smaller IOMNs (10 nm and 20 nm) more effectively changed the expression level of sensitive genes related to oxidant stress, iron transport, metabolic process, apoptosis, and others.In spite of the immense benefits from iron oxide magnetic nanoparticles (IOMNs), there is scanty information regarding their metabolic activities and toxicity in vivo. In this study, we investigated the size dependent in vivo biodistribution, toxicokinetics, and toxicity and gene expression changes of various sizes of carboxyl coated IOMNs (diameters of 10, 20, 30, and 40 nm). Our findings demonstrated that the various sizes of IOMNs accumulated primarily in the liver and spleen on the first day post-injection. Interestingly, size dependent biodistribution and transport were observed: the smallest IOMNs (10 nm) showed the highest uptake by the liver, whereas the largest IOMNs (40 nm) showed the highest uptake by the spleen. Moreover, the IOMNs with the smallest size (10 nm) were cleared faster from the liver and kidneys, but more readily entered the brain and the uterus. IOMNs with the largest size (40 nm) accumulated more readily but were easily eliminated in the spleen. However, the level of iron in the heart decreased in all IOMN exposed groups. In addition, blood biochemistry, hematological analyses and histological examination demonstrated that there was no apparent acute toxicity caused by IOMNs in mice. However, smaller IOMNs (10 nm and 20 nm) more effectively changed the expression level of sensitive genes related to oxidant stress, iron transport, metabolic process, apoptosis, and others. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr05061d

Developing an in vitro technology to study the inflammation potential of ambient particle types

NASA Astrophysics Data System (ADS)

Haddrell, Allen E.

Elevated levels of suspended particles in the troposphere, termed particulate matter, elicit a myriad of adverse health effects in humans, ranging from shortness of breath and wheezing to myocardial infarction and death. It is currently believed that the adverse health effects associated with particulate matter are mediated by the inflammatory response initiated by the lung following particulate matter inhalation. What remains an area of much interest is elucidating the specific properties of particulate matter, physical or chemical, that cause the upregulation of proinflammatory mediators. The basic premise of this thesis was to identify the specific chemical components of particulate matter responsible for its adverse health effects. To address this issue, instrumentation and methodology were developed wherein one could design, create, levitate and deposit particles of both known chemical composition and size onto lung cells, in vitro, followed by the monitoring of the downstream biological response. An initial study focused on the role of the endotoxin component in particulate matter toxicity. Through a series of blocking studies we found that endotoxin acted synergistically with the particle core to elicit upregulation of proinflammatory mediators, including IL-1beta, TNF-alpha and ICAM-1; all of which are associated with the NF-kappaB pathway. Through characterizing this relatively simple system, one observation became apparent: the presence of the insoluble particle core had a profound effect on the cellular response; that is to say, the particle core was not simply a delivery vector, but a determinant factor in the final intracellular location of the toxic chemical. The latter observation held true as other particle types were studied and in addition, it was found that the nature of the actual chemical species itself plays a dual role in particle toxicity; first by retaining its toxic properties and second by altering the physical properties of the particle. It stems from these findings that the toxicity of the chemical components must be studied in concert and not as individual entities.

Toxicity of used drilling fluids to mysids (Mysidopsis bahia)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gaetz, C.T.; Montgomery, R.; Duke, T.W.

1986-01-01

Static, acute toxicity tests were conducted with mysids (Mysidopsis bahia) and 11 used drilling fluids (also called drilling muds) obtained from active drilling platforms in the Gulf of Mexico, U.S.A. Each whole mud was tested, along with three phases of each mud: a liquid phase with all particulate materials removed; a suspended particulate phase composed of soluble and lighter particulate fractions; and a solid phase composed mainly of drill cuttings and rapidly settling particulates. These muds represented seven of the eight generic mud types described by the U.S. Environmental Protection Agency for use on the U.S. Outer Continental Shelf. Themore » toxicity of the 11 muds tested was apparently enhanced by the presence of aromatics. Furthermore, one mud tested repeatedly showed loss of toxicity with time, possibly from volatilization of aromatic fractions. The data demonstrated that aromatics in the drilling fluids affected their toxicity to M. bahia.« less

Diet composition exacerbates or attenuates soman toxicity in rats: implied metabolic control of nerve agent toxicity.

PubMed

Myers, Todd M; Langston, Jeffrey L

2011-06-01

To evaluate the role of diet composition on nerve agent toxicity, rats were fed four distinct diets ad libitum for 28 d prior to challenge with 110 μg/kg (1.0 LD(50), sc) soman. The four diets used were a standard rodent diet, a choline-enriched diet, a glucose-enriched diet, and a ketogenic diet. Body weight was recorded throughout the study. Toxic signs and survival were evaluated at key times for up to 72 h following soman exposure. Additionally, acquisition of discriminated shuttlebox avoidance performance was characterized beginning 24h after soman challenge and across the next 8 d (six behavioral sessions). Prior to exposure, body weight was highest in the standard diet group and lowest in the ketogenic diet group. Upon exposure, differences in soman toxicity as a function of diet became apparent within the first hour, with mortality in the glucose-enriched diet group reaching 80% and exceeding all other groups (in which mortality ranged from 0 to 6%). At 72 h after exposure, mortality was 100% in the glucose-enriched diet group, and survival approximated 50% in the standard and choline-enriched diet groups, but equaled 87% in the ketogenic diet group. Body weight loss was significantly reduced in the ketogenic and choline-enriched diet groups, relative to the standard diet group. At 1 and 4h after exposure, rats in the ketogenic diet group had significantly lower toxic sign scores than all other groups. The ketogenic diet group performed significantly better than the standard diet group on two measures of active avoidance performance. The exacerbated soman toxicity observed in the glucose-enriched diet group coupled with the attenuated soman toxicity observed in the ketogenic diet group implicates glucose availability in the toxic effects of soman. This increased glucose availability may enhance acetylcholine synthesis and/or utilization, thereby exacerbating peripheral and central soman toxicity. Published by Elsevier B.V.

Prediction of the developmental toxicity hazard potential of halogenated drinking water disinfection by-products tested by the in vitro hydra assay

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fu, L.J.; Johnson, E.M.; Newman, L.M.

A series of seven randomly selected potential halogenated water disinfection by-products were evaluated in vitro by the hydra assay to determine their developmental toxicity hazard potential. For six of the chemicals tested by this assay (dibromoacetonitrile; trichloroacetonitrile; 2-chlorophenol; 2,4,6-trichlorophenol; trichloroacetic acid; dichloroacetone) it was predicted that they would be generally equally toxic to both adult and embryonic mammals when studied by means of standard developmental toxicity teratology tests. However, the potential water disinfection by-product chloroacetic acid (CA) was determined to be over eight times more toxic to the embryonic developmental portion of the assay than it was to the adults.more » Because of this potential selectivity, CA is a high-priority item for developmental toxicity tests in pregnant mammals to confirm or refute its apparent unique developmental hazard potential and/or to establish a NOAEL by the route of most likely human exposure.« less

[Toxicity and toxin profiles of xanthid crabs collected around Nakanoshima in the Tokara Islands, Japan].

PubMed

Sagara, Takefumi; Taniyama, Shigeto; Takatani, Tomohiro; Nishibori, Naoyoshi; Nishio, Sachio; Noguchi, Tamao; Arakawa, Osamu

2009-10-01

A total of 36 specimens of 5 xanthid crab species, Zosimus aeneus (n=16), Xanthias lividus (n=4), Leptodius sanguineus (n=3), Daira perlata (n=10) and Eriphia sebana (n=3), were collected around Nakanoshima Island, which is located at the northeastern part of the Tokara Islands, Kagoshima Prefecture, Japan in May and July 2000, and their toxicity was determined by mouse bioassay. Nine of 16 Z. aeneus specimens and all of 4 X. lividus specimens showed lethal potency to mice (2.1-11 MU/g, 2.8-8.6 MU/g, respectively), whereas all the other species were non-toxic (less than 2.0 MU/g). LC/MS analyses indicated that the toxin of the Z. aeneus specimens was mainly composed of tetrodotoxin (41% of total toxicity), and 11-oxotetrodotoxin contributed to the remaining toxicity. The toxin of the X. lividus specimens, however, was apparently not tetrodotoxin. In HPLC-FLD analyses, no paralytic shellfish poison component was detected in either of the two toxic species.

Toxicity of tungsten carbide and cobalt-doped tungsten carbide nanoparticles in mammalian cells in vitro.

PubMed

Bastian, Susanne; Busch, Wibke; Kühnel, Dana; Springer, Armin; Meissner, Tobias; Holke, Roland; Scholz, Stefan; Iwe, Maria; Pompe, Wolfgang; Gelinsky, Michael; Potthoff, Annegret; Richter, Volkmar; Ikonomidou, Chrysanthy; Schirmer, Kristin

2009-04-01

Tungsten carbide nanoparticles are being explored for their use in the manufacture of hard metals. To develop nanoparticles for broad applications, potential risks to human health and the environment should be evaluated and taken into consideration. We aimed to assess the toxicity of well-characterized tungsten carbide (WC) and cobalt-doped tungsten carbide (WC-Co) nanoparticle suspensions in an array of mammalian cells. We examined acute toxicity of WC and of WC-Co (10% weight content Co) nanoparticles in different human cell lines (lung, skin, and colon) as well as in rat neuronal and glial cells (i.e., primary neuronal and astroglial cultures and the oligodendrocyte precursor cell line OLN-93). Furthermore, using electron microscopy, we assessed whether nanoparticles can be taken up by living cells. We chose these in vitro systems in order to evaluate for potential toxicity of the nanoparticles in different mammalian organs (i.e., lung, skin, intestine, and brain). Chemical-physical characterization confirmed that WC as well as WC-Co nanoparticles with a mean particle size of 145 nm form stable suspensions in serum-containing cell culture media. WC nanoparticles were not acutely toxic to the studied cell lines. However, cytotoxicity became apparent when particles were doped with Co. The most sensitive were astrocytes and colon epithelial cells. Cytotoxicity of WC-Co nanoparticles was higher than expected based on the ionic Co content of the particles. Analysis by electron microscopy demonstrated presence of WC nanoparticles within mammalian cells. Our findings demonstrate that doping of WC nanoparticles with Co markedly increases their cytotoxic effect and that the presence of WC-Co in particulate form is essential to elicit this combinatorial effect.

Toxicity of Tungsten Carbide and Cobalt-Doped Tungsten Carbide Nanoparticles in Mammalian Cells in Vitro

PubMed Central

Bastian, Susanne; Busch, Wibke; Kühnel, Dana; Springer, Armin; Meißner, Tobias; Holke, Roland; Scholz, Stefan; Iwe, Maria; Pompe, Wolfgang; Gelinsky, Michael; Potthoff, Annegret; Richter, Volkmar; Ikonomidou, Chrysanthy; Schirmer, Kristin

2009-01-01

Background Tungsten carbide nanoparticles are being explored for their use in the manufacture of hard metals. To develop nanoparticles for broad applications, potential risks to human health and the environment should be evaluated and taken into consideration. Objective We aimed to assess the toxicity of well-characterized tungsten carbide (WC) and cobaltdoped tungsten carbide (WC-Co) nanoparticle suspensions in an array of mammalian cells. Methods We examined acute toxicity of WC and of WC-Co (10% weight content Co) nanoparticles in different human cell lines (lung, skin, and colon) as well as in rat neuronal and glial cells (i.e., primary neuronal and astroglial cultures and the oligodendro cyte precursor cell line OLN-93). Furthermore, using electron microscopy, we assessed whether nanoparticles can be taken up by living cells. We chose these in vitro systems in order to evaluate for potential toxicity of the nanoparticles in different mammalian organs (i.e., lung, skin, intestine, and brain). Results Chemical–physical characterization confirmed that WC as well as WC-Co nanoparticles with a mean particle size of 145 nm form stable suspensions in serum-containing cell culture media. WC nanoparticles were not acutely toxic to the studied cell lines. However, cytotoxicity became apparent when particles were doped with Co. The most sensitive were astrocytes and colon epithelial cells. Cytotoxicity of WC-Co nanoparticles was higher than expected based on the ionic Co content of the particles. Analysis by electron microscopy demonstrated presence of WC nanoparticles within mammalian cells. Conclusions Our findings demonstrate that doping of WC nanoparticles with Co markedly increases their cytotoxic effect and that the presence of WC-Co in particulate form is essential to elicit this combinatorial effect. PMID:19440490

Disposition of toxic PCB congeners in snapping turtle eggs: expressed as toxic equivalents of TCDD

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bryan, A.M.; Stone, W.B.; Olafsson, P.G.

1987-11-01

Studies of snapping turtles, taken from the region of the Upper Hudson River, in New York State, revealed exceedingly high levels of PCBs in the adipose tissue. There is evidence to suggest that large reserves of fat provide protection against chlorinated hydrocarbon toxicity. Such storage may protect snapping turtle eggs from disposition of toxic PCB congeners and account for the apparent absence of reports regarding detrimental effects on the hatchability of eggs from turtles living in the vicinity of the upper Hudson River. The present study was undertaken to determine if indeed these eggs are protected against disposition of toxicmore » PCB congeners by the presence of large reserves of fat. Although tissue volumes play an important role in determining the initial site of disposition, the major factor controlling the elimination of these compounds involves metabolism. For simple halogenated benzenes as well as for more complex halogenated biphenyls, oxidative metabolism catalyzed by P-448, occurs primarily at the site of two adjacent unsubstituted carbon atoms via arene oxide formation leading to the formation of water soluble metabolites. Toxicological studies have demonstrated that the most toxic PCB congeners, isosteriomers of tetrachlorodibenzo-p-dioxin (TCDD), require no metabolic activation. These compounds have chlorine atoms in the meta and para positions of both rings. It may be concluded that the structures of PCB congeners and isomers which favor induction of cytochrome P-448 are also those which are toxic and resist metabolism. It is the objective of the present study to determine if the heavy fat bodies of the female turtle provide a sufficiently large sink to retain the toxic congeners and prevent their incorporation into the eggs.« less

Spectral domain optical coherence tomography as an effective screening test for hydroxychloroquine retinopathy (the "flying saucer" sign).

PubMed

Chen, Eric; Brown, David M; Benz, Matthew S; Fish, Richard H; Wong, Tien P; Kim, Rosa Y; Major, James C

2010-10-21

While the long-term incidence of hydroxychloroquine (HCQ) retinopathy is low, there remains no definitive clinical screening test to recognize HCQ toxicity before ophthalmoscopic fundus changes or visual symptoms. Patients receiving HCQ were evaluated with spectral domain optical coherence tomography (SD OCT) to assess the feasibility of identifying HCQ retinopathy at an early stage. Twenty-five patients referred for the evaluation of hydroxychloroquine toxicity underwent a comprehensive ocular examination, Humphrey visual field (HVF) perimetry, time domain OCT, and SD OCT. Some patients with screening abnormalities also underwent further diagnostic testing at the discretion of the treating providers. Five patients were found to have SD OCT findings corresponding to HCQ toxicity and retinal damage as seen by clinical exam and/or HVF perimetry. Two patients with advanced toxicity were found to have significant outer retina disruption in the macula on SD OCT. Three patients with early HCQ toxicity and HVF 10-2 perifoveal defects were found to have loss of the perifoveal photoreceptor inner segment/outer segment (IS/OS) junction with intact outer retina directly under the fovea, creating the "flying saucer" sign. While two of these three patients had early ophthalmoscopic fundus changes, one had none. Outer retinal abnormalities including perifoveal photoreceptor IS/OS junction disruption can be identified by SD OCT in early HCQ toxicity, sometimes even before ophthalmoscopic fundus changes are apparent. SD OCT may have a potential complementary role in screening for HCQ retinopathy due to its quick acquisition and because it is more objective than automated perimetry.

Sulfate transport kinetics and toxicity are modulated by sodium in aquatic insects.

PubMed

Scheibener, Shane; Conley, Justin M; Buchwalter, David

2017-09-01

The salinization of freshwater ecosystems is emerging as a major ecological issue. Several anthropogenic causes of salinization (e.g. surface coal mining, hydro-fracking, road de-icing, irrigation of arid lands, etc.) are associated with biodiversity losses in freshwater ecosystems. Because insects tend to dominate freshwater ecology, it is important that we develop a better understanding of how and why different species respond to salinity matrices dominated by different major ions. This study builds upon previous work demonstrating that major ion toxicity to the mayfly Neocloeon triangulifer was apparently due to the ionic composition of water rather than specific conductance. Synthetic waters with low Ca:Mg ratios and high SO 4 :Na ratios produced toxicity, whereas waters with higher Ca:Mg ratios and lower SO 4 :Na ratios were not toxic to mayflies at comparable conductivities. Here we used a radiotracer approach to show that Mg did not competitively exclude Ca uptake at environmentally realistic ratios in 4 aquatic insect species. We characterized SO 4 uptake kinetics in 5 mayflies and assessed the influence of different ions on SO 4 uptake. Dual label experiments show an inverse relationship between SO 4 and Na transport rates as SO 4 was held constant and Na was increased, suggesting that Na (and not Cl or HCO 3 ) is antagonistic to SO 4 transport. Based on this observation, we tested the hypothesis that increasing Na would protect against SO 4 induced toxicity in a Na-dependent manner. Increasing Na from 0.7 to 10.9mM improved 96-h survivorship associated with 20.8mM SO 4 from 44% to 73% in a concentration dependent manner. However, when Na reached 21.8mM, survivorship decreased to 16%, suggesting that other interactive effects of major ions caused toxicity under those conditions. Thus, the combination of elevated sulfate and low sodium commonly observed in streams affected by mountaintop coal mining has the potential to cause toxicity in sensitive aquatic insects. Overall, it is important that we develop a better understanding of major ion toxicity to effectively mitigate and protect freshwater biodiversity from salinization. Copyright © 2017 Elsevier B.V. All rights reserved.

In vivo assessment of toxicity and pharmacokinetics of methylglyoxal

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ghosh, Manju; Talukdar, Dipa; Ghosh, Swapna

2006-04-01

Previous in vivo studies from several laboratories had shown remarkable curative effect of methylglyoxal on cancer-bearing animals. In contrast, most of the recent in vitro studies have assigned a toxic role for methylglyoxal. The present study was initiated with the objective to resolve whether methylglyoxal is truly toxic in vivo and to reassess its therapeutic potential. Four species of animals, both rodent and non-rodent, were treated with different doses of methylglyoxal through oral, subcutaneous and intravenous routes. Acute (treatment for only 1 day) toxicity tests had been done with mouse and rat. These animals received 2, 1 and 0.3 gmore » of methylglyoxal/kg of body weight in a day through oral, subcutaneous and intravenous routes respectively. Chronic (treatment for around a month) toxicity test had been done with mouse, rat, rabbit and dog. Mouse, rat and dog received 1, 0.3 and 0.1 g of methylglyoxal/kg of body weight in a day through oral, subcutaneous and intravenous routes respectively. Rabbit received 0.55, 0.3 and 0.1 g of methylglyoxal/kg of body weight in a day through oral, subcutaneous and intravenous routes respectively. It had been observed that methylglyoxal had no deleterious effect on the physical and behavioral pattern of the treated animals. Fertility and teratogenecity studies were done with rats that were subjected to chronic toxicity tests. It had been observed that these animals produced healthy litters indicating no damage of the reproductive systems as well as no deleterious effect on the offspring. Studies on several biochemical and hematological parameters of methylglyoxal-treated rats and dogs and histological studies of several organs of methylglyoxal-treated mouse were performed. These studies indicated that methylglyoxal had no apparent deleterious effect on some vital organs of these animals. A detailed pharmacokinetic study was done with mouse after oral administration of methylglyoxal. The effect of methylglyoxal alone and in combination with creatine and ascorbic acid on cancer-bearing animals had been investigated by measuring the increase in life span and tumor cell growth inhibition. The results indicated that anticancer effect of methylglyoxal was significantly augmented by ascorbic acid and further augmented by ascorbic acid and creatine. Nearly 80% of the animals treated with methylglyoxal plus ascorbic acid plus creatine were completely cured and devoid of any malignant cells within the peritoneal cavity.« less

Oxidation of indometacin by ferrate (VI): kinetics, degradation pathways, and toxicity assessment.

PubMed

Huang, Junlei; Wang, Yahui; Liu, Guoguang; Chen, Ping; Wang, Fengliang; Ma, Jingshuai; Li, Fuhua; Liu, Haijin; Lv, Wenying

2017-04-01

The oxidation of indometacin (IDM) by ferrate(VI) (Fe(VI)) was investigated to determine the reaction kinetics, transformation products, and changes in toxicity. The reaction between IDM and Fe(VI) followed first-order kinetics with respect to each reactant. The apparent second-order rate constants (k app ) decreased from 9.35 to 6.52 M -1  s -1 , as the pH of the solution increased from 7.0 to 10.0. The pH dependence of k app might be well explained by considering the species-specific rate constants of the reactions of IDM with Fe(VI). Detailed product studies using liquid chromatography-tandem mass spectrometry (LC-MS/MS) indicated that the oxidation products were primarily derived from the hydrolysis of amide linkages, the addition of hydroxyl groups, and electrophilic oxidation. The toxicity of the oxidation products was evaluated using the Microtox test, which indicated that transformation products exhibited less toxicity to the Vibrio fischeri bacteria. Quantitative structure-activity relationship (QSAR) analysis calculated by the ecological structure activity relationship (ECOSAR) revealed that all of the identified products exhibited lower acute and chronic toxicity than the parent pharmaceutical for fish, daphnid, and green algae. Furthermore, Fe(VI) was effective in the degradation IDM in water containing carbonate ions or fulvic acid (FA), and in lake water samples; however, higher Fe(VI) dosages would be required to completely remove IDM in lake water in contrast to deionized water.

Effects of 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') and para-methoxyamphetamine on striatal 5-HT when co-administered with moclobemide.

PubMed

Freezer, Alexander; Salem, Abdallah; Irvine, Rodney J

2005-04-11

3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") and para-methoxyamphetamine (PMA) are commonly used recreational drugs. PMA, often mistaken for MDMA, is reported to be more toxic in human use than MDMA. Both of these drugs have been shown to facilitate the release and prevent the reuptake of 5-hydroxytryptamine (5-HT, serotonin). PMA is also a potent inhibitor of monoamine oxidase type A (MAO-A), an enzyme responsible for the catabolism of 5-HT, and this characteristic may contribute to its increased toxicity. In humans, co-administration of MDMA with the reversible MAO-A inhibitor moclobemide has led to increased apparent toxicity with ensuing fatalities. In the present study, using microdialysis, we examined the effects of co-administration of MDMA and PMA with moclobemide on extracellular concentrations of 5-HT and 5-hydroxy indol acetic acid (5-HIAA) in the striatum of the rat. 5-HT-mediated effects on body temperature and behavior were also recorded. Rats were pretreated with saline or 20 mg/kg (i.p.) moclobemide and 60 min later injected with 10 mg/kg MDMA, PMA, or saline. Dialysate samples were collected every 30 min for 5 h and analyzed by HPLC-ED. Both MDMA and PMA produced significant increases in extracellular 5-HT concentrations (590% and 360%, respectively, P < 0.05). Rats treated with PMA and MDMA displayed significantly increased 5-HT-related behaviors (P < 0.05). Furthermore, only MDMA was capable of producing additional significant increases in 5-HT concentrations (980%, P < 0.05) when co-administered with moclobemide. These data suggest that co-administration of MDMA with moclobemide increases extracellular 5-HT and 5-HT-mediated behaviors and may cause increased 5-HT related toxicity similar to that reported with PMA.

[Environmental behavior and ecological effect of polydimethylsiloxane: a review].

PubMed

Yang, Shang-Yuan; Li, Xin; Yang, Jia; Shen, Chao-Feng; Yu, Hua-Dong; Lu, Kang

2012-08-01

Polydimethylsiloxane (PDMS) is widely used in industrial products, medical and health care products, and personal care products. In the treatment process of sewage, PDMS can be hardly biodegraded but enter the environment mainly through the discharge of excess sludge, and only a small amount of PDMS adsorbed on the suspended solids or sludge particle surface is discharged into water body and sediment with treated sewage. There is no enough evidence to verify that PDMS can vertically migrate in sediment. The degradation of PDMS in sediment is very slow, but PDMS can be degraded in different types of soils. PDMS has less risk to aquatic ecosystem, and no apparent acute toxicity to benthos. In soil environment, PDMS and its degradation products have no significant effects on the soil microorganisms, soil animals, and crops. Though a few studies indicated that PDMS and its degradation products have relatively low ecological toxicity in various environments, it is still very important to clarify the potential threat of PDMS to the environment because of the increasingly large number of PDMS being produced and used.

The present status of biological effects of toxic metals in the environment: lead, cadmium, and manganese.

PubMed

Shukla, G S; Singhal, R L

1984-08-01

The number of reports concerning the chemical toxicology of metals which are released in the environment by natural as well as anthropogenic sources, have been increasing constantly. Lead, cadmium, and manganese have found a variety of uses in industry, craft, and agriculture owing to their physical and chemical properties. The environmental burden of heavy metals has been rising substantially by smelter emission in air and waste sewage in water. Further, organic compounds of lead and manganese used as antiknock substances in gasoline are emitted into the atmosphere by automobile exhaustion. Such environmental contamination of air, water, soil, and food is a serious threat to all living kinds. Although these metals are known to produce their toxic effects on a variety of body systems, much emphasis has been placed on their effects on the nervous system owing to apparent association of relatively low or "subclinical" levels of metallic exposure with behavioral and psychological disorders. Clinical and animal data on environmental exposure show that while lead and manganese are most toxic to the nervous system, cadmium exerts profound adverse effects on kidney and the male reproductive system. It appears that the consequences of exposure to lead in adults are less severe than the types of exposure associated with hyperactivity in neonates. Except for a few reports, hyperactivity has indeed been observed in animals exposed to either of these three metals. Experimental work has also shown that these metals produce behavioral changes by altering the metabolism of brain neurotransmitters, especially catecholamines. Recently, it is hypothesized that these metals exert their toxic effect by damaging biological defences which exist in the body to serve as protective mechanisms against exogenous toxins. A voluminous publication list with diverse opinions on the biological effects of metals is available and there is an urgent need to compile assessment of the existing literature to identify the future theme of research work. The problem of metal toxicity becomes even more complex owing to simultaneous or successive exposure of the general population to different physical, chemical, biological, and psychological factors in the environment. The net toxic manifestations produced by multiple exposure should, therefore, be different from those produced by a single factor as the result of their additive, synergistic or antagonistic action. Even though a metal may not exist in sufficient amounts to cause any disability, the toxicity could result when a second factor is also present.(ABSTRACT TRUNCATED AT 400 WORDS)

Antitumor effect and toxicity of free rhodium (II) citrate and rhodium (II) citrate-loaded maghemite nanoparticles in mice bearing breast cancer.

PubMed

Carneiro, Marcella Lemos Brettas; Peixoto, Raphael C A; Joanitti, Graziela A; Oliveira, Ricardo G S; Telles, Luis A M; Miranda-Vilela, Ana L; Bocca, Anamélia L; Vianna, Leonora M S; da Silva, Izabel C R; de Souza, Aparecido R; Lacava, Zulmira G M; Báo, Sônia N

2013-02-16

Magnetic fluids containing superparamagnetic iron oxide nanoparticles represent an attractive platform as nanocarriers in chemotherapy. Recently, we developed a formulation of maghemite nanoparticles coated with rhodium (II) citrate, which resulted in in vitro cytotoxicity enhanced up to 4.6 times when compared to free rhodium (II) citrate formulation on breast carcinoma cells. In this work, we evaluate the antitumor activity and toxicity induced by these formulations in Balb/c mice bearing orthotopic 4T1 breast carcinoma. Mice were evaluated with regard to the treatments' toxicity through analyses of hemogram, serum levels of alanine aminotransferase, iron, and creatinine; DNA fragmentation and cell cycle of bone marrow cells; and liver, kidney and lung histology. In addition, the antitumor activity of rhodium (II) citrate and maghemite nanoparticles coated with rhodium (II) citrate was verified by tumor volume reduction, histology and immunohistochemistry. Regarding the treatments' toxicity, no experimental groups had alterations in levels of serum ALT or creatinine, and this suggestion was corroborated by the histopathologic examination of liver and kidney of mice. Moreover, DNA fragmentation frequency of bone marrow cells was lower than 15% in all experimental groups. On the other hand, the complexes rhodium (II) citrate-functionalized maghemite and free rhodium (II) citrate led to a marked growth inhibition of tumor and decrease in CD31 and Ki-67 staining. In summary, we demonstrated that both rhodium (II) citrate and maghemite nanoparticles coated with rhodium (II) citrate formulations exhibited antitumor effects against 4T1 metastatic breast cancer cell line following intratumoral administration. This antitumor effect was followed by inhibition of both cell proliferation and microvascularization and by tumor tissue injury characterized as necrosis and fibrosis. Remarkably, this is the first published report demonstrating the therapeutic efficacy of maghemite nanoparticles coated with rhodium (II) citrate. This treatment prolonged the survival period of treated mice without inducing apparent systemic toxicity, which strengthens its use for future breast cancer therapeutic applications.

Multiplexed biosensors for detection of mycotoxins

USDA-ARS?s Scientific Manuscript database

As analytical methods have improved it has become apparent that mycotoxins exist in many forms within a commodity or food. For the established toxins there has been increased interest in the presence of metabolites that might also harbor toxicity. These include biosynthetic precursors as well as pro...

How pharmacokinetic modeling could improve a risk assessment for manganese

EPA Science Inventory

The neurotoxicity of manganese (Mn) is well established, yet the risk assessment of Mn is made complex by certain enigmas. These include apparently greatertoxicity via inhalation compared to oral exposure and greater toxicity in humans compared to rats. In addition, until recentl...

The path forward in prostate cancer therapeutics

PubMed Central

Aragon-Ching, Jeanny B; Madan, Ravi A

2018-01-01

The last decade has seen remarkable advances in the treatment of prostate cancer. Until 2010, only docetaxel had demonstrated the ability to improve the survival in metastatic castration-resistant prostate cancer (mCRPC).1 While effective, many men were reluctant to get treatment with docetaxel because of the perceived toxicity, thereby further limiting the benefit of the one available and effective therapy. Remarkably, within the last 8 years, the field has seen a multitude of therapies that demonstrate an ability to extend survival for men with prostate cancer. Abiraterone and enzalutamide demonstrated the importance of the androgen axis in propelling prostate cancer growth.23 Sipuleucel-T was immunotherapy's entry into the evolving prostate cancer armamentarium, as the therapeutic cancer vaccine established an ability to extend survival despite an apparent lack of short-term effect on progression-free survival and prostate-specific antigen (PSA).4 Radium-223 built on the palliative success of previous radiopharmaceuticals, but this alpha-emitting agent importantly had limited hematologic-related toxicity and was associated with a survival advantage, unlike its in-class predecessors.5 Cabazitaxel also emerged as a second-line chemotherapy option in patients who had already progressed on docetaxel.6 PMID:29536949

Ammonium and arsenic trioxide are potent facilitators of oligonucleotide function when delivered by gymnosis

PubMed Central

Zhang, Xiaowei; Castanotto, Daniela; Liu, Xueli; Shemi, Amotz; Stein, Cy A

2018-01-01

Abstract Oligonucleotide (ON) concentrations employed for therapeutic applications vary widely, but in general are high enough to raise significant concerns for off target effects and cellular toxicity. However, lowering ON concentrations reduces the chances of a therapeutic response, since typically relatively small amounts of ON are taken up by targeted cells in tissue culture. It is therefore imperative to identify new strategies to improve the concentration dependence of ON function. In this work, we have identified ammonium ion (NH4+) as a non-toxic potent enhancer of ON activity in the nucleus and cytoplasm following delivery by gymnosis. NH4+ is a metabolite that has been extensively employed as diuretic, expectorant, for the treatment of renal calculi and in a variety of other diseases. Enhancement of function can be found in attached and suspension cells, including in difficult-to-transfect Jurkat T and CEM T cells. We have also demonstrated that NH4+ can synergistically interact with arsenic trioxide (arsenite) to further promote ON function without producing any apparent increased cellular toxicity. These small, inexpensive, widely distributed molecules could be useful not only in laboratory experiments but potentially in therapeutic ON-based combinatorial strategy for clinical applications. PMID:29522198

Feeding on toxic prey. The praying mantis (Mantodea) as predator of poisonous butterfly and moth (Lepidoptera) caterpillars.

PubMed

Mebs, Dietrich; Wunder, Cora; Pogoda, Werner; Toennes, Stefan W

2017-06-01

Caterpillars of the monarch butterfly, Danaus plexippus, feed on milkweed plants, Asclepias spp. (Apocynaceae), and sequester their toxic cardenolides aimed at deterring predators. Nevertheless, Chinese praying mantids, Tenodera sinensis, consume these caterpillars after removing the midgut ("gutting") including its plant content. In the present study, monarch caterpillars raised on A. curassavica, and those of the death's-head hawkmoth, Acherontia atropos, raised on Atropa belladonna containing atropine, were fed to mantids, Hierodula membranacea, which removed the gut of both species discarding about 59% of cardenolides and more than 90% of atropine, respectively. The ingestion of these compounds produced no apparent ill effects in the mantids and both were excreted with faeces. On the other hand, when mantids were fed with larvae of two moth species, Amata mogadorensis and Brahmaea certia, raised on non-poisonous host plants, the mantids showed the same gutting behaviour, thereby discarding indigestible plant material. As polar compounds, e.g. cardenolides and atropine, are not absorbed from the mantids midgut and do not pass the gut membrane, this enables the mantids to feed on toxic prey. Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemopreventive effects of 13alpha,14alpha-epoxy-3beta-methoxyserratan-21beta-ol (PJJ-34), a serratane-type triterpenoid, in a rat multi-organ carcinogenesis bioassay.

PubMed

Doi, Kenichiro; Sakai, Kuniyoshi; Tanaka, Reiko; Toma, Kaori; Yamaguchi, Takashi; Wei, Min; Fukushima, Shoji; Wanibuchi, Hideki

2010-03-28

A novel serratane-type triterpenoid, 13alpha,14alpha-epoxy-3beta-methoxyserratan-21beta-ol (PJJ-34) derived from cuticles of Picea jezoensis Carr. var. jezoensis, has proved to be highly effective at suppressing carcinogenesis both in vitro and in vivo. To investigate possible anti-carcinogenic efficacy at the whole-body level, male Fischer 344 rats were subjected to an established rat multi-organ carcinogenesis bioassay (DMBDD model). After initiation with five carcinogens, groups 1-3 (20 in each) were intragastrically (i.g.) administered PJJ-34 dissolved in 1 ml of 0.5% CMC (5 times/week) at doses of 0, 5 and 10mg/kg body weight (b.w.), respectively, until the end of week 30. PJJ-34 did not show apparent toxicity. Incidences of adenomas (100-->75%) and carcinomas (63-->30%) in the lung were significantly decreased in the 5mg/kg b.w. group, and multiplicity of alveolar hyperplasias and total lung tumors (adenomas+carcinomas) were significantly reduced by both 5 and 10mg/kg. The incidence of colorectal tumors was also significantly decreased in the 10mg/kg group (63-->28%) along with the multiplicity. Rat liver pre-neoplastic lesions, glutathione S-transferase placental form (GST-P) foci, and tumor development in the other organs were not affected. Immunohistochemical indices for proliferating cell nuclear antigen (PCNA) and cyclin D1 in normal alveolar epithelium of the lung were significantly suppressed at both doses. In conclusion, PJJ-34 is chemopreventive against lung and colon carcinogenesis without exerting apparent toxicity, and suppression of cell proliferation could play a key role in the underlying mechanisms. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

Inhibition of CYP6B1-mediated detoxification of xanthotoxin by plant allelochemicals in the black swallowtail (Papilio polyxenes).

PubMed

Wen, Zhimou; Berenbaum, May R; Schuler, Mary A

2006-03-01

The structural and biosynthetic diversity of allelochemicals in plants is thought to arise from selection for additive toxicity as a consequence of toxin mixture or for enhanced toxicity as a result of synergism. In order to understand how insects cope with this type of plant defense, we tested the effects of some allelochemicals in host plants of the black swallowtail Papilio polyxenes on the xanthotoxin-metabolic activity of CYP6B1, the principal enzyme responsible for the detoxification of furanocoumarins in this caterpillar. Additionally, the effects of some synthetic compounds not normally encountered by P. polyxenes on CYP6B1 were tested. These studies demonstrate that the integrity of furanocoumarin structure is important for competitive binding to the active site of CYP6B1, even though the carbonyl group on the pyranone ring apparently does not affect its inhibitory capacity, as in the case of furanochromones. Angular furanocoumarins are generally less phototoxic to many organisms than linear furanocoumarins due to their reduced capacity for cross-linking DNA strands, yet they are more toxic than linear furanocoumarins to black swallowtail larvae. This enhanced toxicity in vivo may be due to the ability of angular furanocoumarins to bind to the active site of CYP6B1 without being rapidly metabolized. This binding reduces the availability of CYP6B1 to metabolize other linear furanocoumarins. The structure-activity relationships for methylenedioxyphenyl compounds, flavonoids, imidazole, and imidazole derivatives are also discussed in light of their capacity to inhibit the xanthotoxin-metabolic activity of CYP6B1.

High pH ammonia toxicity, and the search for life on the Jovian planets.

PubMed

Deal, P H; Souza, K A; Mack, H M

1975-10-01

Jovian plants have enviroments apparently suitable for the evolution of life, but nevertheless, present severe challenges to organisms. One such challenge arises from the presence of ammonia. Ammonia is an efficient biocide, its effect being dependent on pH as well as on concentration. The effects of pH and ammonia concentration were studied separately, where possible, on a variety of organisms, including some isolated from natural enviornments of high pH and/or ammonia concentration. Escherichia coli and Bacillus subtilis are both extremely sensitive to ammonia. An aerobic organism (growth up to pH 11.4) from an alkaline spring is more resistant, but exhibits a toxic response to ammonia at a pH much lower than its maximum for growth. The greatest ammonia resistance has been found in an unidentified organism growing at near neutral pH. Even in this case, however, survival at ammonia concentrations reasonably expected on the Jovian planets is measured in hours. This is, nevertheless, two to three orders of magnitude longer than for E. coli. Our data support the tentative conclusion that contamination of the Jovian planets with terrestrial organisms that can grow is unlikely. However, the range of toxic response noted, coupled with the observation that terrestrial life has not been exposed to high ammonia concentrations for millions of years, suggests that adaptation to greater ammonia tolerance may be possible.

ROLE OF PROTEIN BINDING IN THE URINARY EXCRETION OF PBDES IN MICE

EPA Science Inventory

Polybrominated diphenyl ethers (PBDEs) are commercial chemical products used to prevent combustion of various

consumer goods. Concern for PBDEs has risen due to their detection in the environment and in human biota,

apparent persistence, and potential toxicity. The ...

Comparative transfection of DNA into primary and transformed mammalian cells from different lineages

PubMed Central

2010-01-01

Background The delivery of DNA into human cells has been the basis of advances in the understanding of gene function and the development of genetic therapies. Numerous chemical and physical approaches have been used to deliver the DNA, but their efficacy has been variable and is highly dependent on the cell type to be transfected. Results Studies were undertaken to evaluate and compare the transfection efficacy of several chemical reagents to that of the electroporation/nucleofection system using both adherent cells (primary and transformed airway epithelial cells and primary fibroblasts as well as embryonic stem cells) and cells in suspension (primary hematopoietic stem/progenitor cells and lymphoblasts). With the exception of HEK 293 cell transfection, nucleofection proved to be less toxic and more efficient at effectively delivering DNA into the cells as determined by cell proliferation and GFP expression, respectively. Lipofectamine and nucleofection of HEK 293 were essentially equivalent in terms of toxicity and efficiency. Transient transfection efficiency in all the cell systems ranged from 40%-90%, with minimal toxicity and no apparent species specificity. Differences in efficiency and toxicity were cell type/system specific. Conclusions In general, the Amaxa electroporation/nucleofection system appears superior to other chemical systems. However, there are cell-type and species specific differences that need to be evaluated empirically to optimize the conditions for transfection efficiency and cell survival. PMID:20144189

Apolipoprotein E expression and behavioral toxicity of high charge, high energy (HZE) particle radiation

NASA Technical Reports Server (NTRS)

Higuchi, Yoshinori; Nelson, Gregory A.; Vazquez, Marcelo; Laskowitz, Daniel T.; Slater, James M.; Pearlstein, Robert D.

2002-01-01

Apolipoprotein E (apoE) is a lipid binding protein that plays an important role in tissue repair following brain injury. In the present studies, we have investigated whether apoE affects the behavioral toxicity of high charge, high energy (HZE) particle radiation. METHODS: Sixteen male apoE knockout (KO) mice and sixteen genetically matched wild-type (WT) C57BL mice were used in this experiment. Half of the KO and half of the WT animals were irradiated with 600 MeV/amu iron particles (2 Gy whole body). The effect of irradiation on motor coordination and stamina (Rotarod test), exploratory behavior (open field test), and spatial working and reference memory (Morris water maze) was assessed. ROTAROD TEST: Performance was adversely affected by radiation exposure in both KO and WT groups at 30 d after irradiation. By 60 d after radiation, the radiation effect was lost in WT, but still apparent in irradiated KO mice. OPEN FIELD TEST: Radiation reduced open field exploratory activity 14, 28, 56, 84, and 168 d after irradiation of KO mice, but had no effect on WT mice. MORRIS WATER MAZE: Radiation adversely affected spatial working memory in the KO mice, but had no discernible effect in the WT mice as assessed 180 d after irradiation. In contrast, irradiated WT mice showed marked impairment of spatial reference memory in comparison to non-irradiated mice, while no effect of radiation was observed in KO mice. CONCLUSIONS: These studies show that apoE expression influences the behavioral toxicity of HZE particle radiation and suggest that apoE plays a role in the repair/recovery from radiation injury of the CNS. ApoE deficiency may exacerbate the previously reported effects of HZE particle radiation in accelerating the brain aging process.

Application of hydroxy aluminum treated clays to waste water treatment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nolan, T.F.; Fogler, H.S.

1985-01-01

Concern over the possible health effects of chlorinated biphenyls and dibenzodioxins has a scientific basis. Polychlorinated biphenyls are known mutagens and tetragens. The toxicological properties of 2,3,7,8-TCDD are well documented. One study found that 2,3,7,8-TCDD had higher inherent toxicity for mice than better known poisons; sodium cyanide, strychnine, and diphtheria toxin. It is apparent that development of technologies for the reduction of chlorinated polycyclics in the environment is desirable. It has been demonstrated that hydroxyl aluminum treatment of clay can produce an extremely powerful sorbent; even more powerful for octachlorodibenzodioxin than previously reported. The results indicate that the treatment proceduremore » is effective for several different clays.« less

Necroptosis-inducing rhenium(V) oxo complexes.

PubMed

Suntharalingam, Kogularamanan; Awuah, Samuel G; Bruno, Peter M; Johnstone, Timothy C; Wang, Fang; Lin, Wei; Zheng, Yao-Rong; Page, Julia E; Hemann, Michael T; Lippard, Stephen J

2015-03-04

Rhenium(V) oxo complexes of general formula [ReO(OMe)(N^N)Cl2], where N^N = 4,7-diphenyl-1,10-phenanthroline, 1, or 3,4,7,8-tetramethyl-1,10-phenanthroline, 2, effectively kill cancer cells by triggering necroptosis, a non-apoptotic form of cell death. Both complexes evoke necrosome (RIP1-RIP3)-dependent intracellular reactive oxygen species (ROS) production and propidium iodide uptake. The complexes also induce mitochondrial membrane potential depletion, a possible downstream effect of ROS production. Apparently, 1 and 2 are the first rhenium complexes to evoke cellular events consistent with programmed necrosis in cancer cells. Furthermore, 1 and 2 display low acute toxicity in C57BL/6 mice and reasonable stability in fresh human blood.

Necroptosis-Inducing Rhenium(V) Oxo Complexes

PubMed Central

Suntharalingam, Kogularamanan; Awuah, Samuel G.; Bruno, Peter M.; Johnstone, Timothy C.; Wang, Fang; Lin, Wei; Zheng, Yao-Rong; Page, Julia E.; Hemann, Michael T.; Lippard, Stephen J.

2015-01-01

Rhenium(V) oxo complexes of general formula [ReO(OMe)(N^N)Cl2], where N^N = 4,7-diphenyl-1,10-phenanthroline, 1, or 3,4,7,8-tetramethyl-1,10-phenanthroline, 2, effectively kill cancer cells by triggering necroptsosis, a non-apoptotic form of cell death. Both complexes evoke necrosome (RIP1-RIP3)-dependent intracellular ROS production and propidium iodide uptake. The complexes also induce mitochondrial membrane potential depletion, a possible downstream effect of ROS production. Apparently, 1 and 2 are the first rhenium complexes to evoke cellular events consistent with programmed necrosis in cancer cells. Furthermore, 1 and 2 display low acute toxicity in C57BL/6 mice and reasonable stability in fresh human blood. PMID:25698398

JV Task 96 - Phase 2 - Investigating the Importance of the Mercury-Selenium Interaction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nicholas Ralston; Laura Raymond

2008-03-01

In order to improve the understanding of the mercury issue, it is vital to study mercury's effects on selenium physiology. While mercury present in the environment or food sources may pose health risks, the protective effects of selenium have not been adequately considered in establishing regulatory policy. Numerous studies report that vulnerability to mercury toxicity is inversely proportional to selenium status or level. However, selenium status has not been considered in the development of the reference dosage levels for mercury exposure. Experimental animals fed low-selenium diets are far more vulnerable to mercury toxicity than animals fed normal selenium, and animalsmore » fed selenium-rich diets are even more resistant. Selenium-dependent enzymes in brain and endocrine tissues can be impaired by excessive mercury exposure, apparently because mercury has an extremely high binding affinity for selenium. When selenium becomes bound to mercury, it is unable to participate in the metabolic cycling of selenoprotein synthesis. Because of mercury-dependent impairments of selenoprotein synthesis, various antioxidant and regulatory functions in brain biochemistry are compromised. This report details a 2-year multiclient-funded research program designed to examine the interactions between mercury and selenium in animal models. The studies explored the effects of dietary intakes of toxic amounts of methylmercury and the protective effects of the normal dietary range of selenium in counteracting mercury toxicity. This study finds that the amounts of selenium present in ocean fish are sufficient to protect against far larger quantities of methylmercury than those present in typical seafoods. Toxic effects of methylmercury exposure were not directly proportional to mercury concentrations in blood, brain, or any other tissues. Instead, mercury toxicity was proportional to molar ratios of mercury relative to selenium. In order to accurately assess risk associated with methylmercury or mercury exposures, mercury-selenium ratios appear to be far more accurate and effective in identifying risk and protecting human and environmental health. This study also finds that methylmercury toxicity can be effectively treated by dietary selenium, preventing the death and progressive disabilities that otherwise occur in methylmercury-treated subjects. Remarkably, the positive response to selenium therapy was essentially equivalent regardless of whether or not toxic amounts of methylmercury were still administered. The findings of the Physiologically Oriented Integration of Nutrients and Toxins (POINT) models of the effects of mercury and selenium developed in this project are consistent with the hypothesis that mercury toxicity arises because of mercury-dependent inhibition of selenium availability in brain and endocrine tissues. This appears to occur through synergistic effects of mercury-dependent inhibition of selenium transport to these tissues and selective sequestration of the selenium present in the tissues. Compromised transport of selenium to the brain and endocrine tissues would be particularly hazardous to the developing fetus because the rapidly growing tissues of the child have no selenium reserves. Therefore, maternal consumption of foods with high mercury-selenium ratios is hazardous. In summation, methylmercury exposure is unlikely to cause harm in populations that eat selenium-rich diets but may cause harm among populations that consume certain foods that have methylmercury present in excess of selenium.« less

PLATFORM SESSION "IMMUNOTOXICOLOGY", SOCIETY OF TOXICOLOGY 45TH ANNUAL MEETING, MARCH 5-9, 2006, SAN DIEGO, CA

EPA Science Inventory

For many years the primary endpoints for evaluating the toxicity of xenobiotics were carcinogenicity and mutagenicity. However, it gradually became apparent that exposure to chemicals at levels lower than those shown to be directly carcinogenic may negatively impact other facets...

Degradable Molybdenum Oxide Nanosheets with Rapid Clearance and Efficient Tumor Homing Capabilities as a Therapeutic Nanoplatform.

PubMed

Song, Guosheng; Hao, Jiali; Liang, Chao; Liu, Teng; Gao, Min; Cheng, Liang; Hu, Junqing; Liu, Zhuang

2016-02-05

Molybdenum oxide (MoOx) nanosheets with high near-infrared (NIR) absorbance and pH-dependent oxidative degradation properties were synthesized, functionalized with polyethylene glycol (PEG), and then used as a degradable photothermal agent and drug carrier. The nanosheets, which are relatively stable under acidic pH, could be degraded at physiological pH. Therefore, MoOx-PEG distributed in organs upon intravenous injection would be rapidly degraded and excreted without apparent in vivo toxicity. MoOx-PEG shows efficient accumulation in tumors, the acidic pH of which then leads to longer tumor retention of those nanosheets. Along with the capability of acting as a photothermal agent for effective tumor ablation, MoOx-PEG can load therapeutic molecules with high efficiencies. This concept of inorganic theranostic nanoagent should be relatively stable in tumors to allow imaging and treatment, while being readily degradable in normal organs to enable rapid excretion and avoid long-term retention/toxicity. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Cellulose nanocrystals from grape pomace: Production, properties and cytotoxicity assessment.

PubMed

Coelho, Caroline C S; Michelin, Michele; Cerqueira, Miguel A; Gonçalves, Catarina; Tonon, Renata V; Pastrana, Lorenzo M; Freitas-Silva, Otniel; Vicente, António A; Cabral, Lourdes M C; Teixeira, José A

2018-07-15

Cellulose nanocrystals (CNCs) were obtained from grape pomace through chemical and physical pretreatments. Bleached cellulose pulp was subjected to acid hydrolysis (AH) for 30 or 60 min and an ultrasound treatment to obtain CNCs (AH 30S and AH 60S ). Compositional analyses of untreated (UGP) and pretreated (PGP) grape pomace showed the effectiveness of pretreatment in removing non-cellulosic components, recovering 80.1% cellulose in PGP (compared to 19.3% of UGP). Scanning and transmission electron microscopies were used to evaluate the CNCs morphology. AH in combination with ultrasound treatment led to needle-shaped structures and apparently more dispersed suspensions. Crystallinity index and thermal stability were studied by X-ray diffraction and thermogravimetric analysis, respectively. The AH 60S sample presented high aspect ratio, crystallinity and thermal stability. CNCs toxicity was evaluated by exposing Caco-2 cells to CNCs suspension and evaluating their viability. Results showed that CNCs are non-toxic, opening the opportunity for their use on food and pharmaceutical applications. Copyright © 2018 Elsevier Ltd. All rights reserved.

HAMLET kills tumor cells by apoptosis: structure, cellular mechanisms, and therapy.

PubMed

Gustafsson, Lotta; Hallgren, Oskar; Mossberg, Ann-Kristin; Pettersson, Jenny; Fischer, Walter; Aronsson, Annika; Svanborg, Catharina

2005-05-01

New cancer treatments should aim to destroy tumor cells without disturbing normal tissue. HAMLET (human alpha-lactalbumin made lethal to tumor cells) offers a new molecular approach to solving this problem, because it induces apoptosis in tumor cells but leaves normal differentiated cells unaffected. After partial unfolding and binding to oleic acid, alpha-lactalbumin forms the HAMLET complex, which enters tumor cells and freezes their metabolic machinery. The cells proceed to fragment their DNA, and they disintegrate with apoptosis-like characteristics. HAMLET kills a wide range of malignant cells in vitro and maintains this activity in vivo in patients with skin papillomas. In addition, HAMLET has striking effects on human glioblastomas in a rat xenograft model. After convection-enhanced delivery, HAMLET diffuses throughout the brain, selectively killing tumor cells and controlling tumor progression without apparent tissue toxicity. HAMLET thus shows great promise as a new therapeutic with the advantage of selectivity for tumor cells and lack of toxicity.

Aquatic plants for removal of mevinphos from the aquatic environment

NASA Technical Reports Server (NTRS)

Wolverton, B. C.

1975-01-01

Fragrant waterlily (Nymphaea odorata, Ait.), joint-grass (Paspalum distichum L.), and rush (Juncus repens, Michx.) were used to evaluate the effectiveness of vascular aquatic plants in removing the insecticide mevinphos (dimethyl-1-carbomethoxy-1propen-2-yl phosphate) from waters contaminated with this chemical. The emersed aquatic plants fragrant waterlily and joint-grass removed 87 and 93 ppm of mevinphos from water test systems in less than 2 weeks without apparent damage to the plants; whereas rush, a submersed plant, removed less insecticide than the water-soil controls. Water-soil control still contained toxic levels of this insecticide, as demonstrated by fish bioassay studies, after 35 days.

The effects of a salicylate, ibuprofen, and naproxen on the disposition of methotrexate in patients with rheumatoid arthritis.

PubMed

Tracy, T S; Krohn, K; Jones, D R; Bradley, J D; Hall, S D; Brater, D C

1992-01-01

We have studied the pharmacokinetics of methotrexate in patients with rheumatoid arthritis concurrently treated with choline magnesium trisalicylate, ibuprofen, naproxen, or a non-NSAID analgesic (control treatment). The apparent systemic clearance of methotrexate was significantly reduced by all three treatments. Trisalicylate and ibuprofen both significantly reduced methotrexate renal clearance, but only the trisalicylate significantly displaced methotrexate from protein, increasing the fraction unbound by 28%. These data show that NSAIDs can affect the disposition of methotrexate, possibly increasing the potential for toxicity and necessitating dosage adjustments. However, large inter-subject variability precludes specific dosage recommendations.

Avoiding false positives and optimizing identification of true ...

EPA Pesticide Factsheets

The potential for chemicals to affect endocrine signaling is commonly evaluated via in vitro receptor binding and gene activation, but these assays, especially antagonism assays, have potential artifacts that must be addressed for accurate interpretation. Results are presented from screening 94 chemicals from 54 chemical groups for estrogen receptor (ER) activation in a competitive rainbow trout ER (rtER) binding assay and a trout liver slice vitellogenin mRNA expression assay. Results from true competitive agonists and antagonists, and inactive chemicals with little or no indication of ER binding or gene activation were easily interpreted. However, results for numerous industrial chemicals were more challenging to interpret, including chemicals with: (1) apparent competitive binding curves but no gene activation, (2) apparent binding and gene inhibition with evidence of either cytotoxicity or changes in assay media pH, (3) apparent binding but non-competitive gene inhibition of unknown cause, or (4) no rtER binding and gene inhibition not due to competitive ER interaction but due to toxicity, pH change, or some unknown cause. The use of endpoints such as toxicity, pH, precipitate formation, and determination of inhibitor dissociation constants (Ki) for interpreting the results of antagonism and binding assays for diverse chemicals is presented. Of the 94 chemicals tested for antagonism only two, tamoxifen and ICI-182,780, were found to be true competitive

Tumor regression with a combination of drugs interfering with the tumor metabolism: efficacy of hydroxycitrate, lipoic acid and capsaicin.

PubMed

Schwartz, Laurent; Guais, Adeline; Israël, Maurice; Junod, Bernard; Steyaert, Jean-Marc; Crespi, Elisabetta; Baronzio, Gianfranco; Abolhassani, Mohammad

2013-04-01

Cellular metabolic alterations are now well described as implicated in cancer and some strategies are currently developed to target these different pathways. In previous papers, we demonstrated that a combination of molecules (namely alpha-lipoic acid and hydroxycitrate, i.e. Metabloc™) targeting the cancer metabolism markedly decreased tumor cell growth in mice. In this work, we demonstrate that the addition of capsaicin further delays tumor growth in mice in a dose dependant manner. This is true for the three animal model tested: lung (LLC) cancer, bladder cancer (MBT-2) and melanoma B16F10. There was no apparent side effect of this ternary combination. The addition of a fourth drug (octreotide) is even more effective resulting in tumor regression in mice bearing LLC cancer. These four compounds are all known to target the cellular metabolism not its DNA. The efficacy, the apparent lack of toxicity, the long clinical track records of these medications in human medicine, all points toward the need for a clinical trial. The dramatic efficacy of treatment suggests that cancer may simply be a disease of dysregulated cellular metabolism.

Enhanced tetrazolium violet reduction of Salmonella spp. by magnesium addition to the culture media.

PubMed

Junillon, Thomas; Morand, Lucie; Flandrois, Jean Pierre

2014-09-01

Tetrazolium salts (TTZ), such as tetrazolium violet (TV), have been widely used for microbiological studies. The formation of the colored formazan product due to bacterial reduction of the uncolored reagent is extensively exploited to stain cells or colonies in agar or on filters. But an important toxic effect of tetrazolium salts on bacteria exists that limits their use at high concentrations, impairing the efficient staining of the colonies. This is especially the case for Salmonella spp. where we observed, using a classic photometric approach and mathematical modeling of the growth, an important impact of tetrazolium violet on the apparent growth rate below the inhibitory concentration. In this study, we demonstrate that adding magnesium to the medium in the presence of TV leads to a significant increase in the apparent growth rate. Moreover, when higher TV concentrations are used which lead to total inhibition of Salmonella strains, magnesium addition to the culture media allows growth and TV reduction. This effect of magnesium may allow the use of higher TTZ concentrations in liquid growth media and enhance bacteria detection capabilities. Copyright © 2014 Elsevier Ltd. All rights reserved.

Response of brown treesnakes to reduction of their rodent prey

USGS Publications Warehouse

Gragg, J.E.; Rodda, G.H.; Savidge, J.A.; White, Gary C.; Dean-Bradley, K.; Ellingson, A.R.

2007-01-01

Trapping brown treesnakes (Boiga irregularis; BTS) with live-mouse (Mus domesticus) lures is the principal control technique for this invasive species on Guam. Lure-based trapping is also used on other islands as a precaution against undetected arrivals and in response to verified BTS sightings. However, the effectiveness of lure-based trapping on other islands is questionable, as it has yielded no BTS despite other evidence of their presence. Some evidence suggests that high rodent numbers may interfere with BTS control. To test the relationship between rodent abundance and snake trappability, we conducted a controlled, replicated field experiment incorporating a rodenticide treatment during a BTS mark-recapture study. Using open population modeling in Program MARK, we estimated BTS apparent survival and recapture probabilities. Rodent reduction increased BTS recapture probabilities by 52-65% in 2002 and 22-36% in 2003, and it decreased apparent survival by <1% both years. This appears to be the first published instance of manipulating wild prey to influence snake behavior. Rodent reduction may enhance detection and control of BTS with traps on Guam and other islands. It may also amplify the effectiveness of oral toxicants against BTS.

Medical Machiavellianism: the tradeoff between benefit and harm with targeted chemotherapy

PubMed Central

Oronsky, Bryan; Carter, Corey; Scicinska, Anna; Oronsky, Arnold; Oronsky, Neil; Lybeck, Michelle; Scicinski, Jan

2016-01-01

Machiavellianism is a word synonymous with the phrase “the end justifies the means”, and in this article we have coined the term Medical Machiavellianism to describe the ‘cruel-to-be-kind’ administration of toxic chemotherapeutic agents in apparent violation of the precept first do no harm, while acknowledging the ‘dirty hands’ dilemma of having to decide between and choose the lesser of two evils in the setting of advanced cancer—i.e. to treat or not to treat. The perception that ‘targeted’ therapies are relatively non-toxic and therefore respect the Hippocratic First Commandment by virtue of their narrow selectivity is belied by their often inherent promiscuity, addressing multiple targets either inadvertently or deliberately, which may result in multiple side effects. The remarkable success of immunotherapy may have taken the bloom off the ‘targeted agent’ rose, however due to a lack of other approved treatment alternatives the toxicity of these agents may be overlooked or, at least, undervalued, especially given that the official measure of treatment success in oncology is overall survival (OS), not quality-of-life improvements. By analogy with the MACH-IV personality survey (1970), [1] which measures high and low Machiavellian orientation, we have defined in this article a rudimentary MACH scale for selected targeted chemotherapies, based on the means-to-ends ratio of toxicity and benefit. It is our hope that this comparison between targeted agents will itself function as a means to an end—to help oncologists strike the right balance between efficacy, toxicity and quality of life in the management of their patients. PMID:26814434

Effects of microcystin-LR, cylindrospermopsin and a microcystin-LR/cylindrospermopsin mixture on growth, oxidative stress and mineral content in lettuce plants (Lactuca sativa L.).

PubMed

Freitas, Marisa; Azevedo, Joana; Pinto, Edgar; Neves, Joana; Campos, Alexandre; Vasconcelos, Vitor

2015-06-01

Toxic cyanobacterial blooms are documented worldwide as an emerging environmental concern. Recent studies support the hypothesis that microcystin-LR (MC-LR) and cylindrospermopsin (CYN) produce toxic effects in crop plants. Lettuce (Lactuca sativa L.) is an important commercial leafy vegetable that supplies essential elements for human nutrition; thus, the study of its sensitivity to MC-LR, CYN and a MC-LR/CYN mixture is of major relevance. This study aimed to assess the effects of environmentally relevant concentrations (1, 10 and 100 µg/L) of MC-LR, CYN and a MC-LR/CYN mixture on growth, antioxidant defense system and mineral content in lettuce plants. In almost all treatments, an increase in root fresh weight was obtained; however, the fresh weight of leaves was significantly decreased in plants exposed to 100 µg/L concentrations of each toxin and the toxin mixture. Overall, GST activity was significantly increased in roots, contrary to GPx activity, which decreased in roots and leaves. The mineral content in lettuce leaves changed due to its exposure to cyanotoxins; in general, the mineral content decreased with MC-LR and increased with CYN, and apparently these effects are time and concentration-dependent. The effects of the MC-LR/CYN mixture were almost always similar to the single cyanotoxins, although MC-LR seems to be more toxic than CYN. Our results suggest that lettuce plants in non-early stages of development are able to cope with lower concentrations of MC-LR, CYN and the MC-LR/CYN mixture; however, higher concentrations (100 µg/L) can affect both lettuce yield and nutritional quality. Copyright © 2015 Elsevier Inc. All rights reserved.

Friend or Foe? The Current Epidemiologic Evidence on Selenium and Human Cancer Risk

PubMed Central

Vinceti, Marco; Crespi, Catherine M.; Malagoli, Carlotta; Del Giovane, Cinzia; Krogh, Vittorio

2013-01-01

Scientific opinion on the relationship between selenium and the risk of cancer has undergone radical change over the years, with selenium first viewed as a possible carcinogen in the 1940s then as a possible cancer preventive agent in the 1960s–2000s. More recently, randomized controlled trials have found no effect on cancer risk but suggest possible low-dose dermatologic and endocrine toxicity, and animal studies indicate both carcinogenic and cancer-preventive effects. A growing body of evidence from human and laboratory studies indicates dramatically different biological effects of the various inorganic and organic chemical forms of selenium, which may explain apparent inconsistencies across studies. These chemical form-specific effects also have important implications for exposure and health risk assessment. Overall, available epidemiologic evidence suggests no cancer preventive effect of increased selenium intake in healthy individuals and possible increased risk of other diseases and disorders. PMID:24171437

Is senna laxative use associated to cathartic colon, genotoxicity, or carcinogenicity?

PubMed

Morales, M A; Hernández, D; Bustamante, S; Bachiller, I; Rojas, A

2009-01-01

Due to their natural origin, apparent low oral toxicity, effectiveness, and accessibility without a medical prescription, the anthranoid laxatives are a popular remedy for constipation and are frequently used abusively. Therefore, it is important to characterize its harmful and/or toxic effects. The sennosides, main active metabolites of senna, exhibit a very low toxicity in rats, and its genotoxic activity in bacterial strains as well as mammal cells was classified as weak in those cases where it was shown to be significant. The toxicological and mutagenic status of the crude extract of senna, however, is not as well characterized, and it is necessary to do so since it is frequently, and at the same time incorrectly, believed that the chronic use of anthranoid laxatives is a risk factor for the development of colorectal cancer. The objective of this article was to review the information that arises in various scientific medical databases using key words such as senna, sen, Senna alexandrina, Cassia angustifolia, sennosides, laxative toxicity, mainly ISI and non-ISI articles of journals with an editorial committee. Web pages of products or companies that publicize or commercialize this type of laxative were not included. This analysis establishes that (1) there is no convincing evidence that the chronic use of senna has, as a consequence, a structural and/or functional alteration of the enteric nerves or the smooth intestinal muscle, (2) there is no relation between long-term administration of a senna extract and the appearance of gastrointestinal tumors or any other type in rats, (3) senna is not carcinogenic in rats even after a two-year daily dose of up to 300 mg/kg/day, and (4) the current evidence does not show that there is a genotoxic risk for patients who take laxatives containing senna extracts or sennosides.

Evaluation of acute toxicity and anti-ulcerogenic study of rhizome starch of two source plants of Tugaksheeree (Curcuma angustifolia Roxb. and Maranta arundinacea Linn.).

PubMed

Rajashekhara, N; Ashok, B K; Sharma, Parmeshwar P; Ravishankar, B

2014-01-01

Disorders like hyperacidity and gastric ulcers are found very frequently now days because of a faulty lifestyle. Starches (Satwa) obtained from the rhizomes of two plants namely, Curcuma angustifolia Roxb. (Fam. Zingiberaceae) and Maranta arundinacea Linn. (Fam. Marantaceae) are used in folklore practice, as Tugaksheeree, for the treatment of the above-mentioned complaints. To assess the acute toxicity potential of the C. angustifolia and M. arundinacea along with their assessment for adaptogenic activity, by noting their effect on forced swimming-induced hypothermia and gastric ulceration in rats. For acute toxicity study, the effect of test drugs C. angustifolia and M. arundinacea rhizome starch were studied after a single administration of up to three dose levels, with 4400 mg/kg as the maximum dose. The animals were observed for 72 hours periodically and mortality was recorded up to seven days. The adaptogenic and anti-ulcer activities were assessed by determining and comparing the changes in rectal temperature, ponderal changes, ulcer index and histopathological parameters in the test drug group with that of stress control group. Both the drugs did not produce any toxic symptoms or mortality even up to the maximum dose level of 4400 mg/kg. Both the test drugs significantly reversed the stress-induced gastric ulceration in comparison to stress-control rats. Starch from rhizome of C. angustifolia reversed forced swimming-induced hypothermia apparently, but not to a significant extent. However, the reversal of hypothermia found statistically significant in the rhizome starch of the M. arundinacea treated group. M. arundinacea had better anti-stress activity in comparision to C. angustifolia.

Behavioral responses of juvenile Daphnia magna after exposure to glyphosate and glyphosate-copper complexes.

PubMed

Hansen, Lone Rykær; Roslev, Peter

2016-10-01

Glyphosate (N-(phosphonomethyl)glycine) is the active ingredient in a range of popular broad-spectrum herbicide formulations. Glyphosate is a chelating agent that can form stable complexes with divalent metal ions including Cu(II). Little is known about the bioavailability and ecotoxicity of glyphosate-Cu(II) complexes to aquatic organisms. In this study, we used video tracking and behavior analysis to investigate sublethal effects of binary mixtures of glyphosate and Cu(II) to juvenile D. magna. Behavioral responses were quantified for individual D. magna after 24h and 48h exposure to glyphosate and glyhosate-Cu(II) mixtures. Sublethal concentrations resulted in decreases in swimming velocity, acceleration speed, and distance moved whereas inactive time of D. magna increased. Distance moved and inactive time were the most responsive parameters to glyphosate and glyphosate-Cu(II) exposure. On a molar basis, glyphosate-Cu(II) complexes appeared more toxic to D. magna than glyphosate alone. The 48h EC50 for glyphosate and glyphosate-Cu(II) determined from swimming distance were 75.2μM and 8.4μM, respectively. In comparison, traditional visual observation of mobility resulted in 48h EC50 values of 52.8μM and 25.5μM for glyphosate and glyphosate-Cu(II), respectively. The behavioral responses indicated that exposure of D. magna to mixtures of glyphosate and Cu(II) attenuated acute metal toxicity but increased apparent glyphosate toxicity due to complexation with Cu(II). The study suggests that glyphosate is a likely mediator of aquatic metal toxicity, and that video tracking provides an opportunity for quantitative studies of sublethal effects of pesticide complexes. Copyright © 2016 Elsevier B.V. All rights reserved.

A non-proteinaceous toxin from the venomous spines of the lionfish Pterois volitans (Linnaeus).

PubMed

Nair, M S; Cheung, P; Leong, I; Ruggieri, G D

1985-01-01

The venomous spines of P. volitans contain a non-proteinaceous ichthyotoxin of low molecular weight. This toxin could be isolated only from spines excised from the living fish; the toxin is apparently destroyed following death, as the extracts of the spines of the dead fish were non-toxic.

The taste of toxicity: A quantitative analysis of bitter and toxic molecules.

PubMed

Nissim, Ido; Dagan-Wiener, Ayana; Niv, Masha Y

2017-12-01

The role of bitter taste-one of the few basic taste modalities-is commonly assumed to signal toxicity and alert animals against consuming harmful compounds. However, it is known that some toxic compounds are not bitter and that many bitter compounds have negligible toxicity while having important health benefits. Here we apply a quantitative analysis of the chemical space to shed light on the bitterness-toxicity relationship. Using the BitterDB dataset of bitter molecules, The BitterPredict prediction tool, and datasets of toxic compounds, we quantify the identity and similarity between bitter and toxic compounds. About 60% of the bitter compounds have documented toxicity and only 56% of the toxic compounds are known or predicted to be bitter. The LD 50 value distributions suggest that most of the bitter compounds are not very toxic, but there is a somewhat higher chance of toxicity for known bitter compounds compared to known nonbitter ones. Flavonoids and alpha acids are more common in the bitter dataset compared with the toxic dataset. In contrast, alkaloids are more common in the toxic datasets compared to the bitter dataset. Interestingly, no trend linking LD 50 values with the number of activated bitter taste receptors (TAS2Rs) subtypes is apparent in the currently available data. This is in accord with the newly discovered expression of TAS2Rs in several extra-oral tissues, in which they might be activated by yet unknown endogenous ligands and play non-gustatory physiological roles. These results suggest that bitter taste is not a very reliable marker for toxicity, and is likely to have other physiological roles. © 2017 IUBMB Life, 69(12):938-946, 2017. © 2017 International Union of Biochemistry and Molecular Biology.

Exposure-related health effects of silver and silver compounds: a review.

PubMed

Drake, Pamela L; Hazelwood, Kyle J

2005-10-01

A critical review of studies examining exposures to the various forms of silver was conducted to determine if some silver species are more toxic than others. The impetus behind conducting this review is that several occupational exposure limits and guidelines exist for silver, but the values for each depend on the form of silver as well as the individual agency making the recommendations. For instance, the American Conference of Governmental Industrial Hygienists has established separate threshold limit values for metallic silver (0.1 mg/m3) and soluble compounds of silver (0.01 mg/m3). On the other hand, the permissible exposure limit (PEL) recommended by the Occupational Safety and Health Administration and the Mine Safety and Health Administration and the recommended exposure limit set by the National Institute for Occupational Safety and Health is 0.01 mg/m3 for all forms of silver. The adverse effects of chronic exposure to silver are a permanent bluish-gray discoloration of the skin (argyria) or eyes (argyrosis). Most studies discuss cases of argyria and argyrosis that have resulted primarily from exposure to the soluble forms of silver. Besides argyria and argyrosis, exposure to soluble silver compounds may produce other toxic effects, including liver and kidney damage, irritation of the eyes, skin, respiratory, and intestinal tract, and changes in blood cells. Metallic silver appears to pose minimal risk to health. The current occupational exposure limits do not reflect the apparent difference in toxicities between soluble and metallic silver; thus, many researchers have recommended that separate PELs be established.

Comparative developmental toxicity of planar polychlorinated biphenyl congeners in chickens, American kestrels, and common terns

USGS Publications Warehouse

Hoffman, D.J.; Melancon, M.J.; Klein, P.N.; Eisemann, J.D.; Spann, J.W.

1998-01-01

The effects of PCB congeners, PCB 126 (3,3',4,4',5-pentaCB) and PCB 77 (3,3'4,4'-tetraCB), were examined in chicken (Gallus gallus), American kestrel (Falco sparverius), and common tern (Sterna hirundo) embryos through hatching, following air cell injections on day 4. PCB 126 caused malformations and edema in chickens starting at 0.3 ppb, in kestrels at 2.3 ppb, but in terns only at levels affecting hatching success (44 ppb). Extent of edema was most severe in chickens and least in terns. Defects of the beak were common in all species, but with crossed beak most prevalent in terns. Effects on embryo growth were most apparent for PCB 126 in chickens and kestrels. The approximate LD50 for PCB 126 in chickens was 0.4 ppb, in kestrels was 65 ppb, and in terns was 104 ppb. The approximate LD50 for PCB 77 in chickens was 2.6 ppb and in kestrels was 316 ppb. Induction of cytochrome P450 associated monooxygenase activity (EROD activity) by PCB 126 in chick embryo liver was about 800 times more responsive than in tern and at least 1000 times more responsive than in kestrel. High concentrations of PCB 126 found in bald eagle eggs are nearly 20-fold higher than the lowest toxic concentration tested in kestrels. Concentrations of PCB 126 causing low level toxic effects in common tern eggs are comparable to highest levels in common terns and Forster's terns in the field, suggesting additional involvement of other compounds in the Great Lakes.

Combined effects of depleted uranium and ionising radiation on zebrafish embryos.

PubMed

Ng, C Y P; Pereira, S; Cheng, S H; Adam-Guillermin, C; Garnier-Laplace, J; Yu, K N

2015-11-01

In the environment, living organisms are exposed to a mixture of stressors, and the combined effects are deemed as multiple stressor effects. In the present work, the authors studied the multiple stressor effect in embryos of the zebrafish (Danio rerio) from simultaneous exposure to alpha particles and depleted uranium (DU) through quantification of apoptotic signals at 24 h post-fertilisation (hpf) revealed by vital dye acridine orange staining. In each set of experiments, dechorionated zebrafish embryos were divided into 4 groups, each having 10 embryos: Group (C) in which the embryos did not receive any further treatment; Group (IU) in which the embryos received an alpha-particle dose of 0.44 mGy at 5 hpf and were then exposed to 100 µg l(-1) of DU from 5 to 6 hpf; Group (I) in which the embryos received an alpha-particle dose of 0.44 mGy at 5 hpf and Group (U) in which the dechorionated embryos were exposed to 100 µg l(-1) of DU from 5 to 6 hpf. The authors confirmed that an alpha-particle dose of 0.44 mGy and a DU exposure for 1 h separately led to hormetic and toxic effects assessed by counting apoptotic signals, respectively, in the zebrafish. Interestingly, the combined exposure led to an effect more toxic than that caused by the DU exposure alone, so effectively DU changed the beneficial effect (hormesis) brought about by alpha-particle irradiation into an apparently toxic effect. This could be explained in terms of the promotion of early death of cells predisposed to spontaneous transformation by the small alpha-particle dose (i.e. hormetic effect) and the postponement of cell death upon DU exposure. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Solid Lipid Nanoparticles Carrying Temozolomide for Melanoma Treatment. Preliminary In Vitro and In Vivo Studies

PubMed Central

Ferrara, Benedetta; Biasibetti, Elena; Schiffer, Davide; Mellai, Marta; Annovazzi, Laura; Cangemi, Luigi; Muntoni, Elisabetta; Dianzani, Umberto

2018-01-01

Aim: To develop an innovative delivery system for temozolomide (TMZ) in solid lipid nanoparticles (SLN), which has been preliminarily investigated for the treatment of melanoma. Materials and Methods: SLN-TMZ was obtained through fatty acid coacervation. Its pharmacological effects were assessed and compared with free TMZ in in vitro and in vivo models of melanoma and glioblastoma. Results: Compared to the standard free TMZ, SLN-TMZ exerted larger effects, when cell proliferation of melanoma cells, and neoangiogeneis were evaluated. SLN-TMZ also inhibited growth and vascularization of B16-F10 melanoma in C57/BL6 mice, without apparent toxic effects. Conclusion: SLN could be a promising strategy for the delivery of TMZ, allowing an increased stability of the drug and thereby its employment in the treatment of aggressive malignacies. PMID:29364157

The cathepsin B inhibitor, z-FA-CMK is toxic and readily induced cell death in human T lymphocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liow, K.Y.; Chow, S.C., E-mail: chow.sek.chuen@monash.edu

The cathepsin B inhibitor, benzyloxycarbonyl-phenylalanine-alanine-chloromethylketone (z-FA-CMK) was found to be toxic and readily induced cell death in the human T cell line, Jurkat, whereas two other analogs benzyloxycarbonyl-phenylalanine-alanine-fluoromethylketone (z-FA-FMK) and benzyloxycarbonyl-phenylalanine-alanine-diazomethylketone (z-FA-DMK) were not toxic. The toxicity of z-FA-CMK requires not only the CMK group, but also the presence of alanine in the P1 position and the benzyloxycarbonyl group at the N-terminal. Dose–response studies showed that lower concentrations of z-FA-CMK induced apoptosis in Jurkat T cells whereas higher concentrations induced necrosis. In z-FA-CMK-induced apoptosis, both initiator caspases (-8 and -9) and effector caspases (-3, -6 and -7) were processed tomore » their respective subunits in Jurkat T cells. However, only the pro-form of the initiator caspases were reduced in z-FA-CMK-induced necrosis and no respective subunits were apparent. The caspase inihibitor benzyloxycarbonyl-valine-alanine-aspartic acid-(O-methyl)-fluoromehylketone (z-VAD-FMK) inhibits apoptosis and caspase processing in Jurkat T cells treated with low concentration of z-FA-CMK but has no effect on z-FA-CMK-induced necrosis and the loss of initiator caspases. This suggests that the loss of initiator caspases in Jurkat T cells during z-FA-CMK-induced necrosis is not a caspase-dependent process. Taken together, we have demonstrated that z-FA-CMK is toxic to Jurkat T cells and induces apoptosis at low concentrations, while at higher concentrations the cells die of necrosis. - Highlights: • z-FA-CMK is toxic and induce cell death in the human T cells. • z-FA-CMK toxicity requires the CMK group, alanine and the benzyloxycarbonyl group. • z-FA-CMK induced apoptosis at low concentration and necrosis at high concentration.« less

Unintentional ingestion of Cordyceps fungus-infected cicada nymphs causing ibotenic acid poisoning in Southern Vietnam.

PubMed

Doan, Uyen Vy; Mendez Rojas, Bomar; Kirby, Ralph

2017-09-01

Cordyceps fungus found in infected cicada nymphs ("cicada flowers") is utilized in traditional Chinese medicine. Cordyceps fungus toxicity in humans has not been previously reported. We report 60 cases of apparent Cordyceps poisoning in Southern Vietnam. We retrospectively collected demographic and clinical data from the medical records (21 cases) and by telephone interview (39 cases) of patients admitted to seven hospitals in Southern Vietnam following ingestion of cicada flowers between 2008 and 2015. We also determined the species of Cordyceps present in the cicada flowers and performed a partial chemical analysis of the fungus. Sixty cases of toxic effects following ingestion of cicada flowers were documented. Symptom onset occurred within 60 minutes following ingestion. Symptoms included dizziness, vomiting, salivation, mydriasis, jaw stiffness, urinary retention, seizures, agitated delirium, hallucinations, somnolence and coma. None of the patients suffered liver or kidney injury. There was one fatality. The Cordyceps fungus involved in these poisoning was identified as Ophiocordyceps heteropoda. The presence of ibotenic acid was confirmed, but musimol and muscarine were absent. Cicada infected with Ophiocordyceps heteropoda in Vietnam contain ibotenic acid and are associated with a clinical syndrome consistent with its effects.

Multifunctional envelope-type mesoporous silica nanoparticles for pH-responsive drug delivery and magnetic resonance imaging.

PubMed

Chen, Yan; Ai, Kelong; Liu, Jianhua; Sun, Guoying; Yin, Qi; Lu, Lehui

2015-08-01

A novel multifunctional envelope-type mesoporous silica nanoparticle (MEMSN) system combining the merits of pH-responsiveness, non-toxicity and biological specificity, is demonstrated for drug delivery and magnetic resonance imaging (MRI). This system is constructed by immobilizing acetals on the surface of mesoporous silica, and then coupling to ultra small lanthanide doped upconverting nanoparticle, which act as a gate keeper. The anticancer drug DOX is thus locked in the pores, and its burst release can be achieved under acidic environment on account of the hydrolyzation reactions of acetals. The nanogated drug release system is highly efficacious for cancer therapy both in vitro and in vivo. Importantly, the nanocomposite could be harmlessly metabolized and degraded into apparently non-toxic products within a few days. The nanoscale effect of the system allows for passive tumor targeting and increased tumor accumulation of the probes via the enhanced permeation and retention (EPR) effect, which is visualized by MRI in vivo. Therefore, such nanosystem should be of great significance in the future development of highly efficient and tumor targeted drug delivery vehicles for cancer chemotherapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

Discovery of Highly Potent Tyrosinase Inhibitor, T1, with Significant Anti-Melanogenesis Ability by zebrafish in vivo Assay and Computational Molecular Modeling

NASA Astrophysics Data System (ADS)

Chen, Wang-Chuan; Tseng, Tien-Sheng; Hsiao, Nai-Wan; Lin, Yun-Lian; Wen, Zhi-Hong; Tsai, Chin-Chuan; Lee, Yu-Ching; Lin, Hui-Hsiung; Tsai, Keng-Chang

2015-01-01

Tyrosinase is involved in melanin biosynthesis and the abnormal accumulation of melanin pigments leading to hyperpigmentation disorders that can be treated with depigmenting agents. A natural product T1, bis(4-hydroxybenzyl)sulfide, isolated from the Chinese herbal plant, Gastrodia elata, is a strong competitive inhibitor against mushroom tyrosinase (IC50 = 0.53 μM, Ki = 58 +/- 6 nM), outperforms than kojic acid. The cell viability and melanin quantification assay demonstrate that 50 μM of T1 apparently attenuates 20% melanin content of human normal melanocytes without significant cell toxicity. Moreover, the zebrafish in vivo assay reveals that T1 effectively reduces melanogenesis with no adverse side effects. The acute oral toxicity study evidently confirms that T1 molecule is free of discernable cytotoxicity in mice. Furthermore, the molecular modeling demonstrates that the sulfur atom of T1 coordinating with the copper ions in the active site of tyrosinase is essential for mushroom tyrosinase inhibition and the ability of diminishing the human melanin synthesis. These results evident that T1 isolated from Gastrodia elata is a promising candidate in developing pharmacological and cosmetic agents of great potency in skin-whitening.

Risk assessment of the amnesic shellfish poison, domoic acid, on animals and humans.

PubMed

Kumar, K Prem; Kumar, Sreeletha Prem; Nair, G Achuthan

2009-05-01

Risk assessment of the amnesic shellfish poison, domoic acid, a potent neurotoxin, is evaluated based on its current knowledge and its harmful effects, and is presented under four headings, viz., (1) hazard identification, (2) dose response assessment, (3) exposure assessment and (4) risk characterization. Domoic acid binds the glutamate receptor site of the central nervous system (CNS) of humans and causes depolarization of neurons and an increase in cellularcalcium. In nature, domoic acid is produced by the algae, Pseudonitzschia spp. and they enter into the body of shellfish through their consumption. This toxin is reported to cause gastroenteritis, renal insufficiency confusion and memory loss in humans, since it affects the hippocampus of the brain. In rats, intraperitonial and oral administration of domoic acid result in scratching, tremor and convulsions, and in monkeys, the toxic symptoms like mastication, salivation, projectile vomiting, weakness, teeth grinding and lethargy are apparent. The no-observed-adverse-effect-level (NOAEL) in animals reveals that pure toxin is more effective than those isolated from shellfish. Based on LD50 values, it is found that intraperitonial administration of this toxin in animals is 31 fold more effective than oral administration. Low levels of domoic acid (0.20-0.75 ppm) show no toxic symptoms in non-human primates, but clinical effects are apparent in them and in humans, at a concentration of 1.0 ppm. The tolerable daily intake (TDI) of domoic acid for humans is calculated as 0.075 ppm, whereas for razor clams and crabs, the TDI are 19.4 and 31.5 ppm respectively. The hazard quotient (HQ) is found to be 2. Being an irreversible neurotoxin, domoic acid has severe public health implications. Death occurs in those above 68 years old. In order to ensure adequate protection to public health, the concentration of domoic acid in shellfish and shellfish parts at point of sale shall not exceed the current permissible limit of 20 microg g(-1) tissue. While processing shellfish, it maybe advisable to pay attention to factors such as environmental conditions, inter-organ variability in concentrations of domoic acid and cross contaminations.

Sustained effects of ecstasy on the human brain: a prospective neuroimaging study in novel users.

PubMed

de Win, Maartje M L; Jager, Gerry; Booij, Jan; Reneman, Liesbeth; Schilt, Thelma; Lavini, Cristina; Olabarriaga, Sílvia D; den Heeten, Gerard J; van den Brink, Wim

2008-11-01

Previous studies have suggested toxic effects of recreational ecstasy use on the serotonin system of the brain. However, it cannot be excluded that observed differences between users and non-users are the cause rather than the consequence of ecstasy use. As part of the Netherlands XTC Toxicity (NeXT) study, we prospectively assessed sustained effects of ecstasy use on the brain in novel ecstasy users using repeated measurements with a combination of different neuroimaging parameters of neurotoxicity. At baseline, 188 ecstasy-naive volunteers with high probability of first ecstasy use were examined. After a mean period of 17 months follow-up, neuroimaging was repeated in 59 incident ecstasy users and 56 matched persistent ecstasy-naives and their outcomes were compared. Neuroimaging included [(123)I]beta-carbomethoxy-3beta-(4-iodophenyl)tropane (CIT) SPECT to measure serotonin transporter densities as indicators of serotonergic function; (1)H-MR spectroscopy ((1)H-MRS) to measure brain metabolites as indicators of neuronal damage; diffusion tensor imaging (DTI) to measure the apparent diffusion coefficient and fractional anisotropy (FA) of the diffusional motion of water molecules in the brain as indicators of axonal integrity; and perfusion weighted imaging (PWI) to measure regional relative cerebral blood volume (rrCBV) which indicates brain perfusion. With this approach, both structural ((1)H-MRS and DTI) and functional ([(123)I]beta-CIT SPECT and PWI) aspects of neurotoxicity were combined. Compared to persistent ecstasy-naives, novel low-dose ecstasy users (mean 6.0, median 2.0 tablets) showed decreased rrCBV in the globus pallidus and putamen; decreased FA in thalamus and frontoparietal white matter; increased FA in globus pallidus; and increased apparent diffusion coefficient in the thalamus. No changes in serotonin transporter densities and brain metabolites were observed. These findings suggest sustained effects of ecstasy on brain microvasculature, white matter maturation and possibly axonal damage due to low dosages of ecstasy. Although we do not know yet whether these effects are reversible or not, we cannot exclude that ecstasy even in low doses is neurotoxic to the brain.

Tributyltin (TBT) inhibition of oligomycin-sensitive Mg-ATPase activity in mussel mitochondria.

PubMed

Pagliarani, Alessandra; Bandiera, Patrizia; Ventrella, Vittoria; Trombetti, Fabiana; Pirini, Maurizio; Nesci, Salvatore; Borgatti, Anna Rosa

2008-06-01

Tributyltin (TBT), one of the most toxic lipophilic aquatic pollutants, can be efficiently incorporated from sea water and sediments by filter-feeding molluscs. As far as we are aware TBT effects on the mitochondrial oligomycin-sensitive Mg-ATPase, the enzymatic core of energy production and a known target of TBT toxicity in mammals, have not been yet investigated in molluscs; thus the hydrolytic capability of the mitochondrial complex in the presence of micromolar concentrations of TBT was assayed in the mussel Mytilus galloprovincialis. Gill and mantle ATPase activities were progressively depressed by increasing TBT doses up to a maximal inhibition (82% in the gills and 74% in the mantle) at 0.62 microM TBT. Non-cooperative inhibition kinetics (n(H) approximately -1) and a non-competitive mechanism with respect to ATP substrate were pointed out. The mitochondrial Mg-ATPase susceptivity to TBT in the marine mussel was consistent with the formation of a TBT-Mg-ATPase complex, apparently more stable in the gills than in the mantle. The complex shape of the dose-response curve and the partial release of Mg-ATPase inhibition within the 0.6-34.4 microM TBT range suggest multiple interactions of TBT with the enzyme complex putatively related to its molecular mechanism of toxicity.

Secrets of the lac operon. Glucose hysteresis as a mechanism in dietary restriction, aging and disease.

PubMed

Mobbs, Charles V; Mastaitis, Jason W; Zhang, Minhua; Isoda, Fumiko; Cheng, Hui; Yen, Kelvin

2007-01-01

Elevated blood glucose associated with diabetes produces progressive and apparently irreversible damage to many cell types. Conversely, reduction of glucose extends life span in yeast, and dietary restriction reduces blood glucose. Therefore it has been hypothesized that cumulative toxic effects of glucose drive at least some aspects of the aging process and, conversely, that protective effects of dietary restriction are mediated by a reduction in exposure to glucose. The mechanisms mediating cumulative toxic effects of glucose are suggested by two general principles of metabolic processes, illustrated by the lac operon but also observed with glucose-induced gene expression. First, metabolites induce the machinery of their own metabolism. Second, induction of gene expression by metabolites can entail a form of molecular memory called hysteresis. When applied to glucose-regulated gene expression, these two principles suggest a mechanism whereby repetitive exposure to postprandial excursions of glucose leads to an age-related increase in glycolytic capacity (and reduction in beta-oxidation of free fatty acids), which in turn leads to an increased generation of oxidative damage and a decreased capacity to respond to oxidative damage, independent of metabolic rate. According to this mechanism, dietary restriction increases life span and reduces pathology by reducing exposure to glucose and therefore delaying the development of glucose-induced glycolytic capacity.

Apparent threshold of lead's effect on child intelligence

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rabinowitz, M.B.; Wang, J.D.; Soong, W.T.

1992-05-01

The developing human brain is perhaps the most sensitive of the many targets of lead toxicity. This particular sensitivity is a driving factor in setting health and environmental standards for lead. A recent compilation of studies of the association between lead and IQ has shown a consistent dose-response pattern across the range of reported exposures. In surveying the neurotoxicity of lead in humans and animals, there has been speculation of the existence of a threshold for these effects which may become apparent at lower lead levels. In that context we examined our data of tooth lead and IQ scores tomore » determine whether there was any apparent threshold for this effect. This cohort's lead levels are among the lowest documented and provide the opportunity to extend downward the range of interest. Family factors are the strongest predictors of a child's intelligence, in particular the parent's intelligence. We therefore followed the model of Perino and Ernhart (1974) by examining whether at various levels of lead there is a disruption of the usual association between family and child intelligence. As noted by Bellinger and Needleman (1983), a difference in the correlations between parental and child intelligence in two groups, high and low lead, may be an artifact of other relationships among the predictor variables. Accordingly, they recommend a more appropriate test that would search for differences in the IQ deficits according to lead level, where the IQ deficit is the difference between a child's observed IQ and the IQ predicted from all available information about the child aside from lead. This is especially appropriate when the lead exposure correlates with the family's educational background. We examined our data this way. 12 refs., 1 fig., 2 tabs.« less

Comparative toxicity and tissue distribution of lead acetate in weanling and adult rats.

PubMed Central

Rader, J I; Peeler, J T; Mahaffey, K R

1981-01-01

The relative toxicity of low doses of lead acetate provided steadily in drinking water or by mouth once per week was studied in weanling and adult rats. Free erythrocyte protoporphyrin and urinary delta-aminolevulinic acid levels were measured, as well as lead levels in blood and kidney. The accumulation of lead in brain tissue and in bone (femur) was measured to determine the effect of age and schedule of administration on tissue distribution and retention of lead. Total intakes of lead during the 60-week experimental period were: weanling and adult rats exposed to drinking water supplemented with 200 microgram of lead acetate/ml: 127 +/- 10 mg and 160 +/- 16 mg, respectively; weanling and adult rats dosed with lead acetate orally once per week: 132 mg and 161 mg, respectively. Increased toxic effects of lead in the weanling animals were apparent in most of the parameters measured (urinary delta-aminolevulinic acid and blood, brain, femur and kidney lead levels). This pattern was observed in weanling rats exposed to lead steadily through drinking water or dosed orally with an equivalent quantity of lead once per week. Lead levels in blood were highly correlated with the accumulation of lead in brain, femur, and kidney tissue in both groups of weanling rats. In adult rats, significant correlations between blood lead and kidney lead and between blood lead and femur lead were found only in the rats receiving lead steadily in drinking water. PMID:7333253

Environmental pollution, chromosomes, and health

NASA Astrophysics Data System (ADS)

Bell, Peter M.

In mid-May, 1980, President Carter declared a state of emergency at the Love Canal area, near Niagara Falls, New York. The reason for this was for the U.S. to underwrite the relocation costs ($3-5 million) of some 2500 residents who, according to a report by the EPA (Environmental Protection Agency) may have suffered damaged chromosomes. These injuries were apparently caused by contact with toxic wastes that had been dumped in the area in the years prior to development for housing.That the toxic compounds exist in the Love Canal and Niagara Falls subsurface zones, including public water supplies, appears to be established fact. That the residents of the Love Canal area suffered chromosomal damage may be established fact as well. Whether or not these two findings can be linked to ill health of the residents is another matter. Recently, the EPA report has been described as having ‘close to zero scientific significance,’ and has been ‘discredited’(Science, 208, 123a, 1980). The reasons for this disparity go beyond differences of opinion, beyond possible inadequacies of the EPA study, and even beyond problems that probably will arise from future studies, including those now in the planning stages. The problem is that even if victims have easily recognizable injuries from toxic substances (injury that apparently has not occurred to Love Canal residents), medical science usually cannot show a causal relationship. Even chromosomal damage is, at best, difficult to interpret. In ideal studies of significant populations and control groups, the association of toxic chemical to chromosome damage and to cancer and birth defects is indirect and, up to now, has been shown to have little or no significance to an individual member of the exposed population.

Dose-mortality assessment upon reuse and recycling of industrial sludge.

PubMed

Lin, Kae-Long; Chen, Bor-Yann

2007-09-05

This study provides a novel attempt to put forward, in general toxicological terms, quantitative ranking of toxicity of various sources of sludge for possible reusability in further applications. The high leaching concentrations of copper in printed circuit board (PCB) sludge and chromium in leather sludge apparently exceeded current Taiwan's EPA regulatory thresholds and should be classified as hazardous wastes. Dose-mortality analysis indicated that the toxicity ranking of different sources of sludge was PCB sludge>CaF(2) sludge>leather sludge. PCB sludge was also confirmed as a hazardous waste since the toxicity potency of PCB sludge was nearly identical to CdCl(2). However, leather sludge seemed to be much less toxic than as anticipated, perhaps due to a significant decrease of toxic species bioavailable in the aqueous phase to the reporter bacterium Escherichia coli DH5alpha. For possible reusability of sludge, maximum concentrations allowable to be considered "safe" (ca. EC(100)/100) were 9.68, 42.1 and 176 mgL(-1) for CaF(2) sludge, PCB sludge and leather sludge, respectively.

Metallomics and NMR-based metabolomics of Chlorella sp. reveal the synergistic role of copper and cadmium in multi-metal toxicity and oxidative stress.

PubMed

Zhang, Wenlin; Tan, Nicole G J; Fu, Baohui; Li, Sam F Y

2015-03-01

Industrial wastewaters often contain high levels of metal mixtures, in which metal mixtures may have synergistic or antagonistic effects on aquatic organisms. A combination of metallomics and nuclear magnetic resonance spectroscopy (NMR)-based metabolomics was employed to understand the consequences of multi-metal systems (Cu, Cd, Pb) on freshwater microalgae. Morphological characterization, cell viability and chlorophyll a determination of metal-spiked Chlorella sp. suggested synergistic effects of Cu and Cd on growth inhibition and toxicity. While Pb has no apparent effect on Chlorella sp. metabolome, a substantial decrease of sucrose, amino acid content and glycerophospholipid precursors in Cu-spiked microalgae revealed Cu-induced oxidative stress. Addition of Cd to Cu-spiked cultures induced more drastic metabolic perturbations, hence we confirmed that Cu and Cd synergistically influenced photosynthesis inhibition, oxidative stress and membrane degradation. Total elemental analysis revealed a significant decrease in K, and an increase in Na, Mg, Zn and Mn concentrations in Cu-spiked cultures. This indicated that Cu is more toxic to Chlorella sp. as compared to Cd or Pb, and the combination of Cu and Cd has a strong synergistic effect on Chlorella sp. oxidative stress induction. Oxidative stress is confirmed by liquid chromatography tandem mass spectrometry analysis, which demonstrated a drastic decrease in the GSH/GSSG ratio solely in Cu-spiked cultures. Interestingly, we observed Cu-facilitated Cd and Pb bioconcentration in Chlorella sp. The absence of phytochelatins and an increment of extracellular polymeric substances (EPS) yields in Cu-spiked cultures suggested that the mode of bioconcentration of Cd and Pb is through adsorption of free metals onto the algal EPS rather than intracellular chelation to phytochelatins.

Environmental safety review of methoprene and bacterially-derived pesticides commonly used for sustained mosquito control.

PubMed

Lawler, Sharon P

2017-05-01

Some pesticides are applied directly to aquatic systems to reduce numbers of mosquito larvae (larvicides) and thereby reduce transmission of pathogens that mosquitoes vector to humans and wildlife. Sustained, environmentally-safe control of larval mosquitoes is particularly needed for highly productive waters (e.g., catchment basins, water treatment facilities, septic systems), but also for other habitats to maintain control and reduce inspection costs. Common biorational pesticides include the insect juvenile hormone mimic methoprene and pesticides derived from the bacteria Bacillus thuringiensis israelensis, Lysinibacillus sphaericus and Saccharopolyspora spinosa (spinosad). Health agencies, the public and environmental groups have especially debated the use of methoprene because some studies have shown toxic effects on non-target organisms. However, many studies have demonstrated its apparent environmental safety. This review critically evaluates studies pertinent to the environmental safety of using methoprene to control mosquito larvae, and provides concise assessments of the bacterial larvicides that provide sustained control of mosquitoes. The review first outlines the ecological and health effects of mosquitoes, and distinguishes between laboratory toxicity and environmental effects. The article then interprets non-target toxicity findings in light of measured environmental concentrations of methoprene (as used in mosquito control) and field studies of its non-target effects. The final section evaluates information on newer formulations of bacterially-derived pesticides for sustained mosquito control. Results show that realized environmental concentrations of methoprene were usually 2-5µg/kg (range 2-45µg/kg) and that its motility is limited. These levels were not toxic to the vast majority of vertebrates and invertebrates tested in laboratories, except for a few species of zooplankton, larval stages of some other crustaceans, and small Diptera. Studies in natural habitats have not documented population reductions except in small Diptera. Bacterial larvicides showed good results for sustained control with similarly limited environmental effects, except for spinosad, which had broader effects on insects in mesocosms and temporary pools. These findings should be useful to a variety of stakeholders in informing decisions on larvicide use to protect public and environmental health in a 'One Health' framework. Copyright © 2017 Elsevier Inc. All rights reserved.

The chemical exposure toxicity space (CETS) model: Displaying exposure time, aqueous and organic concentration, activity, and onset of toxicity.

PubMed

Mackay, Donald; Celsie, Alena K D; Parnis, J Mark; McCarty, Lynn S; Arnot, Jon A; Powell, David E

2017-05-01

A 1-compartment toxicokinetic model is used to characterize the chemical exposure toxicity space (CETS), providing a novel graphic tool that can aid in the design of aquatic toxicity tests for fish and for interpreting their results. The graph depicts the solution to the differential equation describing the uptake kinetics of a chemical by a modeled fish under conventional bioassay conditions. The model relates the exposure concentration in the water to a dimensionless time and the onset of toxicity as determined by an estimated or assumed critical body residue or incipient lethal aqueous concentration. These concentration graphs are specific to each chemical and exposure and organism parameters and clearly demonstrate differences in toxicity between chemicals and how factors such as hydrophobicity influence the toxic endpoint. The CETS plots can also be used to assess bioconcentration test conditions to ensure that concentrations are well below toxic levels. Illustrative applications are presented using a recent set of high-quality toxicity data. Conversion of concentrations to chemical activities in the plots enables results for different baseline toxicants to be superimposed. For chemicals that have different modes of toxic action, the increased toxicity then becomes apparent. Implications for design and interpretation of aquatic toxicity tests are discussed. The model, and pictorial visualization of the time-course of aquatic toxicity tests, may contribute to improvements in test design, implementation, and interpretation, and to reduced animal usage. Environ Toxicol Chem 2017;36:1389-1396. © 2016 The Authors. Environmental Toxicology and Chemistry Published by Wiley Periodicals, Inc. on behalf of SETAC. © 2016 The Authors. Environmental Toxicology and Chemistry Published by Wiley Periodicals, Inc. on behalf of SETAC.

Cytoprotective and Antioxidant Effects of an Edible Herb, Enhydra fluctuans Lour. (Asteraceae), against Experimentally Induced Lead Acetate Intoxication.

PubMed

Dua, Tarun K; Dewanjee, Saikat; Khanra, Ritu; Joardar, Swarnalata; Barma, Sujata; Das, Shilpa; Zia-Ul-Haq, M; De Feo, Vincenzo

2016-01-01

Enhydra fluctuans Lour. (Asteraceae), an edible aquatic herb, is traditionally employed against toxic effects of heavy metals in India. The present study was planned to discover the protective effect of edible extract of E. fluctuans (AEEF) against Pb toxicity. The cytoprotective role of AEEF was determined on murine hepatocytes employing MTT assay and Hoechst staining. The effects on lipid peroxidation, protein carbonylation, endogenous redox systems and the transcription levels of apoptotic proteins were studied after incubating the hepatocytes with AEEF (400 μg/ml) + Pb-acetate (6.8 μM). The defensive role of AEEF (100 mg/kg) against Pb-acetate (5 mg/kg) intoxication was measured in mice by in vivo assays. Biochemical, haematological and histological parameters, intracellular Pb burden and redox status were measured. AEEF exhibited a concentration dependent cytoprotective effect against Pb-induced cytotoxicity in vitro. Pb-acetate incubation significantly (p < 0.01) altered the extents of ROS production ↑, protein carbonylation ↑, lipid peroxidation ↑, endogenous antioxidant enzymes ↓ and GSH ↓ in vitro. Besides, Pb-acetate significantly (p < 0.01) induced apoptosis in the hepatocytes apparent from the altered expressions of apoptotic proteins viz. Apaf-1 ↑, Bad ↑, Bcl-2 ↓, Cyt C ↑, cleaved caspases↑, Bid ↑ and Fas ↑. However, AEEF (400 μg/ml) could significantly (p < 0.05-0.01) attenuate the Pb-acetate mediated toxic manifestation in vitro. In in vivo assay, Pb-acetate (5 mg/kg) treated mice exhibited significantly (p < 0.01) high intracellular Pb content. A high Pb-burden within the tissues caused significant (p < 0.05-0.01) patho-physiological alterations viz. ROS production ↑, protein carbonylation↑, lipid peroxidation ↑, DNA fragmentation ↑, ATP formation ↑, mitochondrial co-enzymes Q ↓, endogenous antioxidant enzymes ↓ and GSH ↓ within the selected tissues. The haematological and serum biochemical parameters were significantly (p < 0.05-0.01) different in the Pb-acetate treated mice. Finally, histological assessment imposed significant toxic occurrence within the organs of Pb-intoxicated animals. However, concurrent administration of AEEF (100 mg/kg) could significantly (p < 0.05-0.01) reinstate the Pb-acetate mediated toxicity. Presence of metal chelators and phyto-antioxidants within AEEF would offer overall protection through promoting Pb clearance coupled with restoring redox balance.

Antitumor effect and toxicity of free rhodium (II) citrate and rhodium (II) citrate-loaded maghemite nanoparticles in mice bearing breast cancer

PubMed Central

2013-01-01

Background Magnetic fluids containing superparamagnetic iron oxide nanoparticles represent an attractive platform as nanocarriers in chemotherapy. Recently, we developed a formulation of maghemite nanoparticles coated with rhodium (II) citrate, which resulted in in vitro cytotoxicity enhanced up to 4.6 times when compared to free rhodium (II) citrate formulation on breast carcinoma cells. In this work, we evaluate the antitumor activity and toxicity induced by these formulations in Balb/c mice bearing orthotopic 4T1 breast carcinoma. Methods Mice were evaluated with regard to the treatments’ toxicity through analyses of hemogram, serum levels of alanine aminotransferase, iron, and creatinine; DNA fragmentation and cell cycle of bone marrow cells; and liver, kidney and lung histology. In addition, the antitumor activity of rhodium (II) citrate and maghemite nanoparticles coated with rhodium (II) citrate was verified by tumor volume reduction, histology and immunohistochemistry. Results Regarding the treatments’ toxicity, no experimental groups had alterations in levels of serum ALT or creatinine, and this suggestion was corroborated by the histopathologic examination of liver and kidney of mice. Moreover, DNA fragmentation frequency of bone marrow cells was lower than 15% in all experimental groups. On the other hand, the complexes rhodium (II) citrate-functionalized maghemite and free rhodium (II) citrate led to a marked growth inhibition of tumor and decrease in CD31 and Ki-67 staining. Conclusions In summary, we demonstrated that both rhodium (II) citrate and maghemite nanoparticles coated with rhodium (II) citrate formulations exhibited antitumor effects against 4T1 metastatic breast cancer cell line following intratumoral administration. This antitumor effect was followed by inhibition of both cell proliferation and microvascularization and by tumor tissue injury characterized as necrosis and fibrosis. Remarkably, this is the first published report demonstrating the therapeutic efficacy of maghemite nanoparticles coated with rhodium (II) citrate. This treatment prolonged the survival period of treated mice without inducing apparent systemic toxicity, which strengthens its use for future breast cancer therapeutic applications. PMID:23414068

The toxicity of arsenic(III), chromium(VI) and zinc to groundwater copepods.

PubMed

Hose, G C; Symington, K; Lott, M J; Lategan, M J

2016-09-01

Groundwater ecosystems globally are threatened by anthropogenic contamination, yet there are few ecotoxicological data using obligate groundwater biota on which to base risk assessments. Copepods are found inhabiting aquifers of different geologies around the world and so are a useful taxon for use in ecotoxicological studies of groundwater. The aim of this study was to test the sensitivity of obligate groundwater copepods to metal contaminants (arsenic(III), chromium(VI) and zinc) in groundwater in static 96 h, 14 days and 28 days exposure tests. The copepods were variably sensitive to As, Cr and Zn, with Cr being the most toxic across all taxa. No taxon was consistently most sensitive and there was no apparent relationship between the hardness, pH and organic carbon concentration of the diluent water and the sensitivity of biota. As expected, toxicity increased with exposure period and we encourage the use of longer exposure periods in future toxicity tests with groundwater organisms to reflect the greater exposure periods likely to be associated with groundwater contamination.

Mechanisms of copper homeostasis in bacteria

PubMed Central

Argüello, José M.; Raimunda, Daniel; Padilla-Benavides, Teresita

2013-01-01

Copper is an important micronutrient required as a redox co-factor in the catalytic centers of enzymes. However, free copper is a potential hazard because of its high chemical reactivity. Consequently, organisms exert a tight control on Cu+ transport (entry-exit) and traffic through different compartments, ensuring the homeostasis required for cuproprotein synthesis and prevention of toxic effects. Recent studies based on biochemical, bioinformatics, and metalloproteomics approaches, reveal a highly regulated system of transcriptional regulators, soluble chaperones, membrane transporters, and target cuproproteins distributed in the various bacterial compartments. As a result, new questions have emerged regarding the diversity and apparent redundancies of these components, their irregular presence in different organisms, functional interactions, and resulting system architectures. PMID:24205499

Differential toxic effects of Carbofuran and Diazinon on time of flight in pigeons (Columba livia): Potential for pesticide effects on migration

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brasel, Jeffrey M.; Environmental Sciences and Health Graduate Program, University of Nevada, Reno, NV 89557; Collier, Abby C.

Cholinesterase inhibiting compounds such as carbamates and organophosphate insecticides have been widely used in agriculture since the ban on organochlorines in the 1970s. Carbofuran, a carbamate, and diazinon, an organophosphate, are among the most commonly implicated cholinesterase inhibitors in episodes of accidental avian toxicity and mortality. Despite the apparent effects of these compounds, little work has been done to study effects of low-level, environmentally relevant doses at the population level in migratory bird species. In this study, homing pigeons were used as surrogate species to assess the differences in the effect of incrementally low doses (0.0, 0.25, 0.5, and 1.0more » mg/kg) of carbofuran and diazinon on time of flight and determine whether there was a threshold dose of either or both xenobiotics when orally administered at these levels. The results indicate that there is a significant dose-dependent increase in flight time in pigeons dosed with carbofuran while diazinon exposed pigeons showed little effect. More profound effects were noted with carbofuran with pigeons falling off the pace of the flock and a dose for highly significant increase in flight time elucidated between 0.5 and 1.0 mg/kg. The results of the studies validate the homing pigeon as a good subject for comparative studies of cholinesterase inhibitors in birds and the need for further research on repeated low-level exposures on populations of avian species.« less

Integrated assessment of contaminated sediments in the lower Fox River and Green Bay, Wisconsin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ankley, G.T.; Lodge, K.; Call, D.J.

Samples of sediment and biota were collected from sites in the lower Fox River and southern Green Bay to determine existing or potential impacts of sediment-associated contaminants on different ecosystem components of this Great Lakes area of concern. Evaluation of benthos revealed a relatively depauperate community, particularly at the lower Fox River sites. Sediment pore water and bulk sediments from several lower Fox River sites were toxic to a number of test species including Pimephales promelas, Ceriodaphnia dubia, Hexagenia limbata, Selenastrum capricornutum, and Photobacterium phosphorum. An important component of the observed toxicity appeared to be due to ammonia. Evaluation ofmore » three bullhead (Ictalurus) species from the lower Fox River revealed an absence of preneoplastic or neoplastic liver lesions, and the Salmonella typhimurium bioassay indicated relatively little mutagenicity in sediment extracts. Apparent adverse reproductive effects were noted in two species of birds nesting along the lower Fox River and on a confined disposal facility for sediments near the mouth of the river, and there were measurable concentrations of potentially toxic 2,3,7,8-substituted polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs), and planar polychlorinated biphenyls (PCBs) both in the birds and in sediments from several of the study sites. Based on toxic equivalency factors and the results of an in vitro bioassay with H4IIE rat hepatoma cells, it appeared that the majority of potential toxicity of the PCB/PCDF/PCDD mixture in biota from the lower Fox River/Green Bay system was due to the planar PCBs. The results of these studies are discussed in terms of an integrated assessment focused on providing data for remedial action planning.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guidarelli, Andrea; Fiorani, Mara; Carloni, Silvia

We herein report the results from a comparative study of arsenite toxicity in respiration-proficient (RP) and -deficient (RD) U937 cells. An initial characterization of these cells led to the demonstration that the respiration-deficient phenotype is not associated with apparent changes in mitochondrial mass and membrane potential. In addition, similar levels of superoxide (O{sub 2}{sup .-}) were generated by RP and RD cells in response to stimuli specifically triggering respiratory chain-independent mitochondrial mechanisms or extramitochondrial, NADPH-oxidase dependent, mechanisms. At the concentration of 2.5 μM, arsenite elicited selective formation of O{sub 2}{sup .-} in the respiratory chain of RP cells, with hardlymore » any contribution of the above mechanisms. Under these conditions, O{sub 2}{sup .-} triggered downstream events leading to endoplasmic reticulum (ER) stress, autophagy and apoptosis. RD cells challenged with similar levels of arsenite failed to generate O{sub 2}{sup .-} because of the lack of a functional respiratory chain and were therefore resistant to the toxic effects mediated by the metalloid. Their resistance, however, was lost after exposure to four fold greater concentrations of arsenite, coincidentally with the release of O{sub 2}{sup .-} mediated by NADPH oxidase. Interestingly, extramitochondrial O{sub 2}{sup .-} triggered the same downstream events and an identical mode of death previously observed in RP cells. Taken together, the results obtained in this study indicate that arsenite toxicity is strictly dependent on O{sub 2}{sup .-} availability that, regardless of whether generated in the mitochondrial or extramitochondrial compartments, triggers similar downstream events leading to ER stress, autophagy and apoptosis. - Highlights: • Mitochondrial superoxide mediates arsenite toxicity in respiration-proficient cells. • NADPH-derived superoxide mediates arsenite toxicity in respiration-deficient cells. • Arsenite causes apoptosis in respiration-proficient and -deficient cells. • Apoptosis is in both circumstances associated with ER stress and autophagy.« less

Efficacy of some plant oils alone and/or combined with different insecticides on the cotton leaf-worm Spodoptera littoralis (Boisd.) (Lepidoptera: Noctuidae) in Egypt.

PubMed

Mesbah, H A; Mourad, A K; Rokaia, A Z M

2006-01-01

The present work was conducted to evaluate the efficiency of two essential oils ((Flax or "Linseed" and Sesame ), five volatile plant oils ( Camphor, Red basil, Rose, Menthol and Clove ), four pesticides (Methoxyfenozide; Permethrin; Profenofos and Spinosad) and their mixtures on the cotton leaf-worm Spodoptera littoralis (Boisd.). This study was also devoted to minimize the usage of conventional insecticides, reduce the environmental pollution, and protect human-beings and domestic animals from hazards due to pesticides applications. In the meantime, the delayed effect of these tested plant oils on the developing immatures and moths of the cotton leaf-worm, Spodoptera littoralis was determined. Most of the evaluated plant oils were found to have an insecticidal effect on the 4th instar larvae of the cotton leaf-worm, S. littoralis. Both the essential Sesame oil and Clove volatile oil showed rather weak toxic effect corresponding to the same concentrations and periods of the bioassay tests. Comparing the toxicity of the tested plant oils, it was affirmed that both Rose and Red basil volatile oils were the highest efficient natural phytocompounds against the treated larvae and alternatively ranked either the 1st and/or the 2nd rank, throughout the different periods of the bioassay tests, followed by the other three tested oils which were more or less efficient phytocompounds. According to the toxicity index, all the tested oils were less toxic than the superior Red basil volatile oil after 48 h. post treatment followed by the gradual decrease in toxicity of Rose, Flax and Menthol, respectively. The development of the treated 4th larval instar was blocked due to treatment with the tested plant oils. With no exception, all the efficiently tested essential and/or volatile oils acted principally as Insect Growth Inhibitors (IGIs) rather than antifeedants causing disruption of the insect development, abnormal larvae, pupae and adults that were lead finally to death. The tested mixtures of Clove and Sesame oils increased the percentage of larval mortality in comparison to their use alone against the treated 4th larval instar.Contrarily, antagonism was revealed for the mixture of Sesame/Flax oils, the calculated value of LC50 greatly increased compared to the corresponding values of their individual evaluation after 48 h. from initiating the treatment. The delayed effect of tested plant oils was inspected on certain parameters of the fitness components of the subject insect and was mainly determined for the rates of hatched eggs and emerged moths. Remarkably, the Methoxyfenozide treated 4th larval instar became passive, or ceased feeding on the treated leaves and were unable to complete normally the moulting process, which partially took place in most'of the other treated individuals. The treated larvae with the tested lower concentrations, hardly succeeded in completing moulting process. The survived larvae failed to complete the next moulting at the end of the treatments. The toxic effect of Spinosad was more apparent against the treated larvae after 72 h from application. The calculated LC50 values indicated the gradual increase of its toxic effect in the subsequent prolonged intervals of the test. Spinosad showed its activity either by contact or ingestion and caused larval characteristic symptoms. Permethrin exhibited superior toxic efficacy overall the other tested chemicals, during the period from 72 up to 96 h post treatment. The gradual increase of the toxic effect of Permethrin indicated an efficient continuous persistence of nervous toxicity. According to the specific properties of Profenofos, results revealed that the toxicity by ingestion was more potential than by contact and explained the reason of developing toxicity with the increase of bioassay inspection period. The comparative toxic efficiency of the tested insecticides proved that Permethrin was the most effective one, giving LC50 values of 2.92 and 1.53 ppm after 72 and 96 h. bioassay, respectively, followed by Profenofos, Methoxyfenozide and Spinosad, successively. In addition, the calculated values of toxicity index also proved that all the tested compounds were less toxic than Permethrin (as a standard compound ). It is worth mentioning that the combined action of the mixed pesticides with four efficient volatile plant oils showed synergistic action against the 4th larval instar of S. littoralis.

Cimetidine (Tagamet) is a reproductive toxicant in male rats affecting peritubular cells.

PubMed

França, L R; Leal, M C; Sasso-Cerri, E; Vasconcelos, A; Debeljuk, L; Russell, L D

2000-11-01

Cimetidine (Tagamet) is a potent histaminic H2-receptor antagonist, extensively prescribed for ulcers and now available without prescription. Cimetidine is a known testicular toxicant, but its mechanism of action remains uncertain. Rats were treated i.p. with cimetidine either at 50 mg/kg or 250 mg/kg body weight for 59 days. Accessory sex organ weights, but not testis weight, were significantly reduced in the high dose treated groups. FSH levels were significantly elevated in both treated groups, but testosterone levels were unchanged. A high degree of variability characterized testis histology, with most tubules appearing normal and some tubules (15-17%) partially lacking or devoid of germ cells. Morphometry showed that although seminiferous tubule volume was not significantly changed, the volume of peritubular tissue was reduced in the high dose group. There was extensive duplication of the basal lamina, lamina densa in both apparently normal spermatogenic tubules and severely damaged tubules. Apoptotic peritubular myoid cells were also found. TUNEL labeling confirmed extensive apoptotic cell death in peritubular cells, but revealed apoptosis of vascular smooth muscle. Given that 1) peritubular myoid cell apoptosis occurs in apparently normal tubules, that 2) basal lamina disorders are found, and that 3) peritubular cells are lost from the testis, it is suggested that the primary event in cimetidine-related damage is targeted to testicular smooth muscle cells. This is the first in vivo-administered toxicant to be described that targets myoid cells, resulting in abnormal spermatogenesis.

Subchronic toxicity evaluation of sulfur mustard in rats.

PubMed

Sasser, L B; Miller, R A; Kalkwarf, D R; Cushing, J A; Dacre, J C

1996-01-01

Occupational exposure criteria have not been established for sulfur mustard (bis(2-chlorethyl) sulfide), a strong alkylating agent with known mutagenic properties. Seventy-two Sprague-Dawley rats of each sex, 6-7 weeks old, were divided into six groups (12 of each sex per group) and gavaged with 0, 0.003, 0.01, 0.03, 0.1 or 0.3 mg kg-1 sulfur mustard in sesame oil for 5 days a week for 13 weeks. No dose-related mortality was observed. A significant decrease (P > 0.05) in body weight was observed in both sexes of rats only in the 0.3 mg kg-1 group. Hematological evaluations and clinical chemistry measurements found non consistent treatment-related effects at the doses studied. The only treatment-related lesion associated with gavage exposure upon histopathological evaluation was epithelial hyperplasia of the forestomach of both sexes at 0.3 mg kg-1 and of males at 0.1 mg kg-1. The hyperplastic change was minimal and characterized by cellular disorganization of the basilar layer, apparent increase in mitotic activity of the basilar epithelial cells and thickening of the epithelial layer due to the apparent increase in cellularity. The estimated no-observed-effect level (NOEL) for sulfur mustard in this 90-day study was 0.1 mg kg-1 day-1 when administered orally.

Biocompatible gold nanorods: one-step surface functionalization, highly colloidal stability, and low cytotoxicity.

PubMed

Liu, Kang; Zheng, Yuanhui; Lu, Xun; Thai, Thibaut; Lee, Nanju Alice; Bach, Udo; Gooding, J Justin

2015-05-05

The conjugation of gold nanorods (AuNRs) with polyethylene glycol (PEG) is one of the most effective ways to reduce their cytotoxicity arising from the cetyltrimethylammonium bromide (CTAB) and silver ions used in their synthesis. However, typical PEGylation occurs only at the tips of the AuNRs, producing partially modified AuNRs. To address this issue, we have developed a novel, facile, one-step surface functionalization method that involves the use of Tween 20 to stabilize AuNRs, bis(p-sulfonatophenyl)phenylphosphine (BSPP) to activate the AuNR surface for the subsequent PEGylation, and NaCl to etch silver from the AuNRs. This method allows for the complete removal of the surface-bound CTAB and the most active surface silver from the AuNRs. The produced AuNRs showed far lower toxicity than other methods to PEGylate AuNRs, with no apparent toxicity when their concentration is lower than 5 μg/mL. Even at a high concentration of 80 μg/mL, their cell viability is still four times higher than that of the tip-modified AuNRs.

Branchial versus intestinal silver toxicity and uptake in the marine teleost Parophrys vetulus.

PubMed

Grosell, M; Wood, C M

2001-10-01

Exposure to elevated waterborne silver as AgNO3 (4.07 microM=448 microg l(-1)) in seawater resulted in osmoregulatory disturbance in the lemon sole (Parophrys vetulus). The main effects were increased plasma Na+ and Cl- concentrations which translated into increased plasma osmolality. Plasma Mg2+ levels were also slightly increased after 96 h exposure. Using radioisotopic flux measurements, a 50% reduction in branchial unidirectional Na+ extrusion was observed after 48 h silver exposure. By applying an intestinal perfusion approach, we were able to separate and thus quantify the intestinal contribution to the observed silver-induced physiological disturbance and internal silver accumulation. This analysis revealed that the intestinal contribution to silver-induced ionoregulatory toxicity was as high as 50-60%. In marked contrast, internal silver accumulation (in liver and kidney) was found to be derived exclusively from uptake across the gills. Drinking of silver-contaminated seawater resulted in substantial silver accumulation in the intestinal tissue (but apparently not silver uptake across the intestine), which probably explains the intestinal contribution to silver-induced physiological disturbance.

Design and Biological Evaluation of Antifouling Dihydrostilbene Oxime Hybrids.

PubMed

Moodie, Lindon W K; Cervin, Gunnar; Trepos, Rozenn; Labriere, Christophe; Hellio, Claire; Pavia, Henrik; Svenson, Johan

2018-04-01

By combining the recently reported repelling natural dihydrostilbene scaffold with an oxime moiety found in many marine antifoulants, a library of nine antifouling hybrid compounds was developed and biologically evaluated. The prepared compounds were shown to display a low antifouling effect against marine bacteria but a high potency against the attachment and growth of microalgae down to MIC values of 0.01 μg/mL for the most potent hybrid. The mode of action can be characterized as repelling via a reversible non-toxic biostatic mechanism. Barnacle cyprid larval settlement was also inhibited at low μg/mL concentrations with low levels or no toxicity observed. Several of the prepared compounds performed better than many reported antifouling marine natural products. While several of the prepared compounds are highly active as antifoulants, no apparent synergy is observed by incorporating the oxime functionality into the dihydrostilbene scaffold. This observation is discussed in light of recently reported literature data on related marine natural antifoulants and antifouling hybrids as a potentially general strategy for generation of improved antifoulants.

Organotin compounds and aquatic bacteria: A review

NASA Astrophysics Data System (ADS)

Cooney, J. J.

1995-03-01

Organotins are toxic to microorganisms. Trisubstituted organotins (R3SnX) are considered more toxic than disubstituted (R2SnX2) or monosubstituted (RSnX3) compounds, and tetrasubstituted compounds (R4Sn) are not considered toxic. In the R3Sn series propyl-, butyl-, pentyl-, phenyl- and cyclohexyltins are the most toxic to microorganisms. Toxicity towards aerobes in the R3Sn series is related to total molecular surface area and to the octanol: water partition coefficient, Kow, which is a measure of hydrophobicity. Care must be taken when testing the toxicity of tin compounds in the laboratory, for a number of biological, chemical and physical factors can influence the apparent toxicity. Although TBT is generally the most toxic of the butyltins, there are instances where monobutyltin (MBT) is as toxic, or more toxic, than TBT to microorganisms. Thus, debutylation in the sequence TBT→DBT→MBT→Sn does not detoxity TBT for all microorganisms. Some microorganisms can methylate inorganic or organic tins under aerobic or anaerobic conditions. Methylation can also occur by chemical means and the relative contributions of biotic and abiotic mechanisms are not clear. It is difficult to isolate a pure culture which can methylate tin compounds aerobically, and it is difficult to isolate a pure culture which degrades TBT, suggesting that microbial consortiums may be involved in transformations of organotins in the aquatic environment. Methylation and debutylation alter the adsorbtivity and solubility of tin compounds; thus microorganisms can influence the environmental mobility of tin. TBT-resistant microorganisms can be isolated, and in some of them resistance to TBT can be plasmid-mediated.

Disruption of the Putative Vascular Leak Peptide Sequence in the Stabilized Ricin Vaccine Candidate RTA1-33/44-198

PubMed Central

Janosi, Laszlo; Compton, Jaimee R.; Legler, Patricia M.; Steele, Keith E.; Davis, Jon M.; Matyas, Gary R.; Millard, Charles B.

2013-01-01

Vitetta and colleagues identified and characterized a putative vascular leak peptide (VLP) consensus sequence in recombinant ricin toxin A-chain (RTA) that contributed to dose-limiting human toxicity when RTA was administered intravenously in large quantities during chemotherapy. We disrupted this potentially toxic site within the more stable RTA1-33/44-198 vaccine immunogen and determined the impact of these mutations on protein stability, structure and protective immunogenicity using an experimental intranasal ricin challenge model in BALB/c mice to determine if the mutations were compatible. Single amino acid substitutions at the positions corresponding with RTA D75 (to A, or N) and V76 (to I, or M) had minor effects on the apparent protein melting temperature of RTA1-33/44-198 but all four variants retained greater apparent stability than the parent RTA. Moreover, each VLP(−) variant tested provided protection comparable with that of RTA1-33/44-198 against supralethal intranasal ricin challenge as judged by animal survival and several biomarkers. To understand better how VLP substitutions and mutations near the VLP site impact epitope structure, we introduced a previously described thermal stabilizing disulfide bond (R48C/T77C) along with the D75N or V76I substitutions in RTA1-33/44-198. The D75N mutation was compatible with the adjacent stabilizing R48C/T77C disulfide bond and the Tm was unaffected, whereas the V76I mutation was less compatible with the adjacent disulfide bond involving C77. A crystal structure of the RTA1-33/44-198 R48C/T77C/D75N variant showed that the structural integrity of the immunogen was largely conserved and that a stable immunogen could be produced from E. coli. We conclude that it is feasible to disrupt the VLP site in RTA1-33/44-198 with little or no impact on apparent protein stability or protective efficacy in mice and such variants can be stabilized further by introduction of a disulfide bond. PMID:23364220

Comparative developmental toxicity of planar polychlorinated biphenyl congeners in chickens, American kestrels, and common terns

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hoffman, D.J.; Melancon, M.J.; Klein, P.N.

1998-04-01

The effects of polychlorinated biphenyl (PCB) congeners, PCB 126 (3,3{prime},4,4{prime},5-pentaCB) and PCB 77 (3,3{prime},4,4{prime}-tetraCB), were examined in chicken (Gallus gallus), American kestrel (Falco sparverius), and common tern (Sterna hirundo) embryos through hatching, following air cell injections on day 4. PCB 126 caused malformations and edema in chickens starting at 0.3 ppb, in kestrels at 2.3 to 23 ppb, but in terns only at levels affecting hatching success (44 ppb). Extent of edema was most severe in chickens and least in terns. Defects of the beak were common in all species but with crossed beak most prevalent in terns. Effects onmore » embryo growth were most apparent for PCB 126 in chickens and kestrels. The approximate 50% lethal dose (LD50) for PCB 126 in chickens was 0.4 ppb, in kestrels was 65 ppb, and in terns was 104 ppb. The approximate LD50 for PCB 77 in chickens was 2.6 ppb and in kestrels was 316 ppb. Induction of cytochrome P450 associated monooxygenase activity (ethoxyresorufin-O-dealkylase activity) by PCB 126 in chick embryo liver was about 800 times more responsive than in tern and at least 1,000 times more responsive than in kestrel. High concentrations of PCB 126 found in bald eagle eggs are nearly 20-fold higher than the lowest toxic concentration tested in kestrels. Concentrations of PCB 126 causing low-level toxic effects in common tern eggs are comparable to highest levels in common terns and Forster`s terns in the field, suggesting additional involvement of other compounds in the Great Lakes.« less

Systemic administration of 3-bromopyruvate reveals its interaction with serum proteins in a rat model.

PubMed

Kunjithapatham, Rani; Geschwind, Jean-Francois H; Rao, Pramod P; Boronina, Tatiana N; Cole, Robert N; Ganapathy-Kanniappan, Shanmugasundaram

2013-07-17

3-bromopyruvate (3-BrPA) is a glycolytic inhibitor that affects cancer cells by targeting energy metabolism. Preclinical reports have established that a 1.75 mM dose of 3-BrPA is effective and sufficient to inhibit tumor growth when administered under a loco-regional approach (intraarterial and intratumoral). This loco-regional therapeutic dose was found to be nontoxic when given systemically as well. Yet, the mechanism underlying this lack of toxicity of 1.75 mM 3-BrPA during systemic delivery is unknown. Here, we investigated the mechanism associated with the lack of organ toxicity when 1.75 mM 3-BrPA was administered systemically using radiolabeled (14C)-3-BrPA in Sprague-Dawley rats. Data obtained from tissue-autoradiography of rats infused with 14C-3-BrPA showed strong 14C-signal in tissue sections of various organs except the brain corroborating that 3-BrPA does not cross the blood-brain barrier. Significantly, Hematoxylin & Eosin staining and apoptosis assay of tissue sections positive for 14C-signal showed no signs of toxicity or apoptosis. Convincingly, the 14C-signal observed in tissue-autoradiography emanates from 3-BrPA that is non-reactive or non-toxic, hence we further investigated whether the lack of toxicity is due to its interaction or alkylation with serum components. Analysis of serum proteins by 1D and 2D-gel electrophoretic autoradiography showed that 14C-BrPA selectively binds to peptides of molecular mass ~50-60 kDa. Mass spectrometry data suggested that 14C-BrPA could interact with alpha1-antitrypsin and a peptide of albuminoid-family. Our data indicate that selective interaction of 3-BrPA with serum proteins could contribute to the apparent lack of tissue-toxicity at the indicated close when the drug is given systematically in Sprague-Dawley rats.

Systemic administration of 3-bromopyruvate reveals its interaction with serum proteins in a rat model

PubMed Central

2013-01-01

Background 3-bromopyruvate (3-BrPA) is a glycolytic inhibitor that affects cancer cells by targeting energy metabolism. Preclinical reports have established that a 1.75 mM dose of 3-BrPA is effective and sufficient to inhibit tumor growth when administered under a loco-regional approach (intraarterial and intratumoral). This loco-regional therapeutic dose was found to be nontoxic when given systemically as well. Yet, the mechanism underlying this lack of toxicity of 1.75 mM 3-BrPA during systemic delivery is unknown. Here, we investigated the mechanism associated with the lack of organ toxicity when 1.75 mM 3-BrPA was administered systemically using radiolabeled (14C)-3-BrPA in Sprague–Dawley rats. Findings Data obtained from tissue-autoradiography of rats infused with 14C-3-BrPA showed strong 14C-signal in tissue sections of various organs except the brain corroborating that 3-BrPA does not cross the blood–brain barrier. Significantly, Hematoxylin & Eosin staining and apoptosis assay of tissue sections positive for 14C-signal showed no signs of toxicity or apoptosis. Convincingly, the 14C-signal observed in tissue-autoradiography emanates from 3-BrPA that is non-reactive or non-toxic, hence we further investigated whether the lack of toxicity is due to its interaction or alkylation with serum components. Analysis of serum proteins by 1D and 2D-gel electrophoretic autoradiography showed that 14C-BrPA selectively binds to peptides of molecular mass ~50-60 kDa. Mass spectrometry data suggested that 14C-BrPA could interact with alpha1-antitrypsin and a peptide of albuminoid-family. Conclusion Our data indicate that selective interaction of 3-BrPA with serum proteins could contribute to the apparent lack of tissue-toxicity at the indicated close when the drug is given systematically in Sprague–Dawley rats. PMID:23866825

Toxicological, medical and industrial hygiene aspects of glutaraldehyde with particular reference to its biocidal use in cold sterilization procedures.

PubMed

Ballantyne, B; Jordan, S L

2001-01-01

Aqueous solutions of > or =5% glutaraldehyde (GA) are of moderate acute peroral toxicity and those of < or =2% are of slight toxicity. By single sustained skin contact, aqueous GA solutions of > or =45% are of moderate acute percutaneous toxicity, those of 25% are of slight toxicity and those of or =5%. Primary skin irritation depends on the duration and contact site, occlusion and solvent. By sustained contact, the threshold for skin irritation is 1%, above which erythema and edema are dose related. With 45% and higher, skin corrosion may occur. There is a low incidence of skin sensitizing reactions, with an eliciting threshold of 0.5% aqueous GA. However, GA is neither phototoxic nor photosensitizing. Subchronic repeated exposure studies by the peroral route show only renal physiological compensatory effects, secondary to reduced water consumption. Repeated skin contact shows only minor skin irritant effects without systemic toxicity. By subchronic vapor exposure, effects are limited to the nasal mucosa at 1.0 ppm, with a no-effect concentration generally at 0.1 ppm. There is no evidence for systemic target organ or tissue toxicity by subchronic repeated exposure by any route. A chronic drinking water study showed an apparent increase, in females only, of large granular cell lymphocytic leukemia but this was not dosage related. This is most likely the result of a modifying effect on the factor(s) responsible for the expression of this commonly occurring rat neoplasm. A chronic (2-year) inhalation toxicity/oncogenicity study showed inflammatory changes in the anterior nasal cavity but no neoplasms or systemic toxicity. In vitro genotoxicity studies--bacterial mutagenicity, forward gene mutation (HGPRT and TK loci), sister chromatid exchange, chromosome aberration, UDS and DNA repair tests--have given variable results, ranging from no effect through to weak positive. In vivo genotoxicity studies--micronucleus, chromosome aberration, dominant lethal and Drosophila tests--generally have shown no activity but one mouse intraperitoneal study showed bone marrow cell chromosome aberrations. Developmental toxicity studies show GA not to be teratogenic, and a two-generation study showed no adverse reproductive effects. Percutaneous pharmacokinetic studies showed low skin penetration, with lowest values measured in vitro in rats and human skin. Overexposure of humans produces typical sensory irritant effects on the eye, skin and respiratory tract. Some reports have described an asthmatic-like reaction by overexposure to GA vapor. In most cases this resembles reactive airways dysfunction syndrome, and the role of immune mechanisms is uncertain. Local mucosal effects may occur if medical instruments or endoscopes are not adequately decontaminated. Protection of individuals from the potential adverse effects of GA exposure requires that there be adequate protection of the skin, eyes and respiratory tract. The airborne concentration of GA vapor should be kept below the recommended safe exposure level (e.g. the threshold limit value) by the use of engineering controls. Those who work with GA should, through a training program, be aware of the properties of GA, its potential adverse effects, how to handle the material safely and how to deal with accidental situations involving GA. If effects develop in exposed workers, the reasons should be determined immediately and corrective methods initiated. (c) 2001 John Wiley & Sons, Ltd.

Inhibitory Effect of Kurarinone on Growth of Human Non-small Cell Lung Cancer: An Experimental Study Both in Vitro and in Vivo Studies

PubMed Central

Yang, Jie; Chen, Hao; Wang, Qiang; Deng, Shihao; Huang, Mi; Ma, Xinhua; Song, Ping; Du, Jingwen; Huang, Yun; Wen, Yanzhang; Ren, Yongshen; Yang, Xinzhou

2018-01-01

Kurarinone, a flavonoid isolated from Sophora flavescens Aiton, has been reported to have significant antitumor activity. However, the cytotoxic activity of kurarinone against non-small cell lung cancer (NSCLC) cells is still under explored. In our study, we have evaluated the inhibitory effects of kurarinone on the growth of NSCLC both in vivo and in vitro as well as the molecular mechanisms underlying kurarinone-induced A549 cell apoptosis. The results showed that kurarinone effectively inhibited the proliferation of A549 cells with little toxic effects on human bronchial epithelial cell line BEAS-2B. FASC examination and Hoechst 33258 staining assay showed that kurarinone dose-dependently provoked A549 cells apoptosis. Mechanistically, kurarinone significantly decreased the ratio of Bcl-2/Bax, thereby causing the activation of caspase 9 and caspase 3, and reduced the expression of Grp78, which led to relieve the inhibition of caspase-12 and caspase-7, as well as suppressing the activity of AKT. Meanwhile, modeling results from the Surflex-Dock program suggested that residue Ser473 of Akt is a potential binding site for kurarinone. In vivo, kurarinone inhibited the growth of A549 xenograft mouse models without apparent signs of toxicity. Our study indicated that kurarinone has the potential effects of anti-NSCLC, implemented through activating mitochondria apoptosis signaling pathway, as well as repressing the activity of endoplasmic reticulum pathway and AKT in A549 cells. PMID:29628889

Examination of toxicity and collagen linearity after the administration of the protein cross-linker genipin in equine tendon and dermis: a pilot study.

PubMed

Bellefeuille, M; Peters, D F; Nolin, M; Slusarewicz, P; Telgenhoff, D

2017-05-01

Collagen cross-linking is an attractive therapeutic route aimed at supplementing natural collagen stabilisation. In this study the toxicity of the cross-linker genipin (GP) was examined in avascular (tendon) and vascular (dermis) tissue. High doses of GP were injected intratendinously into three yearling horses and evaluated at various time points up to 30 days. A second group of three yearlings were injected into the dermis and evaluated at various time points up to 1 year. Metrics used included lameness, circumferential swelling, ultrasound evaluation, microscopic morphology, collagen production and systemic effect on blood parameters. The tendon injection sites exhibited mild lameness and swelling with no apparent systemic toxicity or stabilisation defects. Treated tendons exhibited increased linear collagen microscopically. Dermal injections showed similar results, with mild swelling at the injection site. Microscopic morphology resulted in a decrease in dermal collagen at 30 days post-injection. Dermis injected at the high dose of 355 mmol/L examined 1 year post-treatment appeared similar to the untreated biopsies; however, there was an increase in mature collagen. GP injection appeared to be well tolerated, with transient lameness and mild circumferential swelling when injected into the tendon and local tissue swelling when injected into the dermis. No systemic hypersensitivities or toxicities were observed. Microscopically, GP resulted in increased linear collagen in tendons at 30 days post-injection and overall increased collagen in dermal tissue when evaluated 1 year post-injection. © 2017 Australian Veterinary Association.

[Identification of new genes that affect [PSI^(+)] prion toxicity in Saccharomyces cerevisiae yeast].

PubMed

Matveenko, A G; Belousov, M V; Bondarev, S A; Moskalenko, S E; Zhouravleva, G A

2016-01-01

Translation termination is an important step in gene expression. Its correct processing is governed by eRF1 (Sup45) and eRF3 (Sup35) proteins. In Saccharomyces cerevisiae, mutations in the corresponding genes, as well as Sup35 aggregation in [PSI^(+)] cells that propagate the prion form of Sup35 lead to inaccurate stop codon recognition and, consequently, nonsense suppression. The presence of stronger prion variants results in the more efficient suppression of nonsense mutations. Previously, we proposed a synthetic lethality test that enables the identification of genes that may influence either translation termination factors or [PSI^(+)] manifestation. This is based on the fact that the combination of sup45 mutations with the strong [PSI^(+)] prion variant in diploids is lethal. In this work, a set of genes that were previously shown to enhance nonsense suppression was analyzed. It was found that ABF1, FKH2, and REB1 overexpression decreased the growth of strains in a prion-dependent manner and, thus, might influence [PSI^(+)] prion toxicity. It was also shown that the synthetic lethality of [PSI^(+)] and sup45 mutations increased with the overexpression of GLN3 and MOT3 that encode Q/N-rich transcription factors. An analysis of the effects of their expression on the transcription of the release factors genes revealed an increase in SUP35 transcription in both cases. Since SUP35 overexpression is known to be toxic in [PSI^(+)] strains, these genes apparently enhance [PSI^(+)] toxicity via the regulation of SUP35 transcription.

Protective Effect of Tetracycline against Dermal Toxicity Induced by Jellyfish Venom

PubMed Central

Kang, Changkeun; Jin, Yeung Bae; Kwak, Jeongsoo; Jung, Hongseok; Yoon, Won Duk; Yoon, Tae-Jin; Kim, Jong-Shu; Kim, Euikyung

2013-01-01

Background Previously, we have reported that most, if not all, of the Scyphozoan jellyfish venoms contain multiple components of metalloproteinases, which apparently linked to the venom toxicity. Further, it is also well known that there is a positive correlation between the inflammatory reaction of dermal tissues and their tissue metalloproteinase activity. Based on these, the use of metalloproteinase inhibitors appears to be a promising therapeutic alternative for the treatment of jellyfish envenomation. Methodology and Principal Findings Tetracycline (a metalloproteinase inhibitor) has been examined for its activity to reduce or prevent the dermal toxicity induced by Nemopilema nomurai (Scyphozoa: Rhizostomeae) jellyfish venom (NnV) using in vitro and in vivo models. HaCaT (human keratinocyte) and NIH3T3 (mouse fibroblast) incubated with NnV showed decreases in cell viability, which is associated with the inductions of metalloproteinase-2 and -9. This result suggests that the use of metalloproteinase inhibitors, such as tetracycline, may prevent the jellyfish venom-mediated local tissue damage. In vivo experiments showed that comparing with NnV-alone treatment, tetracycline pre-mixed NnV demonstrated a significantly reduced progression of dermal toxicity upon the inoculation onto rabbit skin. Conclusions/Significance It is believed that there has been no previous report on the therapeutic agent of synthetic chemical origin for the treatment of jellyfish venom-induced dermonecrosis based on understanding its mechanism of action except the use of antivenom treatment. Furthermore, the current study, for the first time, has proposed a novel mechanism-based therapeutic intervention for skin damages caused by jellyfish stings. PMID:23536767

Toxicological and chemical screening of Antarctica sediments: Use of whole sediment toxicity tests, microtox, mutatox and semipermeable membrane devices (SPMDs)

USGS Publications Warehouse

Cleveland, Laverne; Little, Edward E.; Petty, Jimmie D.; Johnson, B. Thomas; Lebo, Jon A.; Orazio, Carl E.; Dionne, Jane

1997-01-01

Eight whole sediment samples from Antarctica (four from Winter Quarters Bay and four from McMurdo Sound) were toxicologically and chemically evaluated. Also, the influence of ultraviolet radiation on the toxicity and bioavailability of contaminants associated with the sediment samples was assessed. The evaluations were accomplished by use of a 10-day whole sediment test with Leptocheirus plumulosus, Microtox®, Mutatox® and semipermeable membrane devices (SPMDs). Winter Quarters Bay sediments contained about 250 ng g−1 (dry weight) total PCBs and 20 μg g−1 total PAHs. These sediments elicited toxicity in the Microtox test and avoidance and inhibited burrowing in the L. plumulosus test. The McMurdo Sound sediment samples contained only trace amounts of PCBs and no PAHs, and were less toxic in both the L. plumulosus and Microtox tests compared to the Winter Quarters Bay sediments. The sediments from McMurdo Sound apparently contained some unidentified substance which was photolytically modified to a more toxic form. The photolytic modification of sediment-associated contaminants, coupled with the polar ozone hole and increased incidence of ultraviolet radiation could significantly increase hazards to Antarctic marine life.

Sydney tar ponds: some problems in quantifying toxic waste.

PubMed

Furimsky, Edward

2002-12-01

Information on the type and amount of hazardous and toxic waste is required to develop a meaningful strategy and estimate a realistic cost for clean up of the Sydney Tar Pond site which is located on Cape Breton, in the province of Nova Scotia, Canada. The site covers the area of the decommissioned Sysco (Sydney Steel Corporation) plant. The materials of concern include BTEX (benzene, toluene, ethylbenzene, and xylenes), PAH (polycyclic aromatic hydrocarbons), PCB (polychlorinated biphenyl), and particulates laden with toxic metals, such as arsenic, lead, and others. The originally nontoxic materials such as soil, blast furnace slag, and vegetation, as well as surface and ground waters, which were subsequently contaminated, must also be included if they fail tests prescribed by environmental regulations. An extensive sampling program must be undertaken to obtain data for an accurate estimate of the waste to be cleaned and disposed of. Apparently, 700,000 tons of toxic waste, which is believed to be present on the site, may represent only a fraction of the actual amount. The clean-up of the site is only part of the solution. Toxic waste has to be disposed of in accordance with environmental regulations.

Azadirachtin, a neem-derived biopesticide, impairs behavioral and hematological parameters in carp (Cyprinus carpio).

PubMed

Murussi, Camila R; Menezes, Charlene C; Nunes, Mauro E M; Araújo, Maria do Carmo S; Quadros, Vanessa A; Rosemberg, Denis B; Loro, Vania L

2016-11-01

Azadirachtin (Aza) is a promisor biopesticide used in organic production and aquaculture. Although this compound is apparently safe, there is evidence that it may have deleterious effects on fish. Behavioral and hematological tests are grouped into a set of parameters that may predict potential toxicity of chemical compounds. Here, we investigate the effects of Aza, in the commercial formulation Neenmax ™ , on carp (Cyprinus carpio) by defining LC 50 (96 h), and testing behavioral and hematological parameters. In our study, LC 50 was estimated at 80 μL/L. We exposed carp to Aza at 20, 40, and 60 μL/L, values based on 25, 50, and 75% of LC 50 , respectively. At 60 μL/L, Aza promoted significant changes in several parameters, increasing the distance traveled and absolute turn angle. In addition, the same concentration decreased the time spent immobile and the number of immobile episodes. Hematological parameters, such as hematocrit, hemoglobin, hematimetrics index, and red cell distribution, were decreased at 60 μL/L Aza exposure. In conclusion, our study demonstrates that 60 μL/L Aza altered locomotor activity, motor pattern, and hematological parameters, suggesting potential toxicity to carp after acute exposure. In addition, this is the first report that evaluates the actions of a chemical contaminant using automated behavioral tracking of carp, which may be a useful tool for assessing the potential toxicity of biopesticides in conjunction with hematological tests. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1381-1388, 2016. © 2015 Wiley Periodicals, Inc.

Cellular Response of Pea Plants to Cadmium Toxicity: Cross Talk between Reactive Oxygen Species, Nitric Oxide, and Calcium1[W][OA

PubMed Central

Rodríguez-Serrano, María; Romero-Puertas, María C.; Pazmiño, Diana M.; Testillano, Pilar S.; Risueño, María C.; del Río, Luis A.; Sandalio, Luisa M.

2009-01-01

Cadmium (Cd) toxicity has been widely studied in different plant species; however, the mechanism involved in its toxicity as well as the cell response against the metal have not been well established. In this work, using pea (Pisum sativum) plants, we studied the effect of Cd on antioxidants, reactive oxygen species (ROS), and nitric oxide (NO) metabolism of leaves using different cellular, molecular, and biochemical approaches. The growth of pea plants with 50 μm CdCl2 affected differentially the expression of superoxide dismutase (SOD) isozymes at both transcriptional and posttranscriptional levels, giving rise to a SOD activity reduction. The copper/zinc-SOD down-regulation was apparently due to the calcium (Ca) deficiency induced by the heavy metal. In these circumstances, the overproduction of the ROS hydrogen peroxide and superoxide could be observed in vivo by confocal laser microscopy, mainly associated with vascular tissue, epidermis, and mesophyll cells, and the production of superoxide radicals was prevented by exogenous Ca. On the other hand, the NO synthase-dependent NO production was strongly depressed by Cd, and treatment with Ca prevented this effect. Under these conditions, the pathogen-related proteins PrP4A and chitinase and the heat shock protein 71.2, were up-regulated, probably to protect cells against damages induced by Cd. The regulation of these proteins could be mediated by jasmonic acid and ethylene, whose contents increased by Cd treatment. A model is proposed for the cellular response to long-term Cd exposure consisting of cross talk between Ca, ROS, and NO. PMID:19279198

A Pragmatic Approach to Assess the Exposure of the Honey Bee (Apis mellifera) When Subjected to Pesticide Spray

PubMed Central

Poquet, Yannick; Bodin, Laurent; Tchamitchian, Marc; Fusellier, Marion; Giroud, Barbara; Lafay, Florent; Buleté, Audrey; Tchamitchian, Sylvie; Cousin, Marianne; Pélissier, Michel; Brunet, Jean-Luc; Belzunces, Luc P.

2014-01-01

Plant protection spray treatments may expose non-target organisms to pesticides. In the pesticide registration procedure, the honey bee represents one of the non-target model species for which the risk posed by pesticides must be assessed on the basis of the hazard quotient (HQ). The HQ is defined as the ratio between environmental exposure and toxicity. For the honey bee, the HQ calculation is not consistent because it corresponds to the ratio between the pesticide field rate (in mass of pesticide/ha) and LD50 (in mass of pesticide/bee). Thus, in contrast to all other species, the HQ can only be interpreted empirically because it corresponds to a number of bees/ha. This type of HQ calculation is due to the difficulty in transforming pesticide field rates into doses to which bees are exposed. In this study, we used a pragmatic approach to determine the apparent exposure surface area of honey bees submitted to pesticide treatments by spraying with a Potter-type tower. The doses received by the bees were quantified by very efficient chemical analyses, which enabled us to determine an apparent surface area of 1.05 cm2/bee. The apparent surface area was used to calculate the exposure levels of bees submitted to pesticide sprays and then to revisit the HQ ratios with a calculation mode similar to that used for all other living species. X-tomography was used to assess the physical surface area of a bee, which was 3.27 cm2/bee, and showed that the apparent exposure surface was not overestimated. The control experiments showed that the toxicity induced by doses calculated with the exposure surface area was similar to that induced by treatments according to the European testing procedure. This new approach to measure risk is more accurate and could become a tool to aid the decision-making process in the risk assessment of pesticides. PMID:25412103

Occupational exposure to pesticides as a possible risk factor for the development of chronic diseases in humans (Review).

PubMed

Gangemi, Silvia; Miozzi, Edoardo; Teodoro, Michele; Briguglio, Giusi; De Luca, Annamaria; Alibrando, Carmela; Polito, Irene; Libra, Massimo

2016-11-01

It is well known that pesticides are widely used compounds. In fact, their use in agriculture, forestry, fishery and the food industry has granted a huge improvement in terms of productive efficiency. However, a great number of epidemiological surveys have demonstrated that these toxic compounds can interact and exert negative effects not only with their targets (pests, herbs and fungi), but also with the rest of the environment, including humans. This is particularly relevant in the case of workers involved in the production, transportation, preparation and application of these toxicants. Accordingly, a growing body of evidence has demonstrated the correlation between occupational exposure to pesticides and the development of a wide spectrum of pathologies, ranging from eczema to neurological diseases and cancer. Pesticide exposure is often quite difficult to establish, as many currently used modules do not take into account all of the many variables that can occur in a diverse environment, such as the agricultural sector, and the assessment of the real risk for every single worker is problematic. Indeed, the use of personal protection equipment is necessary while handling these toxic compounds, but education of workers can be even more important: personal contamination with pesticides may occur even in apparently harmless situations. This review summarises the most recent findings describing the association between pesticide occupational exposure and the development of chronic diseases.

Occupational exposure to pesticides as a possible risk factor for the development of chronic diseases in humans

PubMed Central

Gangemi, Silvia; Miozzi, Edoardo; Teodoro, Michele; Briguglio, Giusi; De Luca, Annamaria; Alibrando, Carmela; Polito, Irene; Libra, Massimo

2016-01-01

It is well known that pesticides are widely used compounds. In fact, their use in agriculture, forestry, fishery and the food industry has granted a huge improvement in terms of productive efficiency. However, a great number of epidemiological surveys have demonstrated that these toxic compounds can interact and exert negative effects not only with their targets (pests, herbs and fungi), but also with the rest of the environment, including humans. This is particularly relevant in the case of workers involved in the production, transportation, preparation and application of these toxicants. Accordingly, a growing body of evidence has demonstrated the correlation between occupational exposure to pesticides and the development of a wide spectrum of pathologies, ranging from eczema to neurological diseases and cancer. Pesticide exposure is often quite difficult to establish, as many currently used modules do not take into account all of the many variables that can occur in a diverse environment, such as the agricultural sector, and the assessment of the real risk for every single worker is problematic. Indeed, the use of personal protection equipment is necessary while handling these toxic compounds, but education of workers can be even more important: personal contamination with pesticides may occur even in apparently harmless situations. This review summarises the most recent findings describing the association between pesticide occupational exposure and the development of chronic diseases. PMID:27748877

Application of Multispectral and Hyperspectral Remote Sensing For Detection of Freshwater Harmful Algal Blooms

NASA Astrophysics Data System (ADS)

Kudela, R. M.; Accorsi, E.; Austerberry, D.; Palacios, S. L.

2013-12-01

Freshwater Cyanobacterial Harmful algal blooms (CHABs) represent a pressing and apparently increasing threat to both human and environmental health. In California, toxin producing blooms of several species, including Aphanizomenon, Microcystis, Lyngbya, and Anabaena are common; toxins from these blooms have been linked to impaired drinking water, domestic and wild animal deaths, and increasing evidence for toxin transfer to coastal marine environments, including the death of several California sea otters, a threatened marine species. California scientists and managers are under increasing pressure to identify and mitigate these potentially toxic blooms, but point-source measurements and grab samples have been less than effective. There is increasing awareness that these toxic events are both spatially widespread and ephememeral, leading to the need for better monitoring methods applicable to large spatial and temporal scales. Based on monitoring in several California water bodies, it appears that Aphanizomenon blooms frequently precede dangerous levels of toxins from Microcystis. We are exploring new detection methods for identifying CHABs and potentially distinguishing between blooms of the harmful cyanobacteria Aphanizomenon and Microcystis using remote sensing reflectance from a variety of airborne and satellite sensors. We suggest that Aphanizomenon blooms could potentially be used as an early warning of more highly toxic subsequent blooms, and that these methods, combined with better toxin monitoring, can lead to improved understanding and prediction of CHABs by pinpointing problematic watersheds.

Biochemical and Metabolic Changes in Arsenic Contaminated Boehmeria nivea L.

PubMed Central

Mubarak, Hussani; Mirza, Nosheen; Chai, Li-Yuan; Yang, Zhi-Hui; Yong, Wang; Tang, Chong-Jian; Mahmood, Qaisar; Pervez, Arshid; Farooq, Umar; Fahad, Shah; Nasim, Wajid; Siddique, Kadambot H. M.

2016-01-01

Arsenic (As) is identified by the EPA as the third highest toxic inorganic contaminant. Almost every 9th or 10th human in more than 70 countries including mainland China is affected by As. Arsenic along with other toxins not only affects human life but also creates alarming situations such as the deterioration of farm lands and desertion of industrial/mining lands. Researchers and administrators have agreed to opt for phytoremediation of As over costly cleanups. Boehmeria nivea L. can soak up various heavy metals, such as Sb, Cd, Pb, and Zn. But the effect of As pollution on the biology and metabolism of B. nivea has been somewhat overlooked. This study attempts to evaluate the extent of As resistance, chlorophyll content, and metabolic changes in As-polluted (5, 10, 15, and 20 mg L−1 As) B. nivea in hydroponics. Toxic effects of As in the form of inhibited growth were apparent at the highest level of added As. The significant changes in the chlorophyll, electrolyte leakage, and H2O2, significant increases in As in plant parts, catalase (CAT), and malondialdehyde (MDA), with applied As revealed the potential of B. nivea for As decontamination. By employing the metabolic machinery of B. nivea, As was sustainably removed from the contaminated areas. PMID:27022603

Biochemical and Metabolic Changes in Arsenic Contaminated Boehmeria nivea L.

PubMed

Mubarak, Hussani; Mirza, Nosheen; Chai, Li-Yuan; Yang, Zhi-Hui; Yong, Wang; Tang, Chong-Jian; Mahmood, Qaisar; Pervez, Arshid; Farooq, Umar; Fahad, Shah; Nasim, Wajid; Siddique, Kadambot H M

2016-01-01

Arsenic (As) is identified by the EPA as the third highest toxic inorganic contaminant. Almost every 9th or 10th human in more than 70 countries including mainland China is affected by As. Arsenic along with other toxins not only affects human life but also creates alarming situations such as the deterioration of farm lands and desertion of industrial/mining lands. Researchers and administrators have agreed to opt for phytoremediation of As over costly cleanups. Boehmeria nivea L. can soak up various heavy metals, such as Sb, Cd, Pb, and Zn. But the effect of As pollution on the biology and metabolism of B. nivea has been somewhat overlooked. This study attempts to evaluate the extent of As resistance, chlorophyll content, and metabolic changes in As-polluted (5, 10, 15, and 20 mg L(-1) As) B. nivea in hydroponics. Toxic effects of As in the form of inhibited growth were apparent at the highest level of added As. The significant changes in the chlorophyll, electrolyte leakage, and H2O2, significant increases in As in plant parts, catalase (CAT), and malondialdehyde (MDA), with applied As revealed the potential of B. nivea for As decontamination. By employing the metabolic machinery of B. nivea, As was sustainably removed from the contaminated areas.

What risks do herbal products pose to the Australian community?

PubMed

Byard, Roger W; Musgrave, Ian; Maker, Garth; Bunce, Michael

2017-02-06

Traditional herbal products are widely used in Australia to treat a broad range of conditions and diseases. It is popularly believed that these products are safer than prescribed drugs. While many may be safe, it is worrying that the specific effects and harmful interactions of a number of their components with prescription medications is not well understood. Some traditional herbal preparations contain heavy metals and toxic chemicals, as well as naturally occurring organic toxins. The effects of these substances can be dire, including acute hepatic and renal failure, exacerbation of pre-existing conditions and diseases, and even death. The content and quality of herbal preparations are not tightly controlled, with some ingredients either not listed or their concentrations recorded inaccurately on websites or labels. Herbal products may also include illegal ingredients, such as ephedra, Asarum europaeum (European wild ginger) and endangered animal species (eg, snow leopard). An additional problem is augmentation with prescription medications to enhance the apparent effectiveness of a preparation. Toxic substances may also be deliberately or inadvertently added: less expensive, more harmful plants may be substituted for more expensive ingredients, and processing may not be adequate. The lack of regulation and monitoring of traditional herbal preparations in Australia and other Western countries means that their contribution to illness and death is unknown. We need to raise awareness of these problems with health care practitioners and with the general public.

Relative effectiveness of sewage sludge as a nitrogen fertilizer for tall fescue

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kiemnec, G.L.; Jackson, T.L.; Hemphill, D.D. Jr.

Sewage sludge application rates on grasses are mainly determined by N availability and concentration of toxic metals in sludge. The exact availability of N in sludge is difficult to predict. A 3-yr study was conducted to determine which sludge rates would give yields of tall fescue (Festuca arundinacea Shreb. Alta) comparable to yields obtained from inorganic N application. Sludge and NH/sub 4/NO/sub 3/ were surface applied at annual rates of 0, 110, 220, 440, and 880 (sludge only) kg N/ha. Dry matter yield of tall fescue from sludge-treated soils was 36, 56, and 50% of that on NH/sub 4/NO/sub 3/-treatedmore » soils for 1976, 1977, and 1978, respectively. Sludge was 27, 41, and 44% as effective as NH/sub 4/NO/sub 3/ as a source of available N in 1976, 1977, and 1978, respectively. Ammonium-N in the sewage sludge apparently provided most of the available N for fescue growth. Concentrations of Zn, Cd, and Cu were higher and Mn lower in tall fescue grown on sludge-treated soil with NH/sub 4/NO/sub 3/ and usually increased toward the end of the growing season. However, plant concentrations of these heavy metals never reached toxic levels at any time. Sewage sludge was an effective and safe nutrient source for tall fescue.« less

Wood combustion particles induce adverse effects to normal and diseased airway epithelia.

PubMed

Krapf, Manuel; Künzi, Lisa; Allenbach, Sandrine; Bruns, Emily A; Gavarini, Ilaria; El-Haddad, Imad; Slowik, Jay G; Prévôt, André S H; Drinovec, Luka; Močnik, Griša; Dümbgen, Lutz; Salathe, Matthias; Baumlin, Nathalie; Sioutas, Constantinos; Baltensperger, Urs; Dommen, Josef; Geiser, Marianne

2017-04-19

Residential wood burning is a major source of poorly characterized, deleterious particulate matter, whose composition and toxicity may vary with wood type, burning condition and photochemical age. The causative link between ambient wood particle constituents and observed adverse health effects is currently lacking. Here we investigate the relationship between chemical properties of primary and atmospherically aged wood combustion particles and acute toxicity in human airway epithelial cells. Emissions from a log wood burner were diluted and injected into a smog chamber for photochemical aging. After concentration-enrichment and removal of oxidizing gases, directly emitted and atmospherically aged particles were deposited on cell cultures at the air-liquid interface for 2 hours in an aerosol deposition chamber mimicking physiological conditions in lungs. Cell models were fully differentiated normal and diseased (cystic fibrosis and asthma) human bronchial epithelia (HBE) and the bronchial epithelial cell line BEAS-2B. Cell responses were assessed at 24 hours after aerosol exposure. Atmospherically relevant doses of wood combustion particles significantly increased cell death in all but the asthma cell model. Expression of oxidative stress markers increased in HBE from all donors. Increased cell death and inflammatory responses could not be assigned to a single chemical fraction of the particles. Exposure to primary and aged wood combustion particles caused adverse effects to airway epithelia, apparently induced by several interacting components.

Promoting effects of chemical permeation enhancers on insulin permeation across TR146 cell model of buccal epithelium in vitro.

PubMed

Xue, Xiao-yan; Zhou, Ying; Chen, Ying-ying; Meng, Jing-ru; Jia, Min; Hou, Zheng; Bai, Hui; Mao, Xing-gang; Luo, Xiao-xing

2012-04-01

To find potential enhancers for facilitating the buccal delivery of insulin, a TR146 cell-culture model of buccal epithelium, cultured on commercially available insert plates, was used to evaluate the permeability-enhancing effects of several traditional and new types of chemical enhancers, including N-acetyl-L-cysteine (NAC), sodium deoxycholate (SDC), sodium nitroprusside (SNP), reduced glutathione (GSH), glutamine (Gln), chitosan (CS), L-arginine (Arg), 1-dodecylazacycloheptan-2-one (Azone), and soybean lecithin (SPC) (50 and 10 μg/mL respectively). Permeability studies were performed to determine the enhancing effects of these compounds on insulin permeation across the cell-culture model. The enhancing effects of the enhancers were assessed by calculating the apparent permeability coefficients and enhancement ratio. Cytotoxicity of the permeation enhancers at different concentrations was investigated by using the methylthiazolydiphenyl-tetrazolium bromide (MTT) assay. Results showed that 50 μg/mL of NAC, SDC, GSH, CS, Arg, Azone, SPC, SNP, and 10 μg/mL of SNP had a significant enhancing effect on promoting the transport of insulin across the TR146 cell model. MTT assays showed that 50 μg/mL of Gln, Azone, SDC, SNP, Arg, 10 μg/mL SDC, and Arg had obvious toxic effects on TR146 cells. Therefore, NAC, GSH, CS, SPC, and SNP appear to be safe, effective permeability enhancers that promote the transport of insulin across the TR146 cell-culture model of buccal epithelium and may be potential enhancers for buccal delivery of insulin with both low toxicity and high efficiency.

Preclinical evaluation of zinc phthalocyanine tetrasulfonate-based PDT

NASA Astrophysics Data System (ADS)

Borgatti-Jeffreys, Antonella; Hooser, Stephen B.; Miller, Margaret A.; Thomas, Rose M.; deGortari, Amalia; Lucroy, Michael D.

2005-04-01

Photodynamic therapy (PDT) involves the light activation of a drug within a tumor causing selective tumor cell death. Unfortunately, some photosensitizing drugs have been associated with adverse reactions in veterinary patients. Zinc phthalocyanine tetrasulfonate (ZnPcS4) is a promising second-generation photosensitizer for use in veterinary medicine, however, it cannot be applied clinically until safety and efficacy data are available. ZnPcS4 was given to Swiss Webster mice to assess acute toxicity. Doses >100 mg/kg were associated with acute toxicity and mortality, and doses >100 mg/kg resulted in renal tubular nephrosis, suggesting that the minimum toxic dose is approximately 100 mg/kg. Based on these data, a Phase I clinical trial of ZnPcS4-based PDT in tumor-bearing dogs is underway, with ZnPcS4 doses up to 2 mg/kg producing no apparent toxicity. Tumor response has been observed after ZnPcS4-based PDT using doses as low as 0.25 mg/kg, suggesting that conventional phase I clinical trials may not be appropriate for PDT protocols.

High hepatotoxic dose of paracetamol produces generalized convulsions and brain damage in rats. A counteraction with the stable gastric pentadecapeptide BPC 157 (PL 14736).

PubMed

Ilic, S; Drmic, D; Zarkovic, K; Kolenc, D; Coric, M; Brcic, L; Klicek, R; Radic, B; Sever, M; Djuzel, V; Ivica, M; Boban Blagaic, A; Zoricic, Z; Anic, T; Zoricic, I; Djidic, S; Romic, Z; Seiwerth, S; Sikiric, P

2010-04-01

We focused on stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, MW 1419, an anti-ulcer peptide efficient in inflammatory bowel disease trials (PL 14736), no toxicity reported) because of its hepatoprotective effects. We investigate a particular aspect of the sudden onset of encephalopathy with extreme paracetamol overdose (5 g/kg intraperitoneally) so far not reported: rapidly induced progressive hepatic encephalopathy with generalized convulsions in rats. BPC 157 therapy (10 microg, 10 ng, 10 pg/kg, intraperitoneally or intragastrically) was effective (microg-ng range) against paracetamol toxicity, given in early (BPC 157 immediately after paracetamol, prophylactically) or advanced stage (BPC 157 at 3 hours after paracetamol, therapeutically). At 25 min post-paracetamol increased ALT, AST and ammonium serum values precede liver lesion while in several brain areas, significant damage became apparent, accompanied by generalized convulsions. Through the next 5 hour seizure period and thereafter, the brain damage, liver damage enzyme values and hyperammonemia increased, particularly throughout the 3-24 h post-paracetamol period. BPC 157 demonstrated clinical (no convulsions (prophylactic application) or convulsions rapidly disappeared (therapeutic effect within 25 min)), microscopical (markedly less liver and brain lesions) and biochemical (enzyme and ammonium serum levels decreased) counteraction. Both, the prophylactic and therapeutic benefits (intraperitoneally and intragastrically) clearly imply BPC 157 (microg-ng range) as a highly effective paracetamol antidote even against highly advanced damaging processes induced by an extreme paracetamol over-dose.

Is Senna Laxative Use Associated to Cathartic Colon, Genotoxicity, or Carcinogenicity?

PubMed Central

Morales, M. A.; Hernández, D.; Bustamante, S.; Bachiller, I.; Rojas, A.

2009-01-01

Due to their natural origin, apparent low oral toxicity, effectiveness, and accessibility without a medical prescription, the anthranoid laxatives are a popular remedy for constipation and are frequently used abusively. Therefore, it is important to characterize its harmful and/or toxic effects. The sennosides, main active metabolites of senna, exhibit a very low toxicity in rats, and its genotoxic activity in bacterial strains as well as mammal cells was classified as weak in those cases where it was shown to be significant. The toxicological and mutagenic status of the crude extract of senna, however, is not as well characterized, and it is necessary to do so since it is frequently, and at the same time incorrectly, believed that the chronic use of anthranoid laxatives is a risk factor for the development of colorectal cancer. The objective of this article was to review the information that arises in various scientific medical databases using key words such as senna, sen, Senna alexandrina, Cassia angustifolia, sennosides, laxative toxicity, mainly ISI and non-ISI articles of journals with an editorial committee. Web pages of products or companies that publicize or commercialize this type of laxative were not included. This analysis establishes that (1) there is no convincing evidence that the chronic use of senna has, as a consequence, a structural and/or functional alteration of the enteric nerves or the smooth intestinal muscle, (2) there is no relation between long-term administration of a senna extract and the appearance of gastrointestinal tumors or any other type in rats, (3) senna is not carcinogenic in rats even after a two-year daily dose of up to 300 mg/kg/day, and (4) the current evidence does not show that there is a genotoxic risk for patients who take laxatives containing senna extracts or sennosides. PMID:20107583

Towards an integrative soil health assessment strategy: a three tier (integrative biomarker response) approach with Eisenia fetida applied to soils subjected to chronic metal pollution.

PubMed

Asensio, Vega; Rodríguez-Ruiz, Amaia; Garmendia, Larraitz; Andre, Jane; Kille, Peter; Morgan, Andrew John; Soto, Manu; Marigómez, Ionan

2013-01-01

This is a pilot study for assessing soil ecosystem health in chronically polluted sites on the basis of a 3-tier approach (screening+scoring+understanding) designed to be cost-effective and scientifically based, and to provide straightforward advice and support to managers and stakeholders involved in environmental protection. For the initial screening (Tier 1), the use of a highly sensitive, low-cost biomarker such as neutral red uptake (NRU) in earthworm coelomocytes is proposed. In sites where an alteration in NRU has been established, the stress level may be further assessed by utilising a suite of low-cost and rapid biomarkers of effect integrated in an integrative biological response (IBR) index to obtain an objective (scored) assessment of the induced stress syndrome (Tier 2). The IBR/n index is based on the integration of biomarkers at different levels of biological organisation. Acyl-CoA oxidase activity (AOX), catalase activity (CAT), lipofuscin optical density (LOD%), NRU and the mean epithelial thickness (MET) have been used to calculate the IBR/n index. Biomarkers are determined in earthworms, Eisenia fetida, exposed ex situ to real soils (three mining sites and a reference) for 3, 10 and 17d. The 3d NRU (Tier 1) provided signal of stress. After 3d, PCA, based on the suite of biomarkers (Tier 2), discriminated reference and polluted sites according to toxicity profiles and at 17d, the most polluted site is segregated from less polluted and reference sites. Soils were classified as harmful, unhealthy (not apparently toxic) or healthy. Soils were investigated by microarray transcriptomics (Tier 3), to understand the causes (aetiology) and consequences (prognosis) of health impairment. Tier 3 discriminates, according to stress syndrome traits, soils that did not fall into the category of highly stressed and revealed the main agent causing toxicity at each site by identifying the toxicity mechanisms and biological responses. Copyright © 2012 Elsevier B.V. All rights reserved.

Synergistic effects of Isatis tinctoria L. and tacrolimus in the prevention of acute heart rejection in mice.

PubMed

Wang, Yongzhi; Qin, Qing; Chen, Jibing; Kuang, Xiaocong; Xia, Junjie; Xie, Baiyi; Wang, Feng; Liang, Hua; Qi, Zhongquan

2009-12-01

Although immunosuppressive treatments are available for acute cardiac rejection no viable treatment exists for long-term cardiac graft failure. Moreover, the extended use of calcineurin inhibitor immunosuppressants, the mainstay of current treatment for cardiac transplantation, leads to significant side effects such as nephrotoxicity and an increased risk of cardiac disease. Because some agents used in Traditional Chinese Medicine (TCM) have strong immunosuppressive effects coupled with low toxicity, we investigated the effect of Compound K (K), the synthesized analogue of highly unsaturated fatty acids from Isatis tinctoria L., either as a single treatment or combined with tacrolimus (FK-506) on acute cardiac allograft rejection. We compared the ability of K alone, or in combination with FK-506, to inhibit acute heart transplant rejection both in vitro and in vivo. We found that the inhibition of lymphocyte proliferation was positively correlated with K concentration. K significantly reduced IL-2 and IFN-gamma expression levels and significantly inhibited lymphocyte proliferation in both a lymphocyte transformation test and a mixed lymphocyte reaction (MLR). We also found that the inhibitory effect of a combination of K and a sub-therapeutic dose of FK-506 (SubFK-506) was stronger than that of full-dose FK-506 alone. Oral administration of K reduced acute cardiac allograft rejection in mice and had no apparent toxicity. In vivo, the immunosuppressive effect of K combined with a half-dose of FK-506 was equivalent to that of a full-dose of FK-506 alone. K combined with a half-dose of FK-506 reduced the expression levels of IL-2 and IFN-gamma (both within the graft and in the recipients' serum) more effectively than a full-dose of FK-506. These results show that K has significant immunosuppressive effects both in vitro and in vivo. When used as a combination therapy with FK-506 we see a powerful inhibition of rejection with no obvious toxic side effects. The mechanism of action is postulated to involve the inhibition of IL-2 and IFN-gamma expressions by lymphocytes, rather than the activation of Tr1 cells via the production of IL-10.

Combined effects of lanthanum (III) chloride and acid rain on photosynthetic parameters in rice.

PubMed

Wang, Lihong; Wang, Wen; Zhou, Qing; Huang, Xiaohua

2014-10-01

Rare earth elements (REEs) pollution and acid rain are environmental issues, and their deleterious effects on plants attract worldwide attention. These two issues exist simultaneously in many regions, especially in some rice-growing areas. However, little is known about the combined effects of REEs and acid rain on plants. Here, the combined effects of lanthanum chloride (LaCl3), one type of REE salt, and acid rain on photosynthesis in rice were investigated. We showed that the combined treatment of 81.6 μM LaCl3 and acid rain at pH 4.5 increased net photosynthetic rate (Pn), stomatic conductance (Gs), intercellular CO2 concentration (Ci), Hill reaction activity (HRA), apparent quantum yield (AQY) and carboxylation efficiency (CE) in rice. The combined treatment of 81.6 μM LaCl3 and acid rain at pH 3.5 began to behave toxic effects on photosynthesis (decreasing Pn, Gs, HRA, AQY and CE, and increasing Ci), and the maximally toxic effects were observed in the combined treatment of 2449.0 μM LaCl3 and acid rain at pH 2.5. Moreover, the combined effects of LaCl3 and acid rain on photosynthesis in rice depended on the growth stage of rice, with the maximal effects occurring at the booting stage. Furthermore, the combined treatment of high-concentration LaCl3 and low-pH acid rain had more serious effects on photosynthesis in rice than LaCl3 or acid rain treatment alone. Finally, the combined effect of LaCl3 and acid rain on Pn in rice resulted from the changes in stomatic (Gs, Ci) and non-stomatic (HRA, AQY and CE) factors. Copyright © 2014 Elsevier Ltd. All rights reserved.

Adjuvant Whole Brain Radiotherapy: Strong Emotions Decide But Rational Studies Are Needed

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brown, Paul D.; Asher, Anthony L.; Farace, Elana

2008-04-01

Brain metastases are common in cancer patients and cause considerable morbidity and mortality. For patients with limited disease and good performance status, treatment typically involves a combination of focal measures (e.g., surgical resection or radiosurgery) for the radiographically apparent disease, followed by adjuvant whole brain radiotherapy (WBRT) to treat subclinical disease. Because of concerns regarding the toxicity of WBRT, especially neurocognitive deterioration, many have advocated withholding adjuvant WBRT. Recently published studies have shed more light on the efficacy of adjuvant WBRT and the neurocognitive effects of WBRT. However, the inclusion of neurocognitive and quality-of-life data in clinical trials are stillmore » required to better define the role of adjuvant WBRT. Currently, two Phase III trials are underway, one in Europe and one in North America, that will determine the effect of adjuvant WBRT on patients' quality of life, neurocognitive function, and survival.« less

Cessation of reproduction: an analytic view of menopause.

PubMed

Spencer, Richard P

2002-10-01

While there is evidence for genetic control of ovarian and follicular development, only recently have reports appeared on genetic components involved in ovarian failure. Unlike predictions of a stable population, age at menarche is decreasing, while female life span is increasing. This leads to examination of genotype-environment interactions. Evolution of the large human brain size has been accompanied by a reduction in size of the gastrointestinal tract. Consequences, in terms of altered diet and effects on menarche/menstruation/menopause were discussed. In the earliest days of human evolution, genotoxic agents and marginal diets could have produced heritable changes in cessation of menstruation. Toxic alterations may still be apparent, such as epidemiological studies on the effects of smoking on age at menopause. Attempts to reconstruct some of the recent past history, from coprolites to findings in frozen human specimens, have to be extended still further into the past.

Ecotoxicity of nanosized TiO2. Review of in vivo data.

PubMed

Menard, Anja; Drobne, Damjana; Jemec, Anita

2011-03-01

This report presents an exhaustive literature review of data on the effect of nanoparticulate TiO(2) on algae, higher plants, aquatic and terrestrial invertebrates and freshwater fish. The aim, to identify the biologically important characteristics of the nanoparticles that have most biological significance, was unsuccessful, no discernable correlation between primary particle size and toxic effect being apparent. Secondary particle size and particle surface area may be relevant to biological potential of nanoparticles, but insufficient confirmatory data exist. The nanotoxicity data from thirteen studies fail to reveal the characteristics actually responsible for their biological reactivity because reported nanotoxicity studies rarely carry information on the physicochemical characteristics of the nanoparticles tested. A number of practical measures are suggested which should support the generation of reliable QSAR models and so overcome this data inadequacy. Copyright © 2010 Elsevier Ltd. All rights reserved.

Adjuvant whole brain radiotherapy: strong emotions decide but rational studies are needed.

PubMed

Brown, Paul D; Asher, Anthony L; Farace, Elana

2008-04-01

Brain metastases are common in cancer patients and cause considerable morbidity and mortality. For patients with limited disease and good performance status, treatment typically involves a combination of focal measures (e.g., surgical resection or radiosurgery) for the radiographically apparent disease, followed by adjuvant whole brain radiotherapy (WBRT) to treat subclinical disease. Because of concerns regarding the toxicity of WBRT, especially neurocognitive deterioration, many have advocated withholding adjuvant WBRT. Recently published studies have shed more light on the efficacy of adjuvant WBRT and the neurocognitive effects of WBRT. However, the inclusion of neurocognitive and quality-of-life data in clinical trials are still required to better define the role of adjuvant WBRT. Currently, two Phase III trials are underway, one in Europe and one in North America, that will determine the effect of adjuvant WBRT on patients' quality of life, neurocognitive function, and survival.

[Gentamicin: various pharmacotherapeutic aspects in comparison with other aminoglycosides].

PubMed

de Visser, N A; van Gogh, H; van Miert, A S

1985-02-15

Gentamicin may be used in the treatment of infection with gram-negative bacteria including Pseudomonas spp and Proteus spp. Resistance will only appear in suboptimal or too prolonged courses of treatment and usually is due to 'multi-step mutation'. This resistance may be prevented, among others, by combined treatment with gentamicin and an antibiotic of the beta lactam group. When gentamicin is used correctly, it will have few toxic side-effects. Thus, 3 mg/kg of body weight three times daily will usually be indicated to ensure an optimum therapeutic effect. Parenteral administration of gentamicin would only appear to be useful in cases of bacteraemia and/or bacterial infection of the kidney and/or urinary excretory ducts; in the last-named case, the dose given at one time may be reduced by fifty per cent. Local treatment, the most recent method of which consists in administration by I(ntra-)T(racheal) route, apparently offers more prospects.

Chemotherapeutic reactions of Chandlerella hawkingi, the filarial parasite of the Indian jungle crow, Corvus macrorhynchos (Wagler)

PubMed Central

Chatterjee, R. K.; Sen, A. B.

1969-01-01

1. A high percentage of Indian jungle crows (Corvus macrorhynchos Wagler), found in and around Lucknow, harbour a natural filarial infection Chandlerella hawkingi. The microfilariae of this species are sheathed and show nocturnal periodicity. 2. Fourteen compounds active against other kinds of filariae, especially against Litomosoides carinii, were tested against Ch. hawkingi in jungle crows to find whether this infection would be suitable for routine filarial chemotherapy. This is apparently the first report of systematic screening of antifilarial compounds against an avian filariasis. 3. Tartar emetic (10 mg/kg intravenously, daily for 6 days) and arsenamide (5 mg/kg intraperitoneally, daily for 6 days) proved to be effective in killing adult worms. Trivalent tryparsamide, though effective, was toxic in the doses tried. Diethylcarbamazine and other compounds tested were ineffective. 4. The chemotherapeutic susceptibilities of Ch. hawkingi differ considerably from those of L. carinii and Wuchereria bancrofti. PMID:5774047

Predictive model of early mortality following acute inhalation of PuO/sub 2/ aerosols. [Extrapolation of beagle data to man

DOE Office of Scientific and Technical Information (OSTI.GOV)

Raabe, O.G.; Goldman, M.

Since data on the pulmonary toxicity of plutonium in people are not available, estimates must be based upon available experimental animal data. For this purpose, inhalation studies with beagle dogs exposed to aerosols of /sup 238/PuO/sub 2/ and /sup 239/PuO/sub 2/ were analyzed and a simple model has been proposed to describe apparent dose-response relationships. It was found that for each aerosol and radionuclide form, the cumulative absorbed lung dose that leads to death from lung damage up to 1000 days could be assumed to have a log-normal distribution of values that was independent of time to death. The datamore » was satisfactorily fit to a model in which the time of death postexposure is given by: t = (K/D), with the time to death, the cumulative dose to lung tissue (the killing dose), and anti D the average dose rate to lung tissue from time of exposure to death. The ratios of median K values, normalized to the value for /sup 90/Sr--Y FAP, indicate a relative biological effectiveness (RBE) of 14 for /sup 239/PuO/sub 2/ particles and 5 for /sup 238/PuO/sub 2/ particles. This demonstrates an effect of particle specific activity on relative biological effectiveness for early mortality, since an increase in specific activity of particles leads to a lower apparent RBE.« less

Laboratory toxicity studies demonstrate no adverse effects of Cry1Ab and Cry3Bb1 to larvae of Adalia bipunctata (Coleoptera: Coccinellidae): the importance of study design.

PubMed

Alvarez-Alfageme, Fernando; Bigler, Franz; Romeis, Jörg

2011-06-01

Scientific studies are frequently used to support policy decisions related to transgenic crops. Schmidt et al., Arch Environ Contam Toxicol 56:221-228 (2009) recently reported that Cry1Ab and Cry3Bb were toxic to larvae of Adalia bipunctata in direct feeding studies. This study was quoted, among others, to justify the ban of Bt maize (MON 810) in Germany. The study has subsequently been criticized because of methodological shortcomings that make it questionable whether the observed effects were due to direct toxicity of the two Cry proteins. We therefore conducted tritrophic studies assessing whether an effect of the two proteins on A. bipunctata could be detected under more realistic routes of exposure. Spider mites that had fed on Bt maize (events MON810 and MON88017) were used as carriers to expose young A. bipunctata larvae to high doses of biologically active Cry1Ab and Cry3Bb1. Ingestion of the two Cry proteins by A. bipunctata did not affect larval mortality, weight, or development time. These results were confirmed in a subsequent experiment in which A. bipunctata were directly fed with a sucrose solution containing dissolved purified proteins at concentrations approximately 10 times higher than measured in Bt maize-fed spider mites. Hence, our study does not provide any evidence that larvae of A. bipunctata are sensitive to Cry1Ab and Cry3Bb1 or that Bt maize expressing these proteins would adversely affect this predator. The results suggest that the apparent harmful effects of Cry1Ab and Cry3Bb1 reported by Schmidt et al., Arch Environ Contam Toxicol 56:221-228 (2009) were artifacts of poor study design and procedures. It is thus important that decision-makers evaluate the quality of individual scientific studies and do not view all as equally rigorous and relevant.

Possible central nervous system oxygen toxicity seizures among US recreational air or enriched air nitrox open circuit diving fatalities 2004-2013.

PubMed

Buzzacott, P; Denoble, P J

2017-01-01

The first diver certification programme for recreational 'enriched air nitrox' (EAN) diving was released in 1985. Concerns were expressed that many EAN divers might suffer central nervous system (CNS) oxygen toxicity seizures and drown. US fatalities on open-circuit scuba occurring between 2004-2013, where the breathing gas was either air or EAN, were identified. Causes of death and preceding circumstances were examined by a medical examiner experienced in diving autopsies. Case notes were searched for witnessed seizures at elevated partial pressures of oxygen. The dataset comprised 344 air divers (86%) and 55 divers breathing EAN (14%). EAN divers' fatal dives were deeper than air divers' (28 msw vs 18 msw, p < 0.0001). Despite this, of the 249 cases where a cause of death was established, only three EAN divers were considered to have possibly died following CNS oxygen toxicity seizures at depth (ppO2 132, 142 and 193 kPa). The analysis of recreational diving fatalities in the US over 10 years found just one death likely from CNS oxygen toxicity among EAN divers. A further two possible, although unlikely, cases were also found. Fears of commonplace CNS oxygen toxicity seizures while EAN diving have not apparently been realized.

Anti-tumor activity of calcitriol: pre-clinical and clinical studies.

PubMed

Trump, Donald L; Hershberger, Pamela A; Bernardi, Ronald J; Ahmed, Sharmilla; Muindi, Josephia; Fakih, Marwan; Yu, Wei-Dong; Johnson, Candace S

2004-05-01

1,25-Dihydroxycholecalciferol (calcitriol) is recognized widely for its effects on bone and mineral metabolism. Epidemiological data suggest that low Vitamin D levels may play a role in the genesis of prostate cancer and perhaps other tumors. Calcitriol is a potent anti-proliferative agent in a wide variety of malignant cell types. In prostate, breast, colorectal, head/neck and lung cancer as well as lymphoma, leukemia and myeloma model systems calcitriol has significant anti-tumor activity in vitro and in vivo. Calcitriol effects are associated with an increase in G0/G1 arrest, induction of apoptosis and differentiation, modulation of expression of growth factor receptors. Glucocorticoids potentiate the anti-tumor effect of calcitriol and decrease calcitriol-induced hypercalcemia. Calcitriol potentiates the antitumor effects of many cytotoxic agents and inhibits motility and invasiveness of tumor cells and formation of new blood vessels. Phase I and II trials of calcitriol either alone or in combination with carboplatin, taxanes or dexamethasone have been initiated in patients with androgen dependent and independent prostate cancer and advanced cancer. Data indicate that high-dose calcitriol is feasible on an intermittent schedule, no dose-limiting toxicity has been encountered and optimal dose and schedule are being delineated. Clinical responses have been seen with the combination of high dose calcitriol+dexamethasone in androgen independent prostate cancer (AIPC) and apparent potentiation of the antitumor effects of docetaxel have been seen in AIPC. These results demonstrate that high intermittent doses of calcitriol can be administered to patients without toxicity, that the MTD is yet to be determined and that calcitriol has potential as an anti-cancer agent.

Adverse health effects in Canada geese (Branta canadensis) associated with waste from zinc and lead mines in the Tri-State Mining District (Kansas, Oklahoma, and Missouri, USA).

PubMed

van der Merwe, Deon; Carpenter, James W; Nietfeld, Jerome C; Miesner, John F

2011-07-01

Lead and zinc poisoning have been recorded in a variety of bird species, including migrating waterfowl such as Canada Geese (Branta canadensis), at sites contaminated with mine waste from lead and zinc mines in the Tri-State Mining District, Kansas, Oklahoma, and Missouri, USA. The adverse health impacts from mine waste on these birds may, however, be more extensive than is apparent from incidental reports of clinical disease. To characterize health impacts from mine waste on Canada Geese that do not have observable signs of poisoning, four to eight apparently healthy birds per site were collected from four contaminated sites and an uncontaminated reference site, and examined for physical and physiologic evidence of metals poisoning. Tissue concentrations of silver, aluminum, arsenic, barium, cadmium, cobalt, chromium, copper, iron, magnesium, manganese, molybdenum, nickel, lead, selenium, thallium, vanadium, and zinc were determined by inductively coupled plasma mass spectroscopy. Adverse health effects due to lead were characterized by assessing blood δ-aminolevulinic acid dehydratase (ALAD) enzyme activity. Adverse effects associated with zinc poisoning were determined from histologic examination of pancreas tissues. Elevated tissue lead concentrations and inhibited blood ALAD enzyme activities were consistently found in birds at all contaminated sites. Histopathologic signs of zinc poisoning, including fibrosis and vacuolization, were associated with elevated pancreatic zinc concentrations at one of the study sites. Adverse health effects associated with other analyzed elements, or tissue concentrations indicating potentially toxic exposure levels to these elements, were not observed.

CbtA toxin of Escherichia coli inhibits cell division and cell elongation via direct and independent interactions with FtsZ and MreB.

PubMed

Heller, Danielle M; Tavag, Mrinalini; Hochschild, Ann

2017-09-01

The toxin components of toxin-antitoxin modules, found in bacterial plasmids, phages, and chromosomes, typically target a single macromolecule to interfere with an essential cellular process. An apparent exception is the chromosomally encoded toxin component of the E. coli CbtA/CbeA toxin-antitoxin module, which can inhibit both cell division and cell elongation. A small protein of only 124 amino acids, CbtA, was previously proposed to interact with both FtsZ, a tubulin homolog that is essential for cell division, and MreB, an actin homolog that is essential for cell elongation. However, whether or not the toxic effects of CbtA are due to direct interactions with these predicted targets is not known. Here, we genetically separate the effects of CbtA on cell elongation and cell division, showing that CbtA interacts directly and independently with FtsZ and MreB. Using complementary genetic approaches, we identify the functionally relevant target surfaces on FtsZ and MreB, revealing that in both cases, CbtA binds to surfaces involved in essential cytoskeletal filament architecture. We show further that each interaction contributes independently to CbtA-mediated toxicity and that disruption of both interactions is required to alleviate the observed toxicity. Although several other protein modulators are known to target FtsZ, the CbtA-interacting surface we identify represents a novel inhibitory target. Our findings establish CbtA as a dual function toxin that inhibits both cell division and cell elongation via direct and independent interactions with FtsZ and MreB.

CbtA toxin of Escherichia coli inhibits cell division and cell elongation via direct and independent interactions with FtsZ and MreB

PubMed Central

Heller, Danielle M.; Tavag, Mrinalini

2017-01-01

The toxin components of toxin-antitoxin modules, found in bacterial plasmids, phages, and chromosomes, typically target a single macromolecule to interfere with an essential cellular process. An apparent exception is the chromosomally encoded toxin component of the E. coli CbtA/CbeA toxin-antitoxin module, which can inhibit both cell division and cell elongation. A small protein of only 124 amino acids, CbtA, was previously proposed to interact with both FtsZ, a tubulin homolog that is essential for cell division, and MreB, an actin homolog that is essential for cell elongation. However, whether or not the toxic effects of CbtA are due to direct interactions with these predicted targets is not known. Here, we genetically separate the effects of CbtA on cell elongation and cell division, showing that CbtA interacts directly and independently with FtsZ and MreB. Using complementary genetic approaches, we identify the functionally relevant target surfaces on FtsZ and MreB, revealing that in both cases, CbtA binds to surfaces involved in essential cytoskeletal filament architecture. We show further that each interaction contributes independently to CbtA-mediated toxicity and that disruption of both interactions is required to alleviate the observed toxicity. Although several other protein modulators are known to target FtsZ, the CbtA-interacting surface we identify represents a novel inhibitory target. Our findings establish CbtA as a dual function toxin that inhibits both cell division and cell elongation via direct and independent interactions with FtsZ and MreB. PMID:28931012

Studies of the pharmacology of 17α-ethynyl-androst-5-ene-3β,7β,17β-triol, a synthetic anti-inflammatory androstene

PubMed Central

Ahlem, Clarence N; Kennedy, Michael R; Page, Theodore M; Reading, Christopher L; White, Steven K; McKenzie, John J; Cole, Phaedra I; Stickney, Dwight R; Frincke, James M

2011-01-01

17α-Ethynyl-androst-5ene-3β, 7β, 17β-triol (HE3286) is an orally bioavailable analogue of androst-5-ene-3β,7β,17β-triol, a non-glucocorticoid anti-inflammatory metabolite of the adrenal steroid, dehydroepiandrosterone. The pharmacology of HE3286 was characterized in preparation for clinical trials in type 2 diabetes mellitus and other diseases of inflammation. Interactions with nuclear hormone receptors and P450 enzymes were measured in vitro. Drug metabolism was studied preclinically in mice, rats, dogs, and monkeys. Neurological and cardiopulmonary safety and dose-ranging and chronic toxicity studies were conducted in rats and dogs in accordance with FDA guidelines. Pharmacokinetics and metabolites were measured in Phase I clinical trials. HE3286 was differentially metabolized between species. HE3286 and metabolites did not bind or transactivate steroid binding nuclear hormone receptors or inhibit P450 enzymes. There were no adverse effects in safety pharmacology and canine toxicology studies. Although HE3286 did not elicit systemic toxicity in rats, mild estrogenic effects were observed, but without apparent association to hormonal changes. Safety margins were greater than 20-fold in rats and dogs with respect to the most commonly used clinical dose of 10 mg/day. The terminal half-life in humans was 8 hours in males and 5.5 hours in females. HE3286 is the first derivative of the DHEA metabolome to undergo a comprehensive pharmacological and safety evaluation. The results of these investigations have shown that HE3286 has a low potential for toxicity and possesses pharmacological properties generally suitable for use in human medicine. The favorable profile of HE3286 warrants further exploration of this new class of anti-inflammatory agents. PMID:21686136

Osmium: An Appraisal of Environmental Exposure

PubMed Central

Smith, Ivan C.; Carson, Bonnie L.; Ferguson, Thomas L.

1974-01-01

In the U.S., the chief source of new osmium is copper refining, where this metal is produced as a byproduct. Probably less than 10% of the osmium in the original copper ore is recovered, and 1000–3000 oz troy of osmium is lost each year to the environment as the toxic, volatile tetroxide from copper smelters. In 1971, about 2000 oz troy of osmium was domestically refined, most of which was from secondary sources. An additional 4169 oz troy of osmium was toll-refined. Major uses for osmium tetroxide identified are for catalysis, especially in steroid synthesis, and for tissue staining. Minor uses of osmium metal are for electrical contacts and for imparting hardness to alloys for mechanical pivots, etc. Unreclaimed osmium tetroxide that reaches wastewater streams is probably rapidly reduced by organic matter to nontoxic osmium dioxide or osmium metal, which would settle out in the sediment of the water course. Waste osmium metal, itself innocuous and chemically resistant, would be oxidized to the toxic tetroxide if incinerated. Because of the small amounts used and their wide dispersal, the amounts of osmium tetroxide in wastewater and air should pose no hazard to man or the environment. The chief acute toxic effects of osmium tetroxide are well known and include eye and respiratory-tract damage. Few data are available that provide information on possible effects of nonacute exposure resulting from environmental contamination by osmium. However, workers continually exposed to osmium tetroxide vapors (refiners and histologists) and rheumatoid arthritis patients who have received intra-articular injections of osmic acid solutions have shown no apparent damage from exposure to low levels of osmium. PMID:4470919

Aluminum Citrate Prevents Renal Injury from Calcium Oxalate Crystal Deposition

PubMed Central

Besenhofer, Lauren M.; Cain, Marie C.; Dunning, Cody

2012-01-01

Calcium oxalate monohydrate crystals are responsible for the kidney injury associated with exposure to ethylene glycol or severe hyperoxaluria. Current treatment strategies target the formation of calcium oxalate but not its interaction with kidney tissue. Because aluminum citrate blocks calcium oxalate binding and toxicity in human kidney cells, it may provide a different therapeutic approach to calcium oxalate-induced injury. Here, we tested the effects of aluminum citrate and sodium citrate in a Wistar rat model of acute high-dose ethylene glycol exposure. Aluminum citrate, but not sodium citrate, attenuated increases in urea nitrogen, creatinine, and the ratio of kidney to body weight in ethylene glycol–treated rats. Compared with ethylene glycol alone, the addition of aluminum citrate significantly increased the urinary excretion of both crystalline calcium and crystalline oxalate and decreased the deposition of crystals in renal tissue. In vitro, aluminum citrate interacted directly with oxalate crystals to inhibit their uptake by proximal tubule cells. These results suggest that treating with aluminum citrate attenuates renal injury in rats with severe ethylene glycol toxicity, apparently by inhibiting calcium oxalate’s interaction with, and retention by, the kidney epithelium. PMID:23138489

Biological and chemical characterization of metal bioavailability in sediments from Lake Roosevelt, Columbia River, Washington, USA

USGS Publications Warehouse

Besser, J.M.; Brumbaugh, W.G.; Ivey, C.D.; Ingersoll, C.G.; Moran, P.W.

2008-01-01

We studied the bioavailability and toxicity of copper, zinc, arsenic, cadmium, and lead in sediments from Lake Roosevelt (LR), a reservoir on the Columbia River in Washington, USA that receives inputs of metals from an upstream smelter facility. We characterized chronic sediment toxicity, metal bioaccumulation, and metal concentrations in sediment and pore water from eight study sites: one site upstream in the Columbia River, six sites in the reservoir, and a reference site in an uncontaminated tributary. Total recoverable metal concentrations in LR sediments generally decreased from upstream to downstream in the study area, but sediments from two sites in the reservoir had metal concentrations much lower than adjacent reservoir sites and similar to the reference site, apparently due to erosion of uncontaminated bank soils. Concentrations of acid-volatile sulfide in LR sediments were too low to provide strong controls on metal bioavailability, and selective sediment extractions indicated that metals in most LR sediments were primarily associated with iron and manganese oxides. Oligochaetes (Lumbriculus variegatus) accumulated greatest concentrations of copper from the river sediment, and greatest concentrations of arsenic, cadmium, and lead from reservoir sediments. Chronic toxic effects on amphipods (Hyalella azteca; reduced survival) and midge larvae (Chironomus dilutus; reduced growth) in whole-sediment exposures were generally consistent with predictions of metal toxicity based on empirical and equilibrium partitioning-based sediment quality guidelines. Elevated metal concentrations in pore waters of some LR sediments suggested that metals released from iron and manganese oxides under anoxic conditions contributed to metal bioaccumulation and toxicity. Results of both chemical and biological assays indicate that metals in sediments from both riverine and reservoir habitats of Lake Roosevelt are available to benthic invertebrates. These findings will be used as part of an ongoing ecological risk assessment to determine remedial actions for contaminated sediments in Lake Roosevelt. ?? 2007 Springer Science+Business Media, LLC.

A review of carbon monoxide sources, sinks, and concentrations in the earth's atmosphere

NASA Technical Reports Server (NTRS)

Bortner, M. H.; Kummler, R. H.; Jaffe, L. S.

1972-01-01

Carbon monoxide is a toxic pollutant which is continually introduced into the earth's atmosphere in significant quantities. There are apparently some mechanisms operating which destroy most of the CO in the atmosphere, i.e., a carbon monoxide sink. These mechanisms have not as yet been established in a quantitative sense. This report discusses the various possible removal mechanisms which warrant serious consideration. Particular emphasis is given to chemical reactions (especially that with OH), soil bacteria and other biological action, and transport effects. The sources of carbon monoxide, both natural and anthropogenic, are reviewed and it is noted that there is quite possibly a significant undefined natural source. Atmospheric CO concentrations are discussed and their implications on carbon monoxide lifetime, sinks and sources are considered.

Synthesis and in vitro cytotoxicity of 5-substituted 2-cyanoimino-4-imidazodinone and 2-cyanoimino-4-pyrimidinone derivatives.

PubMed

Chern, Jyh-Haur; Shia, Kak-Shan; Chang, Chung-Ming; Lee, Chung-Chi; Lee, Yen-Chun; Tai, Chia-Liang; Lin, Ying-Ting; Chang, Chih-Shiang; Tseng, Huan-Yi

2004-03-08

A series of 5-substituted 2-cyanoimino-4-imidazodinone and 2-cyanoimino-4-pyrimidinone derivatives were synthesized and their anticancer cytotoxicity were evaluated in in vitro assay. It was found that the bulky aryl functionality in the 5-position of the 2-cyanoimino-4-imidazolidinone compounds was essential for the cytotoxicity of these heterocyclic compounds. Some of the derivatives exhibited modest cytotoxicity against a variety of cancer cell lines. One of the derivatives, [1-[6-(4-chlorophenoxy)hexyl]-5-oxo-4-phenyl-3-(4-pyridyl)tetrahydro-1H-2-imidazolyliden]aminomethanenitrile (Compound 11), exhibited the most potent cytotoxic activity with IC(50) in the nanomolar range. The cytotoxicity of these derivatives was selection with no apparent toxic effect toward normal fibroblasts.

Application of a redox gradostat reactor for assessing rhizosphere microorganism activity on lambda-cyhalothrin.

PubMed

Peacock, T J; Mikell, A T; Moore, M T; Smith, S

2014-03-01

Bacterial activity on pesticides can lead to decreased toxicity or persistence in aquatic systems. Rhizosphere activity is difficult to measure in situ. To mimic rhizosphere properties of the soft rush, Juncus effusus, a single-stage gradostat reactor was developed to study cycling of lambda-cyhalothrin by rhizobacteria and the effects of Fe(III) and citrate, both common in wetland soil, on lambda-cyhalothrin degradation. Redox gradient changes, greater than ± 10 mV, were apparent within days 5-15 both in the presence and absence of ferric citrate. Through the production of a redox gradient (p < 0.05) by rhizobacteria and the ability to measure pesticide loss over time (p < 0.05), reactors were useful in expanding knowledge on this active environment.

Time-response characteristic and potential biomarker identification of heavy metal induced toxicity in zebrafish.

PubMed

Yin, Jian; Wang, Ai-Ping; Li, Wan-Fang; Shi, Rui; Jin, Hong-Tao; Wei, Jin-Feng

2018-01-01

The present work aims to explore the time-response (from 24 h to 96 h) characteristic and identify early potential sensitive biomarkers of copper (Cu) (as copper chloride dihydrate), cadmium (Cd) (as cadmium acetate), lead (Pb) (as lead nitrate) and chromium (Cr) (as potassium dichromate) exposure in adult zebrafish, focusing on reactive oxygen species (ROS), SOD activity, lipid peroxidation and gene expression related to oxidative stress and inflammatory response. Furthermore, the survival rate decreased apparently by a concentration-dependent manner after Cu, Cr, Cd and Pb exposure, and we selected non-lethal concentrations 0.05 mg/L for Cu, 15 mg/L for Cr, 3 mg/L for Cd and 93.75μg/L for Pb to test the effect on the following biological indicators. Under non-lethal concentration, the four heavy metals have no apparent histological change in adult zebrafish gills. Similar trends in ROS production, MDA level and SOD activity were up-regulated by the four heavy metals, while MDA level responded more sensitive to Pb by time-dependent manner than the other three heavy metals. In addition, mRNA levels related to antioxidant system (SOD1, SOD2 and Nrf2) were up-regulated by non-lethal concentration Cu, Cr, Cd and Pb exposure. MDA level and SOD1 gene have a more delayed response to heavy metals. Genes related to immunotoxicity were increased significantly after heavy metals exposure at non-lethal concentrations. TNF-α and IL-1β gene have similar sensibility to the four heavy metals, while IL-8 gene was more responsive to Cr, Cd and Pb exposure at 48 h groups and IFN-γ gene showed more sensitivity to Cu at 48 h groups than the other heavy metals. In conclusion, the present works have suggested that the IFN-γ gene may applied as early sensitive biomarker to identify Cu-induced toxicity, while MDA content and IL-8 gene may use as early sensitive biomarkers for evaluating the risk of Pb exposure. Moreover, IL-8 and IFN-γ gene were more responsive to heavy metals, which may become early sensitive and potential biomarkers for evaluating inflammatory response induced by heavy metals. This work reinforces the concept of the usefulness of gene expression assays in the evaluation of chemicals effects and helps to establish a background data as well as contributes to evaluate early environmental risk for chemicals, even predicting toxicity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Evidence of ATP assay as an appropriate alternative of MTT assay for cytotoxicity of secondary effluents from WWTPs.

PubMed

Yang, Yang; Lu, Yun; Wu, Qian-Yuan; Hu, Hong-Ying; Chen, Ying-Hua; Liu, Wan-Li

2015-12-01

Biological tests are effective and comprehensive methods to assess toxicity of environmental pollutants to ensure the safety of reclaimed water. In this study, the canonical MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was performed to evaluate the cytotoxicity of dissolved organic matters (DOMs) of secondary effluents from wastewater treatment plants (WWTPs). It was surprising that most concentrated DOMs treated HepG2 cells yielded much higher signal compared with vehicle control regardless of difference of treatment technologies and seasons. However, there was actually no obvious enhancement of the cell proliferation by microscopy. In order to find out potential reason for the discrepancy, another three assays were performed. The results of ATP assay and flow cytometry showed expected toxicity, which was consistent with microscopy and previous studies, while DNA assay did not exhibit apparent change in treated cells. The possible mechanisms of abnormal MTT signal could be that some materials in secondary effluents isolated by solid extraction with HLB resin directly reacted with MTT and/or enhanced the activity of mitochondrial dehydrogenase. Therefore, the MTT assay is not suitable to assess cytotoxicity of complex mixtures such as secondary effluents, while ATP assay is an optional sensitive method. This study also suggests the importance of choosing both suitable extraction methods and detection assays for toxicity evaluation of component-unknown environmental samples. Copyright © 2015 Elsevier Inc. All rights reserved.

Alkylation of histidine residues of Bothrops jararacussu venom proteins and isolated phospholipases A2: a biotechnological tool to improve the production of antibodies.

PubMed

Guimarães, C L S; Andrião-Escarso, S H; Moreira-Dill, L S; Carvalho, B M A; Marchi-Salvador, D P; Santos-Filho, N A; Fernandes, C A H; Fontes, M R M; Giglio, J R; Barraviera, B; Zuliani, J P; Fernandes, C F C; Calderón, L A; Stábeli, R G; Albericio, F; da Silva, S L; Soares, A M

2014-01-01

Crude venom of Bothrops jararacussu and isolated phospholipases A2 (PLA2) of this toxin (BthTX-I and BthTX-II) were chemically modified (alkylation) by p-bromophenacyl bromide (BPB) in order to study antibody production capacity in function of the structure-function relationship of these substances (crude venom and PLA2 native and alkylated). BthTX-II showed enzymatic activity, while BthTX-I did not. Alkylation reduced BthTX-II activity by 50% while this process abolished the catalytic and myotoxic activities of BthTX-I, while reducing its edema-inducing activity by about 50%. Antibody production against the native and alkylated forms of BthTX-I and -II and the cross-reactivity of antibodies to native and alkylated toxins did not show any apparent differences and these observations were reinforced by surface plasmon resonance (SPR) data. Histopathological analysis of mouse gastrocnemius muscle sections after injection of PBS, BthTX-I, BthTX-II, or both myotoxins previously incubated with neutralizing antibody showed inhibition of the toxin-induced myotoxicity. These results reveal that the chemical modification of the phospholipases A2 (PLA2) diminished their toxicity but did not alter their antigenicity. This observation indicates that the modified PLA2 may provide a biotechnological tool to attenuate the toxicity of the crude venom, by improving the production of antibodies and decreasing the local toxic effects of this poisonous substance in animals used to produce antivenom.

A novel approach reveals that zinc oxide nanoparticles are bioavailable and toxic after dietary exposures

USGS Publications Warehouse

Croteau, M.-N.; Dybowska, A.D.; Luoma, S.N.; Valsami-Jones, E.

2011-01-01

If engineered nanomaterials are released into the environment, some are likely to end up associated with the food of animals due to aggregation and sorption processes. However, few studies have considered dietary exposure of nanomaterials. Here we show that zinc (Zn) from isotopically modified 67ZnO particles is efficiently assimilated by freshwater snails when ingested with food. The 67Zn from nano-sized 67ZnO appears as bioavailable as 67Zn internalized by diatoms. Apparent agglomeration of the zinc oxide (ZnO) particles did not reduce bioavailability, nor preclude toxicity. In the diet, ZnO nanoparticles damage digestion: snails ate less, defecated less and inefficiently processed the ingested food when exposed to high concentrations of ZnO. It was not clear whether the toxicity was due to the high Zn dose achieved with nanoparticles or to the ZnO nanoparticles themselves. Further study of exposure from nanoparticles in food would greatly benefit assessment of ecological and human health risks. ?? 2011 Informa UK, Ltd.

Assessment of pollution in road runoff using a Bufo viridis biological assay.

PubMed

Dorchin, A; Shanas, U

2010-12-01

Road runoff is a major source of environmental pollution, significantly threatening nearby aquatic habitats. Chemical analyses indicate high pollutant concentrations in the road's "first flush", but bioassays are more advantageous for addressing the cumulative effects of the numerous pollutants within the runoff. We used Bufo viridis embryos and larvae to assess the toxicity of road runoff from two major highways in Israel. We show, for the first time, that exposure to midseason runoff not only has an adverse effect on growth and development rates of B. viridis larvae but can also lead to increased rates of morphological deformations. Seasonal first flushes, despite having higher metal concentrations, did not adversely affect the toad larvae, apparently due to a counter effect of organic matter that potentially served as a supplementary energy resource. Road runoff can be a major cause for a qualitative decrease in the quality of aquatic habitats threatening amphibians in Israel. Copyright © 2010 Elsevier Ltd. All rights reserved.

Effects of Bread Making and Wheat Germ Addition on the Natural Deoxynivalenol Content in Bread

PubMed Central

Giménez, Isabel; Blesa, Jesús; Herrera, Marta; Ariño, Agustín

2014-01-01

Deoxynivalenol (DON, vomitoxin) is a type-B trichothecene mycotoxin produced by several field fungi such as Fusarium graminearum and Fusarium culmorum and known to have various toxic effects. This study investigated the effect of the bread making process on the stability of DON in common bread and wheat germ-enriched bread using naturally contaminated ingredients at the level of 560 µg/kg. The concentration of DON and its evolution during bread making were determined by immunoaffinity column cleanup followed by liquid chromatography with diode array detection (HPLC-DAD). During the bread making process, DON was reduced by 2.1% after fermentation and dropped by 7.1% after baking, reaching a maximum reduction of 19.8% in the crust as compared with a decrease of 5.6% in the crumb. The addition of 15% wheat germ to the dough did not affect DON stability during bread making, showing an apparent increase of 3.5% after fermentation and a reduction by 10.2% after baking. PMID:24451845

Protease inhibitors from several classes work synergistically against Callosobruchus maculatus.

PubMed

Amirhusin, Bahagiawati; Shade, Richard E; Koiwa, Hisashi; Hasegawa, Paul M; Bressan, Ray A; Murdock, Larry L; Zhu-Salzman, Keyan

2007-07-01

Targeting multiple digestive proteases may be more effective in insect pest control than inhibition of a single enzyme class. We therefore explored possible interactions of three antimetabolic protease inhibitors fed to cowpea bruchids in artificial diets, using a recombinant soybean cysteine protease inhibitor scN, an aspartic protease inhibitor pepstatin A, and soybean Kunitz trypsin inhibitor KI. scN and pepstatin, inhibiting major digestive cysteine and aspartic proteases, respectively, significantly prolonged the developmental time of cowpea bruchids individually. When combined, the anti-insect effect was synergistic, i.e., the toxicity of the mixture was markedly greater than that of scN or pepstatin alone. KI alone did not impact insect development even at relatively high concentrations, but its anti-insect properties became apparent when acting jointly with scN or scN plus pepstatin. Incubating KI with bruchid midgut extract showed that it was partially degraded. This instability may explain its lack of anti-insect activity. However, this proteolytic degradation was inhibited by scN and/or pepstatin. Protection of KI from proteolysis in the insect digestive tract thus could be the basis for the synergistic effect. These observations support the concept that cowpea bruchid gut proteases play a dual role; digesting protein for nutrient needs and protecting insects by inactivating dietary proteins that may otherwise be toxic. Our results also suggest that transgenic resistance strategies that involve multigene products are likely to have enhanced efficacy and durability.

Risks of municipal solid waste incineration: an environmental perspective.

PubMed

Denison, R A; Silbergeld, E K

1988-09-01

The central focus of the debate over incineration of municipal solid waste (MSW) has shifted from its apparent management advantages to unresolved risk issues. This shift is a result of the lack of comprehensive consideration of risks associated with incineration. We discuss the need to expand incinerator risk assessment beyond the limited view of incinerators as stationary air pollution sources to encompass the following: other products of incineration, ash in particular, and pollutants other than dioxins, metals in particular; routes of exposure in addition to direct inhalation; health effects in addition to cancer; and the cumulative nature of exposure and health effects induced by many incinerator-associated pollutants. Rational MSW management planning requires that the limitations as well as advantages of incineration be recognized. Incineration is a waste-processing--not a waste disposal--technology, and its products pose substantial management and disposal problems of their own. Consideration of the nature of these products suggests that incineration is ill-suited to manage the municipal wastestream in its entirety. In particular, incineration greatly enhances the mobility and bioavailability of toxic metals present in MSW. These factors suggest that incineration must be viewed as only one component in an integrated MSW management system. The potential for source reduction, separation, and recycling to increase the safety and efficiency of incineration should be counted among their many benefits. Risk considerations dictate that alternatives to the use of toxic metals at the production stage also be examined in designing an effective, long-term MSW management strategy.

Interactive toxicity of chlorpyrifos and parathion in neonatal rats: Role of esterases in exposure sequence-dependent toxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kacham, R.; Karanth, S.; Baireddy, P.

2006-01-15

We previously reported that sequence of exposure to chlorpyrifos and parathion in adult rats can markedly influence toxic outcome. In the present study, we evaluated the interactive toxicity of chlorpyrifos (8 mg/kg, po) and parathion (0.5 mg/kg, po) in neonatal (7 days old) rats. Rats were exposed to the insecticides either concurrently or sequentially (separated by 4 h) and sacrificed at 4, 8, and 24 h after the first exposure for biochemical measurements (cholinesterase activity in brain, plasma, and diaphragm and carboxylesterase activity in plasma and liver). The concurrently-exposed group showed more cumulative lethality (15/24) than either of the sequentialmore » dosing groups. With sequential dosing, rats treated initially with chlorpyrifos prior to parathion (C/P) exhibited higher lethality (7/23) compared to those treated with parathion before chlorpyrifos (P/C; 1/24). At 8 h after initial dosing, brain cholinesterase inhibition was significantly greater in the C/P group (59%) compared to the P/C group (28%). Diaphragm and plasma cholinesterase activity also followed a relatively similar pattern of inhibition. Carboxylesterase inhibition in plasma and liver was relatively similar among the treatment groups across time-points. Similar sequence-dependent differences in brain cholinesterase inhibition were also noted with lower binary exposures to chlorpyrifos (2 mg/kg) and parathion (0.35 mg/kg). In vitro and ex vivo studies compared relative oxon detoxification of carboxylesterases (calcium-insensitive) and A-esterases (calcium-sensitive) in liver homogenates from untreated and insecticide pretreated rats. Using tissues from untreated rats, carboxylesterases detoxified both chlorpyrifos oxon and paraoxon, while A-esterases only detoxified chlorpyrifos oxon. With parathion pretreatment, A-esterases still detoxified chlorpyrifos oxon while liver from chlorpyrifos pretreated rats had little apparent effect on paraoxon. We conclude that while neonatal rats are less capable than adults at detoxifying many organophosphorus insecticides including chlorpyrifos and parathion, toxicant-selective differences in detoxification play a role in sequence-dependent toxicity in both neonatal and adult rats with these two insecticides.« less

The CsoR-like sulfurtransferase repressor (CstR) is a persulfide sensor in Staphylococcus aureus.

PubMed

Luebke, Justin L; Shen, Jiangchuan; Bruce, Kevin E; Kehl-Fie, Thomas E; Peng, Hui; Skaar, Eric P; Giedroc, David P

2014-12-01

How cells regulate the bioavailability of utilizable sulfur while mitigating the effects of hydrogen sulfide toxicity is poorly understood. CstR [Copper-sensing operon repressor (CsoR)-like sulfurtransferase repressor] represses the expression of the cst operon encoding a putative sulfide oxidation system in Staphylococcus aureus. Here, we show that the cst operon is strongly and transiently induced by cellular sulfide stress in an acute phase and specific response and that cst-encoded genes are necessary to mitigate the effects of sulfide toxicity. Growth defects are most pronounced when S. aureus is cultured in chemically defined media with thiosulfate (TS) as a sole sulfur source, but are also apparent when cystine is used or in rich media. Under TS growth conditions, cells fail to grow as a result of either unregulated expression of the cst operon in a ΔcstR strain or transformation with a non-inducible C31A/C60A CstR that blocks cst induction. This suggests that the cst operon contributes to cellular sulfide homeostasis. Tandem high-resolution mass spectrometry reveals derivatization of CstR by both inorganic tetrasulfide and an organic persulfide, glutathione persulfide, to yield a mixture of Cys31-Cys60' interprotomer cross-links, including di-, tri- and tetrasulfide bonds, which allosterically inhibit cst operator DNA binding by CstR. © 2014 John Wiley & Sons Ltd.

The CsoR-like sulfurtransferase repressor (CstR) is a persulfide sensor in Staphylococcus aureus

PubMed Central

Luebke, Justin L.; Shen, Jiangchuan; Bruce, Kevin E.; Kehl-Fie, Thomas E.; Peng, Hui; Skaar, Eric P.; Giedroc, David P.

2014-01-01

How cells regulate the bioavailability of utilizable sulfur while mitigating the effects of hydrogen sulfide toxicity is poorly understood. CstR (Copper-sensing operon repressor (CsoR)-like sulfurtransferase repressor) represses the expression of the cst operon encoding a putative sulfide oxidation system in Staphylococcus aureus. Here, we show that the cst operon is strongly and transiently induced by cellular sulfide stress in an acute phase and specific response and that cst-encoded genes are necessary to mitigate the effects of sulfide toxicity. Growth defects are most pronounced when S. aureus is cultured in chemically defined media with thiosulfate (TS) as a sole sulfur source, but are also apparent when cystine is used or in rich media. Under TS growth conditions, cells fail to grow as a result of either unregulated expression of the cst operon in a ΔcstR strain or transformation with a non-inducible C31A/C60A CstR that blocks cst induction. This suggests that the cst operon contributes to cellular sulfide homeostasis. Tandem high resolution mass spectrometry reveals derivatization of CstR by both inorganic tetrasulfide and an organic persulfide, glutathione persulfide, to yield a mixture of Cys31-Cys60’ interprotomer crosslinks, including di-, tri- and tetrasulfide bonds, which allosterically inhibit cst operator DNA binding by CstR. PMID:25318663

Use of the peroxisome proliferator-activated receptor (PPAR) gamma ligand troglitazone as treatment for refractory breast cancer: a phase II study.

PubMed

Burstein, Harold J; Demetri, George D; Mueller, Elisabetta; Sarraf, Pasha; Spiegelman, Bruce M; Winer, Eric P

2003-06-01

To evaluate the therapeutic effects of the peroxisome proliferator-activated receptor (PPAR) gamma activating ligand, troglitazone, in patients with refractory metastatic breast cancer. Patients with advanced breast cancer refractory to at least one chemotherapy regimen (ER negative tumors) or two hormonal regimens (ER positive tumors) were treated with troglitazone at 800 mg p.o. QD until disease progression, to determine the percentage of patients free of progression at 6 months. Tumor response, toxicity, and changes in serum tumor markers (CEA, CA27.29) that might reflect alteration in tumor differentiation, were also examined. Twenty-two patients were enrolled before suspension of protocol accrual and treatment when troglitazone was withdrawn from commercial availability following FDA warnings on hepatic toxicity. No objective responses (CR or PR) were observed; only three patients had SD at 8 weeks. Patients came off study for PD (16), DLT (1), FDA withdrawal (2), or other (3) reasons. No patients took troglitazone for more than 20 weeks; all had experienced disease progression or began other systemic therapy within 6 months. All patients with elevated serum tumor markers (CEA and CA27.29) at baseline had rising tumor markers within 8 weeks. While clinical trials among different patient populations might uncover subtle effects on tumor differentiation, PPARgamma activation by troglitazone has little apparent clinical value among patients with treatment-refractory metastatic breast cancer.

Effects of lampricide exposure on the survival, growth, and behavior of the unionid mussels Elliptio complanata and Pyganadon cataracta

USGS Publications Warehouse

Waller, D.L.; Bills, T.D.; Boogaard, M.A.; Johnson, D.A.; Doolittle, T.C.J.

2003-01-01

The effects of a 12-h exposure to the lampricide 3-trifluoromethyl-4- nitrophenol (TFM) and a combination of TFM and 1% niclosamide (active ingredient in Bayluscide 70% wettable powder) on the short and long-term (10 mo post exposure) survival and behavior of two unionid freshwater mussel species Elliptio complanata and Pyganadon cataracta were measured. Growth of juvenile E. complanata mussels 10 months after exposure was also compared. Toxicity was determined after 12 h exposures at maximum concentrations from 2- to 2.5- fold higher than the LC99 for sea lamprey larvae. A logistic model was used to estimate the probability of survival among treatments, trials, species, and sizes. Mortality was minimal in all test concentrations of TFM alone and the TFM/1% niclosamide combination. Estimated survival decreased 6% for each unit increase in the relative toxicity of TFM. Survival was greater for E. complanata than for P. cataracta, and for adults relative to juveniles. Lampricide treatment caused narcotization of both mussels (defined as having gaped shells and an extended foot) in concentrations ??? LC99 for sea lamprey larvae and narcotization ranged from 0-50% among treatments. Recovery from narcosis was apparent by 12 h post-exposure and complete by 36 h post-exposure. The rate of growth of E. complanata over the 10-month post-exposure period did not vary among treatments.

High-level exposure to lithium, boron, cesium, and arsenic via drinking water in the Andes of northern Argentina.

PubMed

Concha, Gabriela; Broberg, Karin; Grandér, Margaretha; Cardozo, Alejandro; Palm, Brita; Vahter, Marie

2010-09-01

Elevated concentrations of arsenic in drinking water are common worldwide, however, little is known about the presence of other potentially toxic elements. We analyzed 31 different elements in drinking water collected in San Antonio de los Cobres and five surrounding Andean villages in Argentina, and in urine of the inhabitants, using ICP-MS. Besides confirmation of elevated arsenic concentrations in the drinking water (up to 210 microg/L), we found remarkably high concentrations of lithium (highest 1000 microg/L), cesium (320 microg/L), rubidium (47 microg/L), and boron (5950 microg/L). Similarly elevated concentrations of arsenic, lithium, cesium, and boron were found in urine of the studied women (N=198): village median values ranged from 26 to 266 microg/L of arsenic, 340 to 4550 microg/L of lithium, 34 to 531 microg/L of cesium, and 2980 to 16,560 microg/L of boron. There is an apparent risk of toxic effects of long-term exposure to several of the elements, and studies on associations with adverse human health effects are warranted, particularly considering the combined, life-long exposure. Because of the observed wide range of concentrations, all water sources used for drinking water should be screened for a large number of elements; obviously, this applies to all drinking water sources globally.

Toxicity and bioavailability of metals in the Missouri River adjacent to a lead refinery

USGS Publications Warehouse

Chapman, Duane C.; Allert, Ann L.; Fairchild, James F.; May, Thomas W.; Schmitt, Christopher J.; Callahan, Edward V.

2001-01-01

This study is an evaluation of the potential environmental impacts of contaminated groundwater from the ASARCO metals refining facility adjacent to the Missouri River in Omaha, Nebraska. Surface waters, sediments, and sediment pore waters were collected from the Burt-Izard drain, which transects the facility, and from the Missouri River adjacent to the facility. Groundwater was also collected from the facility. Waters and sediments were analyzed for inorganic contaminants, and the toxicity of the waters was evaluated with the Ceriodaphnia dubia 7-day test. Concentrations of several elemental contaminants were highly elevated in the groundwater, but not in river sediment pore waters. Lead concentrations were moderately elevated in whole sediment at one site, but lead concentrations in pore waters were low due to apparent sequestration by acid-volatile sulfides. The groundwater sample was highly toxic to C. dubia, causing 100% mortality. Even at the lowest groundwater concentration tested (6.25%) C. dubia survival was reduced; however, at that concentration, reproduction was not significantly different from upstream porewater reference samples. Sediment pore waters were not toxic, except reproduction in pore water collected from one downstream site was somewhat reduced. The decrease in reproduction could not be attributed to measured elemental contaminants.

Toxicity of seabird guano to sea urchin embryos and interaction with Cu and Pb.

PubMed

Rial, Diego; Santos-Echeandía, Juan; Álvarez-Salgado, Xosé Antón; Jordi, Antoni; Tovar-Sánchez, Antonio; Bellas, Juan

2016-02-01

Guano is an important source of marine-derived nutrients to seabird nesting areas. Seabirds usually present high levels of metals and other contaminants because the bioaccumulation processes and biotic depositions can increase the concentration of pollutants in the receiving environments. The objectives of this study were to investigate: the toxicity of seabird guano and the joint toxicity of guano, Cu and Pb by using the sea urchin embryo-larval bioassay. In a first experiment, aqueous extracts of guano were prepared at two loading rates (0.462 and 1.952 g L(-1)) and toxicity to sea-urchin embryos was tested. Toxicity was low and not dependent of the load of guano used (EC50 0.42 ± 0.03 g L(-1)). Trace metal concentrations were also low either in guano or in aqueous extracts of guano and the toxicity of extracts were apparently related to dissolved organic matter. In a second experiment, the toxicity of Cu-Pb mixtures in artificial seawater and in extracts of guano (at two loadings: 0.015 and 0.073 g L(-1)), was tested. According to individual fittings, Cu added to extracts of guano showed less toxicity than when dissolved in artificial seawater. The response surfaces obtained for mixtures of Cu and Pb in artificial seawater, and in 0.015 g L(-1) and 0.073 g L(-1) of guano, were better described by Independent Action model adapted to describe antagonism, than by the other proposed models. This implied accepting that EC50 for Cu and Pb increased with the load of guano and with a greater interaction for Cu than for Pb. Copyright © 2015 Elsevier Ltd. All rights reserved.

Soil fertility and plant diversity enhance microbial performance in metal-polluted soils.

PubMed

Stefanowicz, Anna M; Kapusta, Paweł; Szarek-Łukaszewska, Grażyna; Grodzińska, Krystyna; Niklińska, Maria; Vogt, Rolf D

2012-11-15

This study examined the effects of soil physicochemical properties (including heavy metal pollution) and vegetation parameters on soil basal respiration, microbial biomass, and the activity and functional richness of culturable soil bacteria and fungi. In a zinc and lead mining area (S Poland), 49 sites were selected to represent all common plant communities and comprise the area's diverse soil types. Numerous variables describing habitat properties were reduced by PCA to 7 independent factors, mainly representing subsoil type (metal-rich mining waste vs. sand), soil fertility (exchangeable Ca, Mg and K, total C and N, organic C), plant species richness, phosphorus content, water-soluble heavy metals (Zn, Cd and Pb), clay content and plant functional diversity (based on graminoids, legumes and non-leguminous forbs). Multiple regression analysis including these factors explained much of the variation in most microbial parameters; in the case of microbial respiration and biomass, it was 86% and 71%, respectively. The activity of soil microbes was positively affected mainly by soil fertility and, apparently, by the presence of mining waste in the subsoil. The mining waste contained vast amounts of trace metals (total Zn, Cd and Pb), but it promoted microbial performance due to its inherently high content of macronutrients (total Ca, Mg, K and C). Plant species richness had a relatively strong positive effect on all microbial parameters, except for the fungal component. In contrast, plant functional diversity was practically negligible in its effect on microbes. Other explanatory variables had only a minor positive effect (clay content) or no significant influence (phosphorus content) on microbial communities. The main conclusion from this study is that high nutrient availability and plant species richness positively affected the soil microbes and that this apparently counteracted the toxic effects of metal contamination. Copyright © 2012 Elsevier B.V. All rights reserved.

Toxic effects of dietary methylmercury on immune function and hematology in American kestrels (Falco sparverius)

USGS Publications Warehouse

Fallacara, Dawn M.; Halbrook, Richard S.; French, John B.

2011-01-01

Fifty-nine adult male American kestrels (Falco sparverius) were assigned to one of three diet formulations including 0 (control), 0.6, and 3.9 μg/g (dry wt) methylmercury (MeHg). Kestrels received their diets daily for 13 weeks to assess the effects of dietary MeHg on immunocompetence. Immunotoxic endpoints included assessment of cell-mediated immunity (CMI) using the phytohemagglutinin (PHA) skin-swelling assay and primary and secondary antibody-mediated immune responses (IR) via the sheep red blood cell (SRBC) hemagglutination assay. Select hematology and histology parameters were evaluated to corroborate the results of functional assays and to assess immunosuppression of T and B cell-dependent components in spleen tissue. Kestrels in the 0.6 and 3.9 μg/g MeHg groups exhibited suppression of CMI, including lower PHA stimulation indexes (p = 0.019) and a 42 to 45% depletion of T cell-dependent splenic lymphoid tissue (p = 0.006). Kestrels in the 0.6 μg/g group exhibited suppression of the primary IR to SRBCs (p = 0.014). MeHg did not have a noticeable effect on the secondary IR (p = 0.166). Elevation of absolute heterophil counts (p p p = 0.003) was apparent in the 3.9 μg/g group at week 12. Heterophilia, or the excess of heterophils in peripheral blood above normal ranges, was apparent in seven of 17 (41%) kestrels in the 3.9 μg/g group and was indicative of an acute inflammatory response or physiological stress. This study revealed that adult kestrels were more sensitive to immunotoxic effects of MeHg at environmentally relevant dietary concentrations than they were to reproductive effects as previously reported.

Enantioselectivity in tebuconazole and myclobutanil non-target toxicity and degradation in soils.

PubMed

Li, Yuanbo; Dong, Fengshou; Liu, Xingang; Xu, Jun; Han, Yongtao; Zheng, Yongquan

2015-03-01

Tebuconazole and myclobutanil are two widely used triazole fungicides, both comprising two enantiomers with different fungicidal activity. However, their non-target toxicity and environmental behavior with respect to enantioselectivity have received limited attention. In the present study, tebuconazole and myclobutanil enantiomers were isolated and used to evaluate the occurrence of enantioselectivity in their acute toxicity to three non-target organisms (Scenedesmus obliquus, Daphnia magna, and Danio rerio). Significant differences were found: R-(-)-tebuconazole was about 1.4-5.9 times more toxic than S-(+)-tebuconazole; rac-myclobutanil was about 1.3-6.1 and 1.4-7.3 more toxic than (-)-myclobutanil and (+)-myclobutanil, respectively. Enantioselectivity was further investigated in terms of fungicide degradation in seven soil samples, which were selected to cover a broad range of soil properties. In aerobic or anaerobic soils, the S-(+)-tebuconazole degraded faster than R-(-)-tebuconazole, and the enantioselectivity showed a correlation with soil organic carbon content. (+)-Myclobutanil was preferentially degraded than (-)-myclobutanil in aerobic soils, whereas both enantiomers degraded at similar rates in anaerobic soils. Apparent correlations of enantioselectivity with soil pH and soil texture were observed for myclobutanil under aerobic conditions. In addition, both fungicides were configurationally stable in soils, i.e., no enantiomerization was found. Enantioselectivity may be a common phenomenon in both aquatic toxicity and biodegradation of chiral triazole fungicides, and this should be considered when assessing ecotoxicological risks of these compounds in the environment. Copyright © 2014 Elsevier Ltd. All rights reserved.

The effects of taurolidine alone and in combination with doxorubicin or carboplatin in canine osteosarcoma in vitro.

PubMed

Marley, Kevin; Helfand, Stuart C; Edris, Wade A; Mata, John E; Gitelman, Alix I; Medlock, Jan; Séguin, Bernard

2013-01-18

Osteosarcoma (OS) affects over 8000 dogs/year in the United States. The disease usually arises in the appendicular skeleton and metastasizes to the lung. Dogs with localized appendicular disease benefit from limb amputation and chemotherapy but most die within 6-12 months despite these treatments. Taurolidine, a derivative of taurine, has anti-tumor and anti-angiogenic effects against a variety of cancers. The following in vitro studies tested taurolidine as a candidate for adjuvant therapy for canine OS. Tests for p53 protein status and caspase activity were used to elucidate mechanisms of taurolidine-induced cell death. Taurolidine was cytotoxic to osteosarcoma cells and increased the toxicity of doxorubicin and carboplatin in vitro. Apoptosis was greatly induced in cells exposed to 125 μM taurolidine and less so in cells exposed to 250 μM taurolidine. Taurolidine cytotoxicity appeared caspase-dependent in one cell line; with apparent mutant p53 protein. This cell line was the most sensitive to single agent taurolidine treatment and had a taurolidine-dependent reduction in accumulated p53 protein suggesting taurolidine's effects may depend on the functional status of p53 in canine OS. Taurolidine's cytotoxic effect appears dependent on cell specific factors which may be explained, in part, by the functional status of p53. Taurolidine initiates apoptosis in canine OS cells and this occurs to a greater extent at lower concentrations. Mechanisms of cell death induced by higher concentrations were not elucidated here. Taurolidine combined with doxorubicin or carboplatin can increase the toxicity of these chemotherapy drugs and warrants further investigation in dogs with osteosarcoma.

Ultra-long-duration local anesthesia produced by injection of lecithin-coated methoxyflurane microdroplets.

PubMed

Haynes, D H; Kirkpatrick, A F

1985-11-01

This study was designed to evaluate a new drug delivery system. The authors undertook to determine if microdroplets prepared by encapsulating volatile anesthetics with a membrane of lecithin could be used for local anesthesia. Local anesthesia was determined by monitoring the response of the rat to tail clamping and electrical stimulation of the skin following the intradermal injection of the microdroplets. Microdroplets were prepared from isoflurane, enflurane, halothane, methoxyflurane, diethyl ether, chloroform, and heptane. Although all microdroplet preparations produced local anesthesia, only methoxyflurane microdroplets produced an ultra-long duration of local anesthesia (approximately 24 h). Further characterization of the methoxyflurane microdroplets revealed two important differences from conventional local anesthetics. First, the local anesthetic effect of methoxyflurane reached a plateau that did not change significantly for 20 h while the injection of lidocaine and bupivacaine resulted in a peak effect that returned to baseline within 1 and 3 h, respectively. Second, the anesthetic effect of methoxyflurane remained essentially localized to the site of injection, while the anesthetic effect of lidocaine and bupivacaine migrated 15 cm in less than 1 h. The toxicity and safety of methoxyflurane were evaluated. When administered over the dosage range 1-16% (v/v) intradermally, or by injections into muscle, or by repeat injections every 4 days for 16 days, all animals regained their pretreatment response to painful stimulations, and there was no evidence of gross injury to tissue. Deliberate intravenous injection of 0.8 ml of 6.7% (v/v) methoxyflurane microdroplets had no apparent anesthetic or toxic effect. The present study demonstrates that methoxyflurane microdroplets produce an anesthetic effect that is highly localized, stable in intensity, ultra-long in duration, and reversible.

Dual-modality, fluorescent, PLGA encapsulated bismuth nanoparticles for molecular and cellular fluorescence imaging and computed tomography

NASA Astrophysics Data System (ADS)

Swy, Eric R.; Schwartz-Duval, Aaron S.; Shuboni, Dorela D.; Latourette, Matthew T.; Mallet, Christiane L.; Parys, Maciej; Cormode, David P.; Shapiro, Erik M.

2014-10-01

Reports of molecular and cellular imaging using computed tomography (CT) are rapidly increasing. Many of these reports use gold nanoparticles. Bismuth has similar CT contrast properties to gold while being approximately 1000-fold less expensive. Herein we report the design, fabrication, characterization, and CT and fluorescence imaging properties of a novel, dual modality, fluorescent, polymer encapsulated bismuth nanoparticle construct for computed tomography and fluorescence imaging. We also report on cellular internalization and preliminary in vitro and in vivo toxicity effects of these constructs. 40 nm bismuth(0) nanocrystals were synthesized and encapsulated within 120 nm Poly(dl-lactic-co-glycolic acid) (PLGA) nanoparticles by oil-in-water emulsion methodologies. Coumarin-6 was co-encapsulated to impart fluorescence. High encapsulation efficiency was achieved ~70% bismuth w/w. Particles were shown to internalize within cells following incubation in culture. Bismuth nanocrystals and PLGA encapsulated bismuth nanoparticles exhibited >90% and >70% degradation, respectively, within 24 hours in acidic, lysosomal environment mimicking media and both remained nearly 100% stable in cytosolic/extracellular fluid mimicking media. μCT and clinical CT imaging was performed at multiple X-ray tube voltages to measure concentration dependent attenuation rates as well as to establish the ability to detect the nanoparticles in an ex vivo biological sample. Dual fluorescence and CT imaging is demonstrated as well. In vivo toxicity studies in rats revealed neither clinically apparent side effects nor major alterations in serum chemistry and hematology parameters. Calculations on minimal detection requirements for in vivo targeted imaging using these nanoparticles are presented. Indeed, our results indicate that these nanoparticles may serve as a platform for sensitive and specific targeted molecular CT and fluorescence imaging.Reports of molecular and cellular imaging using computed tomography (CT) are rapidly increasing. Many of these reports use gold nanoparticles. Bismuth has similar CT contrast properties to gold while being approximately 1000-fold less expensive. Herein we report the design, fabrication, characterization, and CT and fluorescence imaging properties of a novel, dual modality, fluorescent, polymer encapsulated bismuth nanoparticle construct for computed tomography and fluorescence imaging. We also report on cellular internalization and preliminary in vitro and in vivo toxicity effects of these constructs. 40 nm bismuth(0) nanocrystals were synthesized and encapsulated within 120 nm Poly(dl-lactic-co-glycolic acid) (PLGA) nanoparticles by oil-in-water emulsion methodologies. Coumarin-6 was co-encapsulated to impart fluorescence. High encapsulation efficiency was achieved ~70% bismuth w/w. Particles were shown to internalize within cells following incubation in culture. Bismuth nanocrystals and PLGA encapsulated bismuth nanoparticles exhibited >90% and >70% degradation, respectively, within 24 hours in acidic, lysosomal environment mimicking media and both remained nearly 100% stable in cytosolic/extracellular fluid mimicking media. μCT and clinical CT imaging was performed at multiple X-ray tube voltages to measure concentration dependent attenuation rates as well as to establish the ability to detect the nanoparticles in an ex vivo biological sample. Dual fluorescence and CT imaging is demonstrated as well. In vivo toxicity studies in rats revealed neither clinically apparent side effects nor major alterations in serum chemistry and hematology parameters. Calculations on minimal detection requirements for in vivo targeted imaging using these nanoparticles are presented. Indeed, our results indicate that these nanoparticles may serve as a platform for sensitive and specific targeted molecular CT and fluorescence imaging. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr01405g

Effects of pesticides on Canada Geese

USGS Publications Warehouse

Blus, L.J.; Rusch, Donald H.; Samuel, Michael D.; Humburg, Dale D.; Sullivan, Brian D.

1998-01-01

This paper summarizes published and unpublished sources relating to exposure of Canada geese (Branta canadensis) to pesticides, emphasizing documented episodes of poisoning by organochlorine (OC), organophosphorus (OP), and carbamate compounds. Canada geese accumulate the lipid-soluble OC compounds, although they have a lower potential for biomagnification of these pesticides than animals at higher trophic levels in food webs. Low residues of p,p'-DDT and its metabolite p,p'-DDE were frequently found in tissues and eggs of Canada geese, but they had no apparent adverse effects on reproductive success or eggshell thickness. Likewise, in an orchard system in central Washington state, the OC rodenticide endrin accumulated in tissues and eggs of Canada geese without apparent adverse effect. In contrast, ingestion of seeds treated with the OC heptachlor caused mortality, lowered reproductive success, and caused a local population decline of geese in Oregon and Washington. In recent years, the most persistent OC's have been banned by law and replaced with less persistent carbamate and OP compounds that do not readily accumulate in animal tissues. However, many of these compounds are acutely toxic and have caused numerous die-offs of Canada geese. Among OP compounds, diazinon was responsible for most reported die-offs (41 incidents involving >535 geese), whereas parathion applied alone or jointly with methyl parathion accounted for most reported mortalities (8 incidents involving >3,000 geese). Three other OP's, a carbamate (carbofuran), zinc phosphide, and strychnine also caused goose die-offs. Mortality from anticholinesterase (antiChE) compounds occurs relatively soon after exposure and death can usually be diagnosed by evaluation of brain cholinesterase (thE) activity. Because geese are primarily grazers, the main route of exposure to antiChE's is apparently ingestion of contaminated grasses and forbs; dermal absorption and inhalation are other routes. Despite the widespread die-offs of Canada geese from antiChE insecticides, there is no evidence of adverse effects on population levels. It is not known how sublethal antiChE exposure relates to long-term survival and reproductive success of birds.

DOE Office of Scientific and Technical Information (OSTI.GOV)

McNulty, W.P.

In rhesus macaques (Macaca mulatta), consumption of food containing commercial polychlorinated biphenyl (PCB) mixtures, some pure polychlorobiphenyl congeners, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and 2,3,7,8-tetrachlorodibenzofuran (TCDF) caused the same clinical toxic manifestations and histopathologic lesions, although the potencies of the toxicants covered a range of five orders of magnitude. Recovery from poisoning by 3,4,3',4'-tetrachlorobiphenyl (34TCB) or TCDF was rapid, whereas recovery from poisoning by Aroclor 1242, 3,4,5,3',4',5'-hexachlorobiphenyl (345HCB), or TCDD was protracted, if it occurred at all. 34TCB did not appreciably accumulate in body fat, but the level of 345HCB in fat rose steadily during ingestion. Among the symmetrical tetra- and hexachlorobiphenyl isomersmore » tested, subacute oral toxicity could be demonstrated only for those without ortho chlorine substitutions. The principal demonstrable histopathological lesions, bone marrow excepted, were metaplasias in some specialized epithelial structures, such as sebaceous glands, nail beds, gastric mucosa, ameloblast, and thymic corpuscles. These changes were interpreted as toxicant-induced, reversible redirection of differentiation. this aberration was wholly reversible. TCDD and 34TCB caused abortions when given in one or a few oral doses early in pregnancy. At the total doses used (1 or 5 g/kg of body weight for TCDD, 3 or 0.6 mg/kg of body weight for 34TCB), maternal toxicity was frequently apparent subsequent to the abortion.« less

A polymeric colchicinoid prodrug with reduced toxicity and improved efficacy for vascular disruption in cancer therapy

PubMed Central

Crielaard, Bart J; van der Wal, Steffen; Lammers, Twan; Le, Huong Thu; Hennink, Wim E; Schiffelers, Raymond M; Storm, Gert; Fens, Marcel HAM

2011-01-01

Colchicinoids are very potent tubulin-binding compounds, which interfere with microtubule formation, giving them strong cytotoxic properties, such as cell mitosis inhibition and induction of microcytoskeleton depolymerization. While this makes them promising vascular disrupting agents (VDAs) in cancer therapy, their dose-limiting toxicity has prevented any clinical application for this purpose. Therefore, colchicinoids are considered attractive lead molecules for the development of novel vascular disrupting nanomedicine. In a previous study, a polymeric colchicinoid prodrug that showed favorable hydrolysis characteristics at physiological conditions was developed. In the current study, this polymeric colchicinoid prodrug was evaluated in vitro and in vivo for its toxicity and vascular disrupting potential. Cell viability studies with human umbilical vein endothelial cells, as an in vitro measure for colchicine activity, reflected the degradation kinetics of the prodrug accordingly. Upon intravenous treatment, in vivo, of B16F10 melanoma-bearing mice with colchicine or with the polymeric colchicinoid prodrug, apparent vascular disruption and consequent tumor necrosis was observed for the prodrug but not for free colchicine at an equivalent dose. Moreover, a five-times-higher dose of the prodrug was well tolerated, indicating reduced toxicity. These findings demonstrate that the polymeric colchicinoid prodrug has a substantially improved efficacy/toxicity ratio compared with that of colchicine, making it a promising VDA for cancer therapy. PMID:22114500

THE ANTIGENIC PROPERTIES OF GLOBIN CASEINATE

PubMed Central

Gay, Frederick P.; Robertson, T. Brailsford

1913-01-01

This study of globin and its compound with casein (globin caseinate) shows that globin fails to produce fixation antibodies in rabbits after repeated injections, thus agreeing with our own work and with that of others with similar histon bodies which are primarily toxic. When globin is combined with casein, however, it gives rise to antibodies that react not only with globin caseinate and casein but also with globin. The antibodies in antiglobin casein serum are apparently separate, one for globin and one for casein. In other words, the change in globin undergone on combination with casein has apparently rendered it antigenic. We did not succeed in demonstrating the genesis of this new antigenic property by anaphylaxis experiments. A further investigation of similar and more complex combined proteins is indicated and gives promise of more light on the nature of biological specificity. PMID:19867665

Bans of WHO Class I Pesticides in Bangladesh—suicide prevention without hampering agricultural output

PubMed Central

Chowdhury, Fazle Rabbi; Dewan, Gourab; Verma, Vasundhara R; Knipe, Duleeka W; Isha, Ishrat Tahsin; Faiz, M Abul; Gunnell, David J; Eddleston, Michael

2018-01-01

Abstract Background Pesticide self-poisoning is a major problem in Bangladesh. Over the past 20-years, the Bangladesh government has introduced pesticide legislation and banned highly hazardous pesticides (HHPs) from agricultural use. We aimed to assess the impacts of pesticide bans on suicide and on agricultural production. Methods We obtained data on unnatural deaths from the Statistics Division of Bangladesh Police, and used negative binomial regression to quantify changes in pesticide suicides and unnatural deaths following removal of WHO Class I toxicity HHPs from agriculture in 2000. We assessed contemporaneous trends in other risk factors, pesticide usage and agricultural production in Bangladesh from 1996 to 2014. Results Mortality in hospital from pesticide poisoning fell after the 2000 ban: 15.1% vs 9.5%, relative reduction 37.1% [95% confidence interval (CI) 35.4 to 38.8%]. The pesticide poisoning suicide rate fell from 6.3/100 000 in 1996 to 2.2/100 000 in 2014, a 65.1% (52.0 to 76.7%) decline. There was a modest simultaneous increase in hanging suicides [20.0% (8.4 to 36.9%) increase] but the overall incidence of unnatural deaths fell from 14.0/100 000 to 10.5/100 000 [25.0% (18.1 to 33.0%) decline]. There were 35 071 (95% CI 25 959 to 45 666) fewer pesticide suicides in 2001 to 2014 compared with the number predicted based on trends between 1996 to 2000. This reduction in rate of pesticide suicides occurred despite increased pesticide use and no change in admissions for pesticide poisoning, with no apparent influence on agricultural output. Conclusions Strengthening pesticide regulation and banning WHO Class I toxicity HHPs in Bangladesh were associated with major reductions in deaths and hospital mortality, without any apparent effect on agricultural output. Our data indicate that removing HHPs from agriculture can rapidly reduce suicides without imposing substantial agricultural costs. PMID:29024951

Vasoactive Intestinal Peptide Inhibits Human Small-Cell Lung Cancer Proliferation in vitro and in vivo

NASA Astrophysics Data System (ADS)

Maruno, Kaname; Absood, Afaf; Said, Sami I.

1998-11-01

Small-cell lung carcinoma (SCLC) is an aggressive, rapidly growing and metastasizing, and highly fatal neoplasm. We report that vasoactive intestinal peptide inhibits the proliferation of SCLC cells in culture and dramatically suppresses the growth of SCLC tumor-cell implants in athymic nude mice. In both cases, the inhibition was mediated apparently by a cAMP-dependent mechanism, because the inhibition was enhanced by the adenylate cyclase activator forskolin and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine in proportion to increases in intracellular cAMP levels, and the inhibition was abolished by selective inhibition of cAMP-dependent protein kinase. If confirmed in clinical trials, this antiproliferative action of vasoactive intestinal peptide may offer a new and promising means of suppressing SCLC in human subjects, without the toxic side effects of chemotherapeutic agents.

Edetate Disodium-Based Treatment for Secondary Prevention in Post-Myocardial Infarction Patients.

PubMed

Lamas, Gervasio A; Issa, Omar M

2016-02-01

An abundance of data, known for decades, is available linking metals, such as lead and cadmium, with cardiovascular disease. However, the idea that these toxic metals could be a modifiable risk factor for atherosclerosis did not become apparent clinically until the completion of the Trial to Assess Chelation Therapy in 2012. This pivotal study was the first double-blind, randomized, controlled trial of its kind to demonstrate a clear improvement in cardiovascular outcomes with edetate disodium therapy in a secondary prevention, post-myocardial infarction population. This effect size was most striking in diabetic patients, where the efficacy of edetate disodium was comparable, if not superior, to that of current guideline-based therapies. Given the economic burden of diabetes and cardiovascular disease, the potential impact of this therapy could be enormous if the results of this study are replicated.

[Laparoscopic aspect and clinical relevance of cholangiofibromas].

PubMed

Henning, H; Friedrich, K; Lüders, C J

1982-12-01

In a current series of 1160 laparoscopies in 38 cases (3.2%) we found cholangiofibromas. The picture of single, sporadic and multiple cholangiofibromas as well as cholangiofibromatosis is both described and documented by laparoscopic photography. Clinically it seems remarkable that only patients with alcohol- or drug-induced liver injury showed such alterations. The prevalence of cholangiofibromas in toxic liver damage suggests that we are here not dealing with embryonal aberrations (hamartomas) but apparently with cellular inductive phenomena.

Role of oxidative stress in methamphetamine-induced dopaminergic toxicity mediated by protein kinase Cδ

PubMed Central

Nguyen, Xuan-Khanh Thi; Li, Zhengyi; Bing, Guoying; Bach, Jae-Hyung; Park, Dae Hun; Nakayama, Keiichi; Ali, Syed F.; Kanthasamy, Anumantha G.; Cadet, Jean Lud; Nabeshima, Toshitaka; Kim, Hyoung-Chun

2014-01-01

This study examined the role of protein kinase C (PKC) isozymes in methamphetamine (MA)-induced dopaminergic toxicity. Multiple-dose administration of MA did not significantly alter PKCα, PKCβI, PKCβII, or PKCζ expression in the striatum, but did significantly increase PKCδ expression. Gö6976 (a co-inhibitor of PKCα and -β), hispidin (PKCβ inhibitor), and PKCζ pseudosubstrate inhibitor (PKCζ inhibitor) did not significantly alter MA-induced behavioral impairments. However, rottlerin (PKCδ inhibitor) significantly attenuated behavioral impairments in a dose-dependent manner. In addition, MA-induced behavioral impairments were not apparent in PKCδ knockout (–/–) mice. MA-induced oxidative stress (i.e., lipid peroxidation and protein oxidation) was significantly attenuated in rottlerin-treated mice and was not apparent in PKCδ (–/–) mice. Consistent with this, MA-induced apoptosis (i.e., terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive apoptotic cells) was significantly attenuated in rottlerin-treated mice. Furthermore, MA-induced increases in the dopamine (DA) turnover rate and decreases in tyrosine hydroxylase (TH) activity and the expression of TH, dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2) were not significantly observed in rottlerin-treated or PKCδ (–/–) mice. Our results suggest that PKCδ gene expression is a key mediator of oxidative stress and dopaminergic damage induced by MA. Thus, inhibition of PKCδ may be a useful target for protection against MA-induced neurotoxicity. PMID:22512859

Role of oxidative stress in methamphetamine-induced dopaminergic toxicity mediated by protein kinase Cδ.

PubMed

Shin, Eun-Joo; Duong, Chu Xuan; Nguyen, Xuan-Khanh Thi; Li, Zhengyi; Bing, Guoying; Bach, Jae-Hyung; Park, Dae Hun; Nakayama, Keiichi; Ali, Syed F; Kanthasamy, Anumantha G; Cadet, Jean Lud; Nabeshima, Toshitaka; Kim, Hyoung-Chun

2012-06-15

This study examined the role of protein kinase C (PKC) isozymes in methamphetamine (MA)-induced dopaminergic toxicity. Multiple-dose administration of MA did not significantly alter PKCα, PKCβI, PKCβII, or PKCζ expression in the striatum, but did significantly increase PKCδ expression. Gö6976 (a co-inhibitor of PKCα and -β), hispidin (PKCβ inhibitor), and PKCζ pseudosubstrate inhibitor (PKCζ inhibitor) did not significantly alter MA-induced behavioral impairments. However, rottlerin (PKCδ inhibitor) significantly attenuated behavioral impairments in a dose-dependent manner. In addition, MA-induced behavioral impairments were not apparent in PKCδ knockout (-/-) mice. MA-induced oxidative stress (i.e., lipid peroxidation and protein oxidation) was significantly attenuated in rottlerin-treated mice and was not apparent in PKCδ (-/-) mice. Consistent with this, MA-induced apoptosis (i.e., terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive apoptotic cells) was significantly attenuated in rottlerin-treated mice. Furthermore, MA-induced increases in the dopamine (DA) turnover rate and decreases in tyrosine hydroxylase (TH) activity and the expression of TH, dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2) were not significantly observed in rottlerin-treated or PKCδ (-/-) mice. Our results suggest that PKCδ gene expression is a key mediator of oxidative stress and dopaminergic damage induced by MA. Thus, inhibition of PKCδ may be a useful target for protection against MA-induced neurotoxicity. Copyright © 2012 Elsevier B.V. All rights reserved.

Quantitation of methylglyoxal bis(guanylhydrazone) in blood plasma and leukemia cells of patients receiving the drug.

PubMed

Seppänen, P; Alhonen-Hongisto, L; Siimes, M; Jänne, J

1980-11-15

Methylglyoxal bis(guanylhydrazone), a cytostatic compound which apparently interferes with the metabolism and/or functions of the natural polyamines (spermidine and spermine), was effectively taken up by cultured human lymphocytic leukemia cells, rapidly resulting in the formation of a concentration gradient of up to 1,000-fold across the cell membrane in cells grown in the presence of micromolar concentrations of the drug. For an anti-proliferative effect on the leukemia cells, an intracellular concentration of more than 0.5 mM was required. The uptake of methylglyoxal bis(guanylhydrazone) was critically dependent on the growth rate of the leukemia cells. Low intracellular concentrations of the drug were present in cells growing slowly, whereas in rapidly dividing cells the intracellular concentration of the drug approached 5mM. When given as repeated intravenous infusions to two leukemic children, methylglyoxal bis(guanylhydrazone) exhibited sharp and transient peaks of plasma concentration, the drug having an apparent half-life in plasma of only 1-2 h. However, as in cultured cells, the drug was rapidly concentrated in the leukemia cells, reaching concentrations that were distinctly anti-proliferative. In contrast to the rapid disappearance of methylglyoxal bis(guanylhydrazone) from plasma, the circulation leukemia cells retained the drug for a period of several days with only minimal decrease in the initial concentrations. Methylglyoxal bis(guanylhydrazone) was given to the patients for 1 to 2 months as intravenous infusions, the timing of which was determined by regular assays of the drug concentrations in the leukemia cells. In agreement with the results obtained with the cultured cells, and intracellular concentration of about 0.5 to 1mM was apparently required for growth-inhibitory action to occur. Regular determination of the cellular drug concentrations indicated that methylglyoxal bis(quanylhydrazone) could be given as weekly infusions. This treatment schedule represents much lower dosing of the drug than the earlier daily regimens which were commonly associated with unacceptable toxicity.

Use of butterflies as nontarget insect test species and the acute toxicity and hazard of mosquito control insecticides.

PubMed

Hoang, Tham C; Pryor, Rachel L; Rand, Gary M; Frakes, Robert A

2011-04-01

Honeybees are the standard insect test species used for toxicity testing of pesticides on nontarget insects for the U.S. Environmental Protection Agency (U.S. EPA) under the Federal Insecticide Fungicide and Rodenticide Act (FIFRA). Butterflies are another important insect order and a valued ecological resource in pollination. The current study conducted acute toxicity tests with naled, permethrin, and dichlorvos on fifth larval instar (caterpillars) and adults of different native Florida, USA, butterfly species to determine median lethal doses (24-h LD50), because limited acute toxicity data are available with this major insect group. Thorax- and wing-only applications of each insecticide were conducted. Based on LD50s, thorax and wing application exposures were acutely toxic to both caterpillars and adults. Permethrin was the most acutely toxic insecticide after thorax exposure to fifth instars and adult butterflies. However, no generalization on acute toxicity (sensitivity) of the insecticides could be concluded based on exposures to fifth instars versus adult butterflies or on thorax versus wing exposures of adult butterflies. A comparison of LD50s of the butterflies from this study (caterpillars and adults) with honeybee LD50s for the adult mosquito insecticides on a µg/organism or µg/g basis indicates that several butterfly species are more sensitive to these insecticides than are honeybees. A comparison of species sensitivity distributions for all three insecticides shows that permethrin had the lowest 10th percentile. Using a hazard quotient approach indicates that both permethrin and naled applications in the field may present potential acute hazards to butterflies, whereas no acute hazard of dichlorvos is apparent in butterflies. Butterflies should be considered as potential test organisms when nontarget insect testing of pesticides is suggested under FIFRA. Copyright © 2011 SETAC.

Consensus sediment quality guidelines for polycyclic aromatic hydrocarbon mixtures

DOE Office of Scientific and Technical Information (OSTI.GOV)

Swartz, R.C.

1999-04-01

Sediment quality guidelines (SQGs) for polycyclic aromatic hydrocarbons (PAHs) have been derived from a variety of laboratory, field, and theoretical foundations. They include the screening level concentration, effects ranges-low and -median, equilibrium partitioning concentrations, apparent effects threshold, {Sigma}PAH model, and threshold and probable effects levels. The resolution of controversial differences among the PAH SQGs lies in an understanding of the effects of mixtures. Polycyclic aromatic hydrocarbons virtually always occur in field-collected sediment as a complex mixture of covarying compounds. When expressed as a mixture concentration, that is, total PAH (TPAH), the guidelines form three clusters that were intended in theirmore » original derivations to represent threshold (TEC = 290 {micro}g/g organic carbon [OC]), median (MEC = 1,800 {micro}g/g OC), and extreme (EEC = 10,000 {micro}g/g OC) effects concentrations. The TEC/MEC/EEC consensus guidelines provide a unifying synthesis of other SQGs, reflect causal rather than correlative effects, account for mixtures, and predict sediment toxicity and benthic community perturbations at sites of PAH contamination. The TEC offers the most useful SQG because PAH mixtures are unlikely to cause adverse effects on benthic ecosystems below the TEC.« less

Rat liver mitochondrial damage under acute or chronic carbon tetrachloride-induced intoxication: Protection by melatonin and cranberry flavonoids

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cheshchevik, V.T.; Department of Biochemistry, Yanka Kupala Grodno State University, Len. Kom. Blvd. - 50, 230017 Grodno; Lapshina, E.A.

In current societies, the risk of toxic liver damage has markedly increased. The aim of the present work was to carry out further research into the mechanism(s) of liver mitochondrial damage induced by acute (0.8 g/kg body weight, single injection) or chronic (1.6 g/ kg body weight, 30 days, biweekly injections) carbon tetrachloride – induced intoxication and to evaluate the hepatoprotective potential of the antioxidant, melatonin, as well as succinate and cranberry flavonoids in rats. Acute intoxication resulted in considerable impairment of mitochondrial respiratory parameters in the liver. The activity of mitochondrial succinate dehydrogenase (complex II) decreased (by 25%, pmore » < 0.05). Short-term melatonin treatment (10 mg/kg, three times) of rats did not reduce the degree of toxic mitochondrial dysfunction but decreased the enhanced NO production. After 30-day chronic intoxication, no significant change in the respiratory activity of liver mitochondria was observed, despite marked changes in the redox-balance of mitochondria. The activities of the mitochondrial enzymes, succinate dehydrogenase and glutathione peroxidase, as well as that of cytoplasmic catalase in liver cells were inhibited significantly. Mitochondria isolated from the livers of the rats chronically treated with CCl{sub 4} displayed obvious irreversible impairments. Long-term melatonin administration (10 mg/kg, 30 days, daily) to chronically intoxicated rats diminished the toxic effects of CCl{sub 4}, reducing elevated plasma activities of alanine aminotransferase and aspartate aminotransferase and bilirubin concentration, prevented accumulation of membrane lipid peroxidation products in rat liver and resulted in apparent preservation of the mitochondrial ultrastructure. The treatment of the animals by the complex of melatonin (10 mg/kg) plus succinate (50 mg/kg) plus cranberry flavonoids (7 mg/kg) was even more effective in prevention of toxic liver injury and liver mitochondria damage. Highlights: ► After 30-day chronic CCl{sub 4} intoxication mitochondria displayed considerable changes. ► The functional parameters of mitochondria were similar to the control values. ► Melatonin + succinate + flavonoids prevented mitochondrial ultrastructure damage. ► The above complex enhanced regenerative processes in the liver.« less

A fully human anti-Ep-CAM scFv-beta-glucuronidase fusion protein for selective chemotherapy with a glucuronide prodrug.

PubMed

de Graaf, M; Boven, E; Oosterhoff, D; van der Meulen-Muileman, I H; Huls, G A; Gerritsen, W R; Haisma, H J; Pinedo, H M

2002-03-04

Monoclonal antibodies against tumour-associated antigens could be useful to deliver enzymes selectively to the site of a tumour for activation of a non-toxic prodrug. A completely human fusion protein may be advantageous for repeated administration, as host immune responses may be avoided. We have constructed a fusion protein consisting of a human single chain Fv antibody, C28, against the epithelial cell adhesion molecule and the human enzyme beta-glucuronidase. The sequences encoding C28 and human enzyme beta-glucuronidase were joined by a sequence encoding a flexible linker, and were preceded by the IgGkappa signal sequence for secretion of the fusion protein. A CHO cell line was engineered to secrete C28-beta-glucuronidase fusion protein. Antibody specificity and enzyme activity were retained in the secreted fusion protein that had an apparent molecular mass of 100 kDa under denaturing conditions. The fusion protein was able to convert a non-toxic prodrug of doxorubicin, N-[4-doxorubicin-N-carbonyl(oxymethyl)phenyl]-O-beta-glucuronyl carbamate to doxorubicin, resulting in cytotoxicity. A bystander effect was demonstrated, as doxorubicin was detected in all cells after N-[4-doxorubicin-N-carbonyl(oxymethyl)phenyl]-O-beta-glucuronyl carbamate administration when only 10% of the cells expressed the fusion protein. This is the first fully human and functional fusion protein consisting of an scFv against epithelial cell adhesion molecule and human enzyme beta-glucuronidase for future use in tumour-specific activation of a non-toxic glucuronide prodrug. Copyright 2002 Cancer Research UK

Morphological, anatomical, and ultrastructural changes (visualized through scanning electron microscopy) induced in Triticum aestivum by Pb²⁺ treatment.

PubMed

Kaur, Gurpreet; Singh, Harminder Pal; Batish, Daizy Rani; Kohli, Ravinder Kumar

2014-11-01

Lead (Pb) causes severe damage to crops, ecosystems, and humans, and alters the physiology and biochemistry of various plant species. It is hypothesized that Pb-induced metabolic alterations could manifest as structural variations in the roots of plants. In light of this, the morphological, anatomical, and ultrastructural variations (through scanning electron microscopy, SEM) were studied in 4-day-old seedlings of Triticum aestivum grown under Pb stress (0, 8, 16, 40, and 80 mg Pb(2+) l(-1); mild to highly toxic). The toxic effect was more pronounced in radicle growth than on the plumule growth. The SEM of the root of T. aestivum depicted morphological alterations and surface ultrastructural changes. Compared to intact and uniform surface cells in the control roots, cells were irregular and desiccated in Pb(2+)-treated roots. In Pb(2+)-treated roots, the number of root hairs increased manifold, showing dense growth, and these were apparently longer. Apart from the deformity in surface morphology and anatomy of the roots in response to Pb(2+) toxicity, considerable anatomical alterations were also observed. Pb(2+)-treated root exhibited signs of injury in the form of cell distortion, particularly in the cortical cells. The endodermis and pericycle region showed loss of uniformity post Pb(2+) exposure (at 80 mg l(-1) Pb(2+)). The cells appeared to be squeezed with greater depositions observed all over the tissue. The study concludes that Pb(2+) treatment caused structural anomalies and induced anatomical and surface ultrastructural changes in T. aestivum.

[Intoxation with paramethoxymethamphetamine].

PubMed

Al-Samarraie, Muhammad S; Vevelstad, Merete; Nygaard, Ilah Le; Bachs, Liliana; Mørland, Jørg

2013-05-07

Since the summer of 2010, there has been an epidemic of deaths related to paramethoxymethamphetamine (PMMA) in Norway. We present a review of the pharmacology and toxicology of the substance. The review is based on a literature search in the databases PubMed, Ovid and MEDLINE. A discretionary selection was made of relevant articles. Paramethoxymethamphetamine and paramethoxyamphetamine (PMA) are two so-called designer amphetamines which appear from time to time on the illegal narcotics market in many countries. They are frequently sold as ecstasy or amphetamine, often mixed with amphetamine or methamphetamine. The substances, known on the street as «Death», have potent serotonergic effects and are associated with significant toxicity. Many deaths have been reported worldwide, even after intake of an «ordinary user dose». The narcotic effect is not very pronounced and the onset is slow, which may lead to unintentional overdosing. In cases of severe intoxation that are apparently related to intake of amphetamine or ecstasy, PMMA/PMA intoxation should be suspected.

Proton Pump Inhibitors in cancer patients: How useful they are? A review of the most common indications for their use.

PubMed

Numico, Gianmauro; Fusco, Vittorio; Franco, Pierfrancesco; Roila, Fausto

2017-03-01

Proton-Pump Inhibitors (PPIs) are commonly prescribed in the general population and in cancer patients. A supposed role in the prevention of gastric mucosal damage apparently justify their use in patients undergoing cytotoxic chemotherapy, steroids and radiotherapy on the gastro-duodenal region. They are frequently given also to patients admitted to Intensive Care Units, for the prevention of stress-related gastric ulcers. The evidence about these use of gastroprotection is reviewed. In the majority of the cases the prescription of PPIs is not justified. In two circumstances (chemotherapy and stress-related gastric disease) randomized studies have shown a protective action of PPIs although this effect did not translate into the reduction of serious clinical consequences. PPIs are not free of toxic effects that are acknowledged by an expanding literature. Also the interaction with anticancer drugs is a potential source of unwanted consequences. Copyright © 2017 Elsevier B.V. All rights reserved.

Ecotoxicological evaluation of area 9 landfill at Crab Orchard National Wildlife Refuge: Biological impact and residues

DOE Office of Scientific and Technical Information (OSTI.GOV)

McKee, M.J.

1992-10-01

Polychlorinated biphenyls (PCBs) and lead were investigated in soil and biota at Crab Orchard National Wildlife Refuge (CONWR) and related to biological effects. PCBs were rapidly mobilized from the soil into the terrestrial food chain as evidenced by high residue levels in adult beetles, caged house crickets, and white-footed mice. Bioaccumulation of lead was not observed in invertebrates, but was observed in white-footed mice. Invertebrate abundance and biomarkers were evaluated for signs of toxic response to soil contaminants. The control site and the Area 9 Landfill did not differ in abundance of five common terrestrial invertebrate families. The absence ofmore » detectable biological effects in invertebrates shows that these animals can tolerate relatively high environmental concentrations of these contaminants. The intensive use of Area 9 Landfill by invertebrates and their apparent tolerance of soil contaminants eludes to the importance of chemical transfer to higher trophic levels, especially for PCBs.« less

Placental transport and in vitro effects of Bisphenol A.

PubMed

Mørck, Thit J; Sorda, Giuseppina; Bechi, Nicoletta; Rasmussen, Brian S; Nielsen, Jesper B; Ietta, Francesca; Rytting, Erik; Mathiesen, Line; Paulesu, Luana; Knudsen, Lisbeth E

2010-08-01

Bisphenol A (BPA), an estrogen-like chemical, leaches from consumer products potentially causing human exposure. To examine the effects of BPA exposure during pregnancy, we performed studies using the BeWo trophoblast cell line, placental explant cultures, placental perfusions and skin diffusion models, all of human origin. Results showed BPA cytotoxicity in BeWo cells with an apparent EC50 at 100-125 microM. BPA exposure significantly increased beta-hCG secretion and caspase-3 expression in placental explants at an environmentally relevant concentration of 1 nM. In the transport studies, a rapid transfer of BPA was observed across the term placentae and the BeWo cell monolayer. Further, transdermal transport of BPA was observed. These results indicate that fetal BPA exposure through placental exchange occurs with potential adverse implications for placental and fetal development. This battery of test systems within the realm of human implantation and fetal development represents important elements in risk assessment of reproductive toxicity. Copyright 2010 Elsevier Inc. All rights reserved.

Fifty-two week chronic toxicity of enzymatically decomposed rutin in Wistar rats.

PubMed

Tamura, T; Mitsumori, K; Muto, S; Kasahara, H; Kobayashi, S; Okuhara, Y; Hayashi, M; Nagasawa, T; Onozato, T; Kuroda, J

2010-01-01

The chronic toxicity of enzymatically decomposed rutin, which consists mainly of isoquercitrin, was evaluated in male and female Wistar rats with dietary administration at concentrations of 0%, 0.04%, 0.2%, 1% and 5% for 52 weeks. No toxicological findings were found in the mortality, body weights, food consumption, hematology, clinical biochemistry or organ weights in either sex. Obvious clinical signs were chromaturia that could be attributed to the color of test substance in the 5% groups of both sexes. Coloration of the urine collected over 24h in the 1% and 5% groups of both sexes was noted. Increased daily urinary calcium excretion was observed in the 5% groups of both sexes and an increase in urinary calcium concentration was observed in the male 5% group. On histopathological examination, incidences of mineralization, inflammatory cell debris, inflammatory cell infiltration and/or transitional cell hyperplasia in the renal pelvis were increased in the 5% male group, whereas treated females showed no apparent difference in these incidences. Based on the above findings, the no observed adverse effect level (NOAEL) was estimated to be 1% in both sexes (542.4 mg/kg body weight/day for males and 674.0mg/kg body--weight/day for females). Copyright (c) 2010 Elsevier Ltd. All rights reserved.

The Ethanolic Stem-Bark Extract of Antrocaryon micraster Inhibits Carrageenan-Induced Pleurisy and Pedal Oedema in Murine Models of Inflammation

PubMed Central

Essel, Leslie B.; Duduyemi, Babatunde M.

2017-01-01

We investigated the antioxidant and anti-inflammatory effects of a 70% v/v ethanol extract of the stem bark of Antrocaryon micraster on murine models of carrageenan-induced pleurisy and paw oedema. Rat pleural fluid was analysed for volume, protein content, and leucocytes, while lung histology was assessed for damage. Lung tissue homogenates were assayed for glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), and myeloperoxidase (MPO). Phytochemical analysis was carried out on the stem bark. Acute toxicity studies were conducted in rats. In the pleurisy model the extract (30–300 mg/kg) significantly reduced the volume and amount of proteins and leucocytes in the exudate and also protected against lung injury. Tissue level of GSH and SOD and CAT expression were increased while MDA level and MPO activity were reduced. The peak and total oedema responses were significantly suppressed when given both preemptively and curatively in the mice paw oedema test. Saponins, alkaloids, triterpenoids, and tannins were present in the stem bark. A. micraster extract exhibited no apparent acute toxicity. We conclude that the ethanolic stem-bark extract of A. micraster has antioxidant action and exhibits significant anti-inflammatory activity through suppression of pleurisy and paw oedema induced with carrageenan. PMID:28798953

Neutralization of Bacterial YoeBSpn Toxicity and Enhanced Plant Growth in Arabidopsis thaliana via Co-Expression of the Toxin-Antitoxin Genes

PubMed Central

Abu Bakar, Fauziah; Yeo, Chew Chieng; Harikrishna, Jennifer Ann

2016-01-01

Bacterial toxin-antitoxin (TA) systems have various cellular functions, including as part of the general stress response. The genome of the Gram-positive human pathogen Streptococcus pneumoniae harbors several putative TA systems, including yefM-yoeBSpn, which is one of four systems that had been demonstrated to be biologically functional. Overexpression of the yoeBSpn toxin gene resulted in cell stasis and eventually cell death in its native host, as well as in Escherichia coli. Our previous work showed that induced expression of a yoeBSpn toxin-Green Fluorescent Protein (GFP) fusion gene apparently triggered apoptosis and was lethal in the model plant, Arabidopsis thaliana. In this study, we investigated the effects of co-expression of the yefMSpn antitoxin and yoeBSpn toxin-GFP fusion in transgenic A. thaliana. When co-expressed in Arabidopsis, the YefMSpn antitoxin was found to neutralize the toxicity of YoeBSpn-GFP. Interestingly, the inducible expression of both yefMSpn antitoxin and yoeBSpn toxin-GFP fusion in transgenic hybrid Arabidopsis resulted in larger rosette leaves and taller plants with a higher number of inflorescence stems and increased silique production. To our knowledge, this is the first demonstration of a prokaryotic antitoxin neutralizing its cognate toxin in plant cells. PMID:27104531

Purification of a toxic metalloprotease produced by the pathogenic Photobacterium damselae subsp. piscicida isolated from cobia (Rachycentron canadum).

PubMed

Liu, Ping-Chung; Chuang, Wen-Hsiao; Lee, Kuo-Kau

2011-01-01

The aim of the present study was to purify and characterize a toxic protease secreted by the pathogenic Photobacterium damselae subsp. piscicida strain CP1 originally isolated from diseased cobia (Rachycentron canadum). The toxin isolated by anion exchange chromatography, was a metalloprotease, inhibited by L-cysteine, ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis(beta-aminoethyl ether)N,N,N',N'-tetraacetic acid (EGTA), 1,10-phenanthroline, N-tosyl-L-phenylalanine-chloromethyl ketone (TPCK), and N-alpha-p-tosyl-L-lysine-chloromethyl ketone (TLCK), and showed maximal activity at pH 6.0-8.0 and an apparent molecular mass of about 34.3 kDa. The toxin was also completely inhibited by HgCl2, and partially by sodium dodecyl sulfate (SDS) and CuCl2. The extracellular products and the partially purified protease were lethal to cobia with LD50 values of 1.26 and 6.8 microg protein/g body weight, respectively. The addition of EDTA completely inhibited the lethal toxicity of the purified protease, indicating that this metalloprotease was a lethal toxin produced by the bacterium.

Environmental hazard of oil shale combustion fly ash.

PubMed

Blinova, Irina; Bityukova, Liidia; Kasemets, Kaja; Ivask, Angela; Käkinen, Aleksandr; Kurvet, Imbi; Bondarenko, Olesja; Kanarbik, Liina; Sihtmäe, Mariliis; Aruoja, Villem; Schvede, Hedi; Kahru, Anne

2012-08-30

The combined chemical and ecotoxicological characterization of oil shale combustion fly ash was performed. Ash was sampled from the most distant point of the ash-separation systems of the Balti and Eesti Thermal Power Plants in North-Eastern Estonia. The fly ash proved potentially hazardous for tested aquatic organisms and high alkalinity of the leachates (pH>10) is apparently the key factor determining its toxicity. The leachates were not genotoxic in the Ames assay. Also, the analysis showed that despite long-term intensive oil-shale combustion accompanied by considerable fly ash emissions has not led to significant soil contamination by hazardous trace elements in North-Eastern Estonia. Comparative study of the fly ash originating from the 'new' circulating fluidized bed (CFB) combustion technology and the 'old' pulverized-fired (PF) one showed that CFB fly ash was less toxic than PF fly ash. Thus, complete transfer to the 'new' technology will reduce (i) atmospheric emission of hazardous trace elements and (ii) fly ash toxicity to aquatic organisms as compared with the 'old' technology. Copyright © 2012 Elsevier B.V. All rights reserved.

Ecotoxicological assessment of the herbicide Winner Top and its active substances-are the other formulants truly inert?

PubMed

Queirós, Libânia; Vidal, Tânia; Nogueira, António J A; Gonçalves, Fernando J M; Pereira, Joana Luísa

2018-05-03

Formulants used in Plant Protection Products (PPPs) to promote their efficiency are normally undisclosed in the PPP documentation, unless they bear a human health or environmental hazardous potential per se. PPP regulation also demands the assessment of putative interactions among formulants within each product recipe and consequent effects, but these results are often unavailable. Such a case is that of the herbicide Winner Top (Selectis®, Portugal), which we selected as a model commercial formulation in the present study specifically aiming at (i) characterising its aquatic toxicity towards sensitive eco-receptors (Raphidocelis subcapitata, Chlorella vulgaris, Lemna minor and Lemna gibba), as well as that of its active substances (a.s.) nicosulfuron and terbuthylazine; (ii) comparing the ecotoxicity among the commercial formulation, the corresponding mixture of its a.s. and this a.s.'s mixture increasingly enriched with the formulants. Single chemical testing revealed that terbuthylazine was the strongest microalgae growth inhibitor and nicosulfuron was the strongest macrophyte growth inhibitor. On the other hand, the commercial formulation was consistently less toxic than the corresponding mixture of the a.s., suggesting that Winner Top formulants (72.9% of the commercial formulation) interact with the a.s., promoting less than additive effects in the selected non-target species. Importantly, this environmentally protective effect of the formulation can be apparent. Because macrophytes share most physiological features with the weeds targeted by the studied herbicide, it is likely that increased application doses are required to reach desired efficacy levels with the consequent detrimental increase of PPP residues load in edge-of-field freshwater ecosystems.

Small Quaternary Inhibitors K298 and K524: Cholinesterases Inhibition, Absorption, Brain Distribution, and Toxicity.

PubMed

Karasova, Jana Zdarova; Hroch, Milos; Musilek, Kamil; Kuca, Kamil

2016-02-01

Inhibitors of acetylcholinesterase (AChE) may be used in the treatment of various cholinergic deficits, among them being myasthenia gravis (MG). This paper describes the first in vivo data for promising small quaternary inhibitors (K298 and K524): acute toxicity study, cholinesterase inhibition, absorption, and blood-brain barrier penetration. The newly prepared AChE inhibitors (bis-quinolinium and quinolinium compounds) possess a positive charge in the molecule which ensures that anti-AChE action is restricted to peripheral effect. HPLC-MS was used for determination of real plasma and brain concentration in the pharmacokinetic part of the study, and standard non-compartmental analysis was performed. The maximum plasma concentrations were attained at 30 min (K298; 928.76 ± 115.20 ng/ml) and 39 min (K524; 812.40 ± 54.96 ng/ml) after i.m. Both compounds are in fact able to target the central nervous system. It seems that the difference in the CNS distribution profile depends on an active efflux system. The K524 brain concentration was actively decreased to below an effective level; in contrast, K298 progressively accumulated in brain tissue. Peripheral AChE inhibitors are still first-line treatment in the mild forms of MG. Commonly prescribed carbamates have many severe side effects related to AChE carbamylation. The search for new treatment strategies is still important. Unlike carbamates, these new compounds target AChE via apparent π-π or π-cationic interaction aside at the AChE catalytic site.

Resveratrol Targets AKT and p53 in Glioblastoma and Glioblastoma Stem-like Cells to Suppress Growth and Infiltration

PubMed Central

Clark, Paul A.; Bhattacharya, Saswati; Elmayan, Ardem; Darjatmoko, Soesiawati R.; Thuro, Bradley A.; Yan, Michael B.; van Ginkel, Paul R.; Polans, Arthur S.; Kuo, John S.

2016-01-01

Object Glioblastoma multiforme (GBM) is an aggressive brain cancer with median survival of less than two years with current treatment. GBM exhibits extensive intra-tumor and inter-patient heterogeneity, suggesting that successful therapies should exert broad anti-cancer activities. Therefore, the natural non-toxic pleiotropic agent, resveratrol, was studied for anti-tumorigenic effects against GBM. Methods Resveratrol’s effects on cell proliferation, sphere-forming ability, and invasion were tested using multiple patient-derived GBM stem-like cell (GSC) lines and established U87 glioma cells, and changes in oncogenic AKT and tumor suppressive p53 were analyzed. Resveratrol was also tested in vivo against U87 glioma flank xenografts using multiple delivery methods, including direct tumor injection. Finally, resveratrol was delivered directly to brain tissue to determine toxicity and achievable drug concentrations in the brain parenchyma. Results Resveratrol significantly inhibited proliferation in U87 glioma and multiple patient-derived GSC lines, demonstrating similar inhibitory concentrations across these phenotypically heterogeneous lines. Resveratrol also inhibited the sphere-forming ability of GSCs, suggesting anti-stem cell effects. Additionally, resveratrol blocked U87 glioma and GSC invasion in an in vitro Matrigel transwell assay at doses similar to those mediating anti-proliferative effects. In U87 glioma cells and GSCs, resveratrol reduced AKT phosphorylation and induced p53 expression and activation that led to transcription of downstream p53 target genes. Resveratrol administration via oral gavage or ad libitum in the water supply significantly suppressed GBM xenograft growth; intra-tumor or peri-tumor resveratrol injection further suppressed growth and approximating tumor regression. Intracranial resveratrol injection resulted in 100-fold higher local drug concentration compared to intravenous delivery, and with no apparent toxicity. Conclusions Resveratrol potently inhibited GBM and GBM stem-like cell growth and infiltration, acting partially via AKT deactivation and p53 induction, and suppressed glioblastoma growth in vivo. The ability of resveratrol to modulate AKT and p53, as well as reportedly many other anti-tumorigenic pathways, is attractive for therapy against a genetically heterogeneous tumor such as GBM. Although resveratrol exhibits low bioavailability when administered orally or intravenously, novel delivery methods such as direct injection (i.e. convection enhanced delivery) could potentially be used to achieve and maintain therapeutic doses in brain. Resveratrol’s non-toxic nature and broad anti-GBM effects make it a compelling candidate to supplement current GBM therapies. PMID:27419830

Induction of lcc2 expression and activity by Agaricus bisporus provides defence against Trichoderma aggressivum toxic extracts

PubMed Central

Sjaarda, Calvin P; Abubaker, Kamal S; Castle, Alan J

2015-01-01

Laccases are used by fungi for several functions including defence responses to stresses associated with attack by other fungi. Laccase activity changes and the induction of two laccase genes, lcc1 and lcc2, in Agaricus bisporus were measured in response to toxic extracts of medium in which Trichoderma aggressivum, the cause of green mould disease, was grown. A strain of A. bisporus that shows resistance to the extracts showed higher basal levels and greater enzymatic activity after extract exposure than did a sensitive strain. Furthermore, pre-incubation of T. aggressivum extract with laccases reduced toxicity. Faster induction and greater numbers of lcc2 transcripts in response to the extract were noted in the resistant strain than in the sensitive strain. The timing and increase in lcc2 transcript abundance mirrored changes in total laccase activity. No correlation between resistance and lcc1 transcription was apparent. Transcript abundance in transformants with a siRNA construct homologous to both genes varied widely. A strong negative correlation between transcript abundance and sensitivity of the transformant to toxic extract was observed in plate assays. These results indicated that laccase activity and in particular that encoded by lcc2 contributes to toxin metabolism and by extension green mould disease resistance. PMID:25824278

Copper-free click chemistry for dynamic in vivo imaging

PubMed Central

Baskin, Jeremy M.; Prescher, Jennifer A.; Laughlin, Scott T.; Agard, Nicholas J.; Chang, Pamela V.; Miller, Isaac A.; Lo, Anderson; Codelli, Julian A.; Bertozzi, Carolyn R.

2007-01-01

Dynamic imaging of proteins in live cells is routinely performed by using genetically encoded reporters, an approach that cannot be extended to other classes of biomolecules such as glycans and lipids. Here, we report a Cu-free variant of click chemistry that can label these biomolecules rapidly and selectively in living systems, overcoming the intrinsic toxicity of the canonical Cu-catalyzed reaction. The critical reagent, a substituted cyclooctyne, possesses ring strain and electron-withdrawing fluorine substituents that together promote the [3 + 2] dipolar cycloaddition with azides installed metabolically into biomolecules. This Cu-free click reaction possesses comparable kinetics to the Cu-catalyzed reaction and proceeds within minutes on live cells with no apparent toxicity. With this technique, we studied the dynamics of glycan trafficking and identified a population of sialoglycoconjugates with unexpectedly rapid internalization kinetics. PMID:17942682

Effects of lampricide exposure on the survival, growth, and behavior of the unionid mussels Elliptio complanata and Pyganadon cataracta

USGS Publications Warehouse

Waller, D.L.; Bills, T.D.; Boogaard, M.A.; Johnson, D.A.; Doolittle, T.C.J.

2003-01-01

The effects of a 12-h exposure to the lampricide 3-trifluoromethyl-4-nitrophenol (TFM) and a combination of TFM and 1% niclosamide (active ingredient in Bayluscide 70% wettable powder) on the short and long-term (10 mo post exposure) survival and behavior of two unionid freshwater mussel species Elliptio complanata and Pyganadon cataracta were measured. Growth of juvenile E. complanata mussels 10 months after exposure was also compared. Toxicity was determined after 12 h exposures at maximum concentrations from 2- to 2.5- fold higher than the LC99 for sea lamprey larvae. A logistic model was used to estimate the probability of survival among treatments, trials, species, and sizes. Mortality was minimal in all test concentrations of TFM alone and the TFM/1% niclosamide combination. Estimated survival decreased 6% for each unit increase in the relative toxicity of TFM. Survival was greater for E. complanata than for P. cataracta, and for adults relative to juveniles. Lampricide treatment caused narcotization of both mussels (defined as having gaped shells and an extended foot) in concentrations greater than or equal to LC99 for sea lamprey larvae and narcotization ranged from 0-50% among treatments. Recovery from narcosis was apparent by 12 h post-exposure and complete by 36 h post-exposure. The rate of growth of E. complanata over the 10-month post-exposure period did not vary among treatments.

Ocular Toxicity Secondary to Asclepias physocarpa: The Balloon Plant.

PubMed

Pina, Susana; Pedrosa, Catarina; Santos, Cristina; Feijóo, Bernardo; Pego, Peter; Vendrell, Cristina; Santos, Maria João; Prieto, Isabel

2014-01-01

We report a case of a 65-year-old woman with symptoms of blurred vision and ocular irritation a few hours after accidental contact of the right eye with Asclepias physocarpa milky latex. Observation showed a diffuse conjunctival hyperemia and stromal corneal edema with Descemet's membrane folds. Recovery was fast and apparently complete in less than one month. However, specular microscopy at 6-months follow-up showed an abnormal endothelial morphology as sequelae, suggesting this condition is not as innocuous as it has been suggested.

[Effects of relic microorganism B. sp. on development, gaseous exchange, spontaneous motor activity, stress resistance and survival of Drosophila melanogaster].

PubMed

Brushkov, A V; Bezrukov, V V; Griva, G I; Muradian, Kh K

2011-01-01

The effect of relic microorganism B. sp., living in severe environment of Siberian permafrost during thousands and millions of years, on development and stress resistance of Drosophila melanogaster has been studied. In manipulating with such objects with practically "eternal life span", molecular carriers of the unprecedented longevity potential and possibilities of their transmission to other biological objects should primarily be addressed. Here we discuss for the first time the influence of B. sp. application on development, survival, stress resistance and the gross physiological predictors of aging rate in D. melanogaster. To establish optimal and toxic doses, wide range of B. sp. concentrations were tested (1-500 million cells of B. sp. per 1 ml of the flies feeding medium). Surprisingly, no toxic effects of B. sp. could be registered even on such a "sensitive" model as the developing larvae. In fact, the rate of development, survival and body mass gradually increased with elevation of B. sp. concentration. The gain of higher body mass within shorter periods of development could indicate enhanced anabolic and/ or declined catabolic effects of B. sp. Higher motor activity and gaseous exchange rates were observed in imagoes developed on the mediums with B. sp. application. Survival of these flies at the heat shock (30 min at 38 degrees C) and ultraviolet irradiation (60 min, 50W UV lamp) was increased, indicating elevated stress resistance, apparently due to stimulation of DNA-repair and chaperone-mediated protection of macromolecules. Further research is clearly warranted to identify more efficient anti-stress and antiaging preparations and schemes of B. sp. application on models of laboratory mammals and human cell cultures.

Interaction of the new monofunctional anticancer agent Phenanthriplatin with transporters for organic cations

NASA Astrophysics Data System (ADS)

Hucke, Anna; Park, Ga Young; Bauer, Oliver B.; Beyer, Georg; Köppen, Christina; Zeeh, Dorothea; Wehe, Christoph A.; Sperling, Michael; Schröter, Rita; Kantauskaitè, Marta; Hagos, Yohannes; Karst, Uwe; Lippard, Stephen J.; Ciarimboli, Giuliano

2018-05-01

Cancer treatment with platinum compounds is an important achievement of modern chemotherapy. However, despite the beneficial effects, the clinical impact of these agents is hampered by the development of drug resistance as well as dose-limiting side effects. The efficacy but also side effects of platinum complexes can be mediated by uptake through plasma membrane transporters. In the kidneys, plasma membrane transporters are involved in their secretion into the urine. Renal secretion is accomplished by uptake from the blood into the proximal tubules cells, followed by excretion into the urine. The uptake process is mediated mainly by organic cation transporters (OCT), which are expressed in the basolateral domain of the plasma membrane facing the blood. The excretion of platinum into the urine is mediated by exchange with protons via multidrug and toxin extrusion proteins (MATE) expressed in the apical domain of plasma membrane. Recently, the monofunctional, cationic platinum agent phenanthriplatin, which is able to escape common cellular resistance mechanisms, has been synthesized and investigated. In the present study, the interaction of phenanthriplatin with transporters for organic cations has been evaluated. Phenanthriplatin is a high affinity substrate for OCT2, but has a lower apparent affinity for MATEs. The presence of these transporters increased cytotoxicity of phenanthriplatin. Therefore, phenanthriplatin may be especially effective in the treatment of cancers that express OCTs, such as colon cancer cells. However, the interaction of phenanthriplatin with OCTs suggests that its use as chemotherapeutic agent may be complicated by OCT-mediated toxicity. Unlike cisplatin, phenanthriplatin interacts with high specificity with hMATE1 and hMATE2K in addition to hOCT2. This interaction may facilitate its efflux from the cells and thereby decrease overall efficacy and/or toxicity.

Comparative venom toxicity between Pteromalus puparum and Nasonia vitripennis (Hymenoptera: Pteromalidae) toward the hemocytes of their natural hosts, non-target insects and cultured insect cells.

PubMed

Zhang, Zhong; Ye, Gong-Yin; Cai, Jun; Hu, Cui

2005-09-01

Crude venoms from two parasitoid species, Pteromalus puparum and Nasonia vitripennis (Hymenoptera: Pteromalidae) were assayed for biological activities toward hemocytes from two species of their natural hosts and eight species of their non-natural hosts as well as two lines of cultured Lepidoptera cells, respectively. By inhibiting the spreading and viability of insect hemocytes, the venom from P. puparum displayed significantly higher activities toward plasmatocytes and granular cells from both larvae and pupae of two natural hosts, Pieris rapae and Papilio xuthus, and lower activity toward those from Spodoptera litura, Musca domestica and Sarcophaga peregrina. However, no effect was found towards any type of hemocytes from other five insects tested, namely, Ectropis oblique, Galleria mellonella, Sesamia inferens, Bombyx mori and Parnara guttata. In contrast, the venom from N. vitripennis showed a narrower range of targeted insects. It appeared to have highly adverse effects on the spreading and viability of plasmatocytes and granular cells only from the natural hosts, M. domestica and S. peregrina, little toxicity to cells from P. rapae and P. xuthus, and no effect on any of the other insects tested. Pteromalus puparum venom also apparently presented a high ability to block the spreading of Tn-5B1-4 cells derived from Trichoplusia ni, and high cytotoxicity to the cells and Ha cells derived from Helicoverpa armigera. Nasonia vitripennis venom, however, only had a marked lethal effect to Ha cells. In addition, the possibility that the host range of a defined parasitoid could be assessed using our method of treating hemocytes from candidate insects with venom in vitro, and the potential of our venoms tested in the development of bio-insecticides, insect-resistant transgenic plants, are discussed.

Transscleral diffusion of ethacrynic acid and sodium fluorescein

PubMed Central

Lin, Cheng-Wen; Wang, Yong; Challa, Pratap; Epstein, David L.

2007-01-01

Purpose One of the current limitations in developing novel glaucoma drugs that target the trabecular meshwork (TM) is the induced corneal toxicity from eyedrop formulations. To avoid the corneal toxicity, an alternative approach would be to deliver TM drugs through the sclera. To this end, we quantified ex vivo diffusion coefficient of a potential TM drug, ethacrynic acid (ECA), and investigated mechanisms of ECA transport in the sclera. Methods An Ussing-type diffusion apparatus was built to measure the apparent diffusion coefficient of ECA in fresh porcine sclera at 4 °C. To understand mechanisms of ECA transport, we quantified the transscleral transport of a fluorescent tracer, sodium fluorescein (NaF), that has a similar molecular weight but is more hydrophilic compared to ECA. Furthermore, we developed a mathematical model to simulate the transport processes and used it to analyze the experimental data. The model was also used to investigate the dependence of diffusion coefficients on volume fraction of viable cells and the binding of NaF and ECA to scleral tissues. Results The diffusion coefficients of ECA and NaF in the sclera were 48.5±15.1x10-7 cm2/s (n=9) and 5.23±1.93x10-7 cm2/s (n=8), respectively. Both diffusion coefficients were insensitive to cell shrinkage caused by ECA during the diffusion experiments and cell damage caused by the storage of tissues ex vivo before the experiments. Binding of ECA to scleral tissues could not be detected. The apparent maximum binding capacity and the apparent equilibrium dissociation constant for NaF were 80±5 mM and 2.5±0.5 mM (n=3), respectively. Conclusions These data demonstrated that ECA diffusion was minimally hindered by structures in the sclera, presumably due to the lack of cells and binding sites for ECA in the sclera. PMID:17356511

Lead in the environment

USGS Publications Warehouse

Pattee, Oliver H.; Pain, Deborah J.; Hoffman, David J.; Rattner, Barnett A.; Burton, G. Allen; Cairns, John

2003-01-01

Anthropogenic uses of lead have probably altered its availability and environmental distribution more than any other toxic element. Consequently, lead concentrations in many living organisms may be approaching thresholds of toxicity for the adverse effects of lead. Such thresholds are difficult to define, as they vary with the chemical and physical form of lead, exposure regime, other elements present and also vary both within and between species. The technological capability to accurately quantify low lead concentrations has increased over the last decade, and physiological and behavioral effects have been measured in wildlife with tissue lead concentrations below those previously considered safe for humans.s.236 Consequently. lead criteria for the protection of wildlife and human health are frequently under review, and 'thresholds' of lead toxicity are being reconsidered. Proposed lead criteria for the protection of natural resources have been reviewed by Eisler. Uptake of lead by plants is limited by its generally low availability in soils and sediments, and toxicity may be limited by storage mechanisms and its apparently limited translocation within most plants. Lead does not generally accumulate within the foliar parts of plants, which limits its transfer to higher trophic levels. Although lead may concentrate in plant and animal tissues, no evidence of biomagnification exists. Acid deposition onto surface waters and soils with low buffering capacity may influence the availability of lead for uptake by plants and animals, and this may merit investigation at susceptible sites. The biological significance of chronic low-level lead exposure to wildlife is sometimes difficult to quantify. Animals living in urban environments or near point sources of lead emission are inevitably subject to greater exposure to lead and enhanced risk of lead poisoning. Increasingly strict controls on lead emissions in many countries have reduced exposure to lead from some sources. and the .reduction of lead in gasoline has resulted in lower tissue lead concentrations in humans and wildlife from many, particularly urban, locations. However, it has been suggested that increasing use of organic lead compounds as catalysts for the production of plastics and as wood preservatives and biocides could adversely affect wildlife. The most significant source of direct wildlife mortality from lead is spent gunshot and fishing sinkers. Elevated mortality from shot ingestion in avian species resulted in the introduction of nontoxic (steel) shot zones along certain flyways in the United States in the mid-1970s and a total ban on the use of lead for waterfowl and coot hunting nationwide by 1992. Several other countries are now following suit and have either banned or are in the process of restricting the use of lead shot for waterfowl hunting. In the United States it has been estimated that since the 1986 hunting season. when the use of nontoxic shot became widespread. over 6 million ducks have not been lost to lead poisoning. Raptors, especially eagles, have also apparently benefited. although lead poisoning from ingestion of bullet fragments remains a problem for the critically threatened California condor. Quantifying reductions in lead mortality rates would be difficult since eagle populations throughout North America are rapidly recovering from other anthropogenic perturbations, especially organochlorine pesticides.

Biodegradable Drug-Loaded Hydroxyapatite Nanotherapeutic Agent for Targeted Drug Release in Tumors.

PubMed

Sun, Wen; Fan, Jiangli; Wang, Suzhen; Kang, Yao; Du, Jianjun; Peng, Xiaojun

2018-03-07

Tumor-targeted drug delivery systems have been increasingly used to improve the therapeutic efficiency of anticancer drugs and reduce their toxic side effects in vivo. Focused on this point, doxorubicin (DOX)-loaded hydroxyapatite (HAP) nanorods consisting of folic acid (FA) modification (DOX@HAP-FA) were developed for efficient antitumor treatment. The DOX-loaded nanorods were synthesized through in situ coprecipitation and hydrothermal method with a DOX template, demonstrating a new procedure for drug loading in HAP materials. DOX could be efficiently released from DOX@HAP-FA within 24 h in weakly acidic buffer solution (pH = 6.0) because of the degradation of HAP nanorods. With endocytosis under the mediation of folate receptors, the nanorods exhibited enhanced cellular uptake and further degraded, and consequently, the proliferation of targeted cells was inhibited. More importantly, in a tumor-bearing mouse model, DOX@HAP-FA treatment demonstrated excellent tumor growth inhibition. In addition, no apparent side effects were observed during the treatment. These results suggested that DOX@HAP-FA may be a promising nanotherapeutic agent for effective cancer treatment in vivo.

Commentary: selenium study on endangered razorback sucker is flawed

USGS Publications Warehouse

Hamilton, Steven J.

2005-01-01

The razorback sucker (Xyrauchen texanus) is listed as federally endangered throughout its range. A massive recovery effort by the Recovery Implementation Program for Endangered Fish Species in the Upper Colorado River Basin has focused its efforts in the upper Colorado River. The upper Colorado River basin also has two locations that have been identified by the National Irrigation Water Quality Program as having substantial selenium contamination. Selenium is toxic to fishes, affecting reproductive success. Thus, there is concern about potential effects of selenium on the endangered razorback sucker. Two sets of studies have investigated the effects of selenium on razorback suckers, but study results are conflicting. This commentary evaluates studies that claim selenium is not a problem for razorback sucker. We find that study bias was so pervasive that purported conclusions were unwarranted. Contaminated control water, older life stages of fish tested, lack of methodology for analysis of selenium in water, diet, or fish, use of rotifer food, low feeding rates, low growth rates of fish, and improper storage of site waters resulted in an apparent erroneous linkage of high selenium in whole-body residues with no adverse effects.

Effect of Citrus bergamia juice on human neuroblastoma cells in vitro and in metastatic xenograft models.

PubMed

Navarra, M; Ursino, M R; Ferlazzo, N; Russo, M; Schumacher, U; Valentiner, U

2014-06-01

Neuroblastoma is the most common extracranial pediatric solid tumor with poor prognosis in children with disseminated stage of disease. A number of studies show that molecules largely distributed in commonly consumed fruits and vegetables may have anti-tumor activity. In this study we evaluate the effect of Citrus bergamia (bergamot) juice (BJ) in vitro and in a spontaneous metastatic neuroblastoma SCID mouse model. Qualitative and quantitative characterizations of BJ flavonoid fractions were performed by RP-HPLC/PDA/MS. We show that BJ significantly affects SK-N-SH and LAN-1 cell proliferation in vitro, but fails to reduce primary tumor weight in vivo. Moreover, BJ reduced cell adhesiveness and invasion of LAN-1 and SK-N-SH cells in vitro and the number of pulmonary metastases under consideration of the number of tumor cells in the blood in mice inoculated with LAN-1 cells in vivo. These effects without any apparent sign of systemic toxicity confirm the potential clinical interest of BJ and lay the basis for further investigation in cancer. Copyright © 2014. Published by Elsevier B.V.

Sublethal landrin toxicity: Behavioral and physiological effects on captive vultures

USGS Publications Warehouse

Forthman-Quick, D.L.; Hill, E.F.

1988-01-01

Use of conditioned taste aversion (CTA) has been proposed to reduce consumption of California condor (Gymnogyps californianus) eggs by ravens (Corvus corax). Although landrin has induced aversions in ravens and other birds, no data were available on behavioral and physiological effects of landrin on condors, non-target birds that might consume treated eggs. Because condors are endangered, we selected taxonomically related surrogates to approximate the effects on condors of acute oral doses of landrin. Seven black vultures (Coragyps atratus), 2 turkey vultures (Cathartes aura), and 2 king vultures (Sarcoramphus papa) received landrin and placebo treatments 1 week apart. Plasma cholinesterase (ChE) activity was monitored at zero, 3, and 24 hours posttreatment, and behavioral observations were made for 2 hours posttreatment. The doses tested were nonlethal, and ChE levels approached normal within 24 hours after treatment. Only the frequency of vomiting differed statistically between the placebo and landrin treatment. We conclude that with appropriate precautions, landrin can be used in applications of CTA to discourage consumption of condor eggs by ravens, while posing no apparent risk to reintroduced condors.

THE STUDY OF THE PROPERTIES OF ERYTHROCYTES BY THE METHOD OF STRICTION (in Russian)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kriger, Yu.A.; Yartsev, E.I.

1959-10-01

With the aid of the toxicometric method, elaborated by B. N. Tarusov, the possibility of formation of toxic products in the irradiated biosubstrate was studied. It was established that when muscular brei is placed into an irradiated suspension of rat's erythrocytes there occurs an inhibition of the striction not attended, however, bv the appearance of peaks on the experimental curve. The appearance of peaks on the latter, indicating the presence of toxic substances, was recorded only in condition of a one-hour incubation of the biosubstrate carried out immediately after the irradiation. The number and amplitude of peaks rose consecutively aftermore » 9.24 and 48 hours following the irradiation with a simultaneous decrease of striction inhibition. After 72 hours there were noted a disappearance of peaks and elimination of striction inhihition. The presence of peaks on the curve when the muscular brei is placed into the suspension serves as a testimony of the transfer inio ihe latter of toxic products, formed upon the irradistion of ervthrocytes. The appearance of the toxicity is apparently characteristic only for radiation injury of erythrocytes. It is observed neither in hypotonic hemolysis nor in saponin hemolysis. On the basis of data obtained and on that of previous electronooptic and electrometric investigations a supposition is made on the relation of toxic substances with phospholinids and products of their disintegration, occurring during the action of gamma -rays on the erythrocytes. (auth)« less

Use of biomarkers for the assessment of chemotherapy-induced cardiac toxicity

PubMed Central

Christenson, Eric S.; James, Theodore; Agrawal, Vineet; Park, Ben H.

2015-01-01

Objectives To review the evidence for the use of various biomarkers in the detection of chemotherapy associated cardiac damage. Design and methods Pubmed.gov was queried using the search words chemotherapy and cardiac biomarkers with the filters of past 10 years, humans, and English language. An emphasis was placed on obtaining primary research articles looking at the utility of biomarkers for the detection of chemotherapy-mediated cardiac injury. Results Biomarkers may help identify patients undergoing treatment who are at high risk for cardiotoxicity and may assist in identification of a low risk cohort that does not necessitate continued intensive screening. cTn assays are the best studied biomarkers in this context and may represent a promising and potentially valuable modality for detecting cardiac toxicity in patients undergoing chemotherapy. Monitoring cTnI levels may provide information regarding the development of cardiac toxicity before left ventricular dysfunction becomes apparent on echocardiography or via clinical symptoms. A host of other biomarkers have been evaluated for their utility in the field of chemotherapy related cardiac toxicity with intermittent success; further trials are necessary to determine what role they may end up playing for prediction and prognostication in this setting. Conclusions Biomarkers represent an exciting potential complement or replacement for echocardiographic monitoring of chemotherapy related cardiac toxicity which may allow for earlier realization of the degree of cardiac damage occurring during treatment, creating the opportunity for more timely modulation of therapy. PMID:25445234

Species differences in susceptibility to 1,3-dinitrobenzene-induced testicular toxicity and methemoglobinemia.

PubMed

Obasaju, M F; Katz, D F; Miller, M G

1991-02-01

The testicular toxicity and methemoglobinemia induced by 1,3-dinitrobenzene (1,3-DNB) was compared in two species, the Sprague-Dawley rat and the golden Syrian hamster. A marked difference in susceptibility to both endpoints of toxicity was observed. The hamster showed no testicular lesions at dose levels up to 50 mg/kg whereas, as previously reported by others, damage to rat testicular tubules in later stages of spermatogenesis was readily apparent at a 25 mg/kg dose level. Similarly, administration of 1,3-DNB induced substantially less methemoglobinemia in the hamster than in the rat. For example, at the 25 mg/kg dose level peak levels of methemoglobin in the hamster were 15% compared with 80% in the rat. Mortality in the rat also occurred at lower doses than in the hamster (50 vs 100 mg/kg, respectively). In in vitro studies, the capacity of 1,3-DNB and 1,3-DNB metabolites (nitroaniline, nitroacetanilide, aminoacetanilide, diacetamidobenzene) to induce methemoglobinemia was examined in suspensions of red blood cells obtained from both species. Only 1,3-DNB caused the formation of methemoglobin and rat red blood cells were twice as sensitive as hamster red blood cells. The species difference in susceptibility to both methemoglobinemia and testicular toxicity could indicate differences in 1,3-DNB clearance and/or formation of toxic metabolites. Additional metabolic work is under way. This study demonstrates that the hamster is more resistant than the rat to the testicular lesion and methemoglobinemia induced by 1,3-DNB.

Effect of air gap on apparent temperature of body wearing various sizes of T-shirt

NASA Astrophysics Data System (ADS)

Takatera, M.; Uchiyama, E.; Zhu, C.; Kim, KO; Ishizawa, H.

2017-10-01

We investigated the effect of air gap on the apparent temperature. Using the developed thermocouple fabric and a thermal manikin, we measured temperature distribution of the measuring garments due to the change of T-shirt sizes. We were able to measure the apparent temperature distribution at points near a body while wearing different sizes of T-shirts. It was observed that the temperature distribution depending on different air gap between clothing and body. The apparent temperature depends on garment size and place. The effect of air gap on apparent temperature of body was experimentally confirmed.

Multiple Weather Factors Affect Apparent Survival of European Passerine Birds

PubMed Central

Salewski, Volker; Hochachka, Wesley M.; Fiedler, Wolfgang

2013-01-01

Weather affects the demography of animals and thus climate change will cause local changes in demographic rates. In birds numerous studies have correlated demographic factors with weather but few of those examined variation in the impacts of weather in different seasons and, in the case of migrants, in different regions. Using capture-recapture models we correlated weather with apparent survival of seven passerine bird species with different migration strategies to assess the importance of selected facets of weather throughout the year on apparent survival. Contrary to our expectations weather experienced during the breeding season did not affect apparent survival of the target species. However, measures for winter severity were associated with apparent survival of a resident species, two short-distance/partial migrants and a long-distance migrant. Apparent survival of two short distance migrants as well as two long-distance migrants was further correlated with conditions experienced during the non-breeding season in Spain. Conditions in Africa had statistically significant but relatively minor effects on the apparent survival of the two long-distance migrants but also of a presumably short-distance migrant and a short-distance/partial migrant. In general several weather effects independently explained similar amounts of variation in apparent survival for the majority of species and single factors explained only relatively low amounts of temporal variation of apparent survival. Although the directions of the effects on apparent survival mostly met our expectations and there are clear predictions for effects of future climate we caution against simple extrapolations of present conditions to predict future population dynamics. Not only did weather explains limited amounts of variation in apparent survival, but future demographics will likely be affected by changing interspecific interactions, opposing effects of weather in different seasons, and the potential for phenotypic and microevolutionary adaptations. PMID:23593131

Microplastics: addressing ecological risk through lessons learned.

PubMed

Syberg, Kristian; Khan, Farhan R; Selck, Henriette; Palmqvist, Annemette; Banta, Gary T; Daley, Jennifer; Sano, Larissa; Duhaime, Melissa B

2015-05-01

Plastic litter is an environmental problem of great concern. Despite the magnitude of the plastic pollution in our water bodies, only limited scientific understanding is available about the risk to the environment, particularly for microplastics. The apparent magnitude of the problem calls for quickly developing sound scientific guidance on the ecological risks of microplastics. The authors suggest that future research into microplastics risks should be guided by lessons learned from the more advanced and better understood areas of (eco) toxicology of engineered nanoparticles and mixture toxicity. Relevant examples of advances in these two fields are provided to help accelerate the scientific learning curve within the relatively unexplored area of microplastics risk assessment. Finally, the authors advocate an expansion of the "vector effect" hypothesis with regard to microplastics risk to help focus research of microplastics environmental risk at different levels of biological and environmental organization. © 2015 SETAC.

Anethole dithiolethione prevents oxidative damage in glutathione-depleted astrocytes.

PubMed

Drukarch, B; Schepens, E; Stoof, J C; Langeveld, C H

1997-06-25

Astrocytes protect neurons against reactive oxygen species such as hydrogen peroxide, a capacity which reportedly is abolished following loss of the antioxidant glutathione. Anethole dithiolethione, a sulfur-containing compound which is used in humans, is known to increase cellular glutathione levels and thought thereby to protect against oxidative damage. In the present study we found that anethole dithiolethione increased the glutathione content of cultured rat striatal astrocytes. This effect was abolished by coincubation with the glutathione synthesis inhibitor buthionine sulfoximine. Nevertheless, in the presence of buthionine sulfoximine, despite the lack of an increase in the lowered glutathione level, anethole dithiolethione fully protected the astrocytes against the enhanced toxicity of hydrogen peroxide. Thus, apparently other mechanisms than stimulation of glutathione synthesis are involved in the compound's protective action in astrocytes. Considering the occurrence of lowered glutathione levels in neurodegenerative syndromes, we conclude that further evaluation of the therapeutic potential of anethole dithiolethione is warranted.

Price tag in nanomaterials?

NASA Astrophysics Data System (ADS)

Gkika, D. A.; Vordos, N.; Nolan, J. W.; Mitropoulos, A. C.; Vansant, E. F.; Cool, P.; Braet, J.

2017-05-01

With the evolution of the field of nanomaterials in the past number of years, it has become apparent that it will be key to future technological developments. However, while there are unlimited research undertakings on nanomaterials, limited research results on nanomaterial costs exist; all in spite of the generous funding that nanotechnology projects have received. There has recently been an exponential increase in the number of studies concerning health-related nanomaterials, considering the various medical applications of nanomaterials that drive medical innovation. This work aims to analyze the effect of the cost factor on acceptability of health-related nanomaterials independently or in relation to material toxicity. It appears that, from the materials studied, those used for cancer treatment applications are more expensive than the ones for drug delivery. The ability to evaluate cost implications improves the ability to undertake research mapping and develop opinions on nanomaterials that can drive innovation.

Inhibition of recombinant Pneumocystis carinii dihydropteroate synthetase by sulfa drugs.

PubMed Central

Hong, Y L; Hossler, P A; Calhoun, D H; Meshnick, S R

1995-01-01

Forty-four sulfa drugs were screened against crude preparations of recombinant Pneumocystis carinii dihydropteroate synthetase. The apparent Michaelis-Menten constants (Km) for p-aminobenzoic acid and 7,8-dihydro-6-hydroxymethylpterin pyrophosphate were 0.34 +/- 0.02 and 2.50 +/- 0.71 microM, respectively. Several sulfa drugs, including sulfathiazole, sulfachlorpyridazine, sulfamethoxypyridazine, and sulfathiourea, inhibited dihydropteroate synthetase approximately as well as sulfamethoxazole, as determined by the concentrations which cause 50% inhibition and/or by Ki. For all sulfones and sulfonamides tested, unsubstituted p-amino groups were necessary for activity, and sulfonamides containing an N1-heterocyclic substituent were found to be the most effective inhibitors. Folate biosynthesis in isolated intact P. carinii was approximately equally sensitive to inhibition by sulfamethoxazole, sulfachlorpyridazine, sulfamethoxypyridazine, sulfisoxazole, and sulfathiazole. Two of these drugs, sulfamethoxypyridazine and sulfisoxazole, are known to be less toxic than sulfamethoxazole and should be further evaluated for the treatment of P. carinii pneumonia. PMID:7486915

Toxic oil syndrome: the perspective after 20 years.

PubMed

Posada de la Paz, M; Philen, R M; Borda, A I

2001-01-01

Toxic oil syndrome burst upon the scene in Spain in May of 1981, draining the resources of a newly evolving political and social medicine system. The vehicle of the causative toxic agent was identified as an illicit oil that had been diverted from industrial use and refined in order to remove the aniline denaturant, and that was sold in unlabeled 5-liter containers by itinerant salesmen. Over 20,000 people were ultimately affected, and over 1,200 deaths from all causes have been recorded in the affected cohort. The epidemiologic investigation of toxic oil syndrome involved all facets of investigative and analytical work; from visits to factories and interviewing workers, to sophisticated chemical and statistical analytical techniques. This investigation serves as a further illustration that data and information of all types, and from a wide range of fields, need to be systematically collected and evaluated in order to best resolve an epidemiologic mystery. Astute clinical observation of the patients, however, led to the hypothesis that toxic oil syndrome was a result of a toxic exposure. In this and other epidemics of unknown etiology, clinical observation and the intense scrutiny of patients' histories, signs, and symptoms by treating clinicians have often led to hypotheses that could be tested epidemiologically. When there are medical unknowns, the role of the astute clinician continues to be crucial. The toxic oil syndrome epidemic is an example of how even a developed country can be affected by a massive epidemic of environmental origin if failures occur in the systems that control and regulate the food supply or other consumer products. However, such failures could occur anywhere that large commercial networks operate on the regulatory edge, and if these business lack an in depth knowledge of the consequences of alterations in manufacturing conditions. Such was the case with eosinophilia-myalgia syndrome as well, when apparently minor alterations in manufacturing conditions of L-tryptophan led to an increase in impurities in the product that were later associated with the illness. These risks are even greater in countries with few or inconsistent control systems, making the food and drug supply potential portals of entry for serious health hazards, as is further exemplified by the tragic episode of pediatric renal failure in Haiti associated with a legitimate consumer product, paracetamol elixir, that had been manufactured using a fraudulently supplied toxic ingredient, diethylene glycol (81). The potential toxicants in the adulterated rapeseed oil were present in extremely small amounts. If fatty acid anilides or related compounds are indeed the etiologic agents in toxic oil syndrome, then these compounds must be extremely toxic at the parts per million concentrations at which they were found. Further, the roles of causative agents in the development of disorders such as scleroderma, eosinophilic fasciitis, eosinophilic perimyositis, and other similar diseases are unknown, but scientists can speculate that some sort of low level environmental agent may play a role if such extremely small quantities of contaminants are indeed capable of causing disease. Although the exact identity of the etiologic agent in toxic oil syndrome remains unknown, work on toxic oil syndrome continues. Follow-up clinical studies and long-term mortality studies are under way. Investigation of the mechanisms involved in toxic oil syndrome continues. The identification of suspect chemical compounds, their characterization, and effects will hopefully one day contribute to the prevention of other similar diseases.

Effects of contaminants on naiad mollusks (Unionidae): a review

USGS Publications Warehouse

Havlik, M.E.; Marking, L.L.

1987-01-01

Although the uptake, storage, and elimination of contaminants by naiad mollusks has been studied, relatively little information is available on toxicity. Contaminants appear to have destroyed some populations directly by exerting toxic effects, or indirectly by causing or contributing to the elimination of essential food organisms or host fish. The most frequently studied contaminants are Cd, Cu, Mn-Mn64, Pb-Pb210. and Zn-Zn65. Manganese seems to be most readily taken up and stored in tissues; no apparent damage has been reported from tissue concentrations of thousands of parts per million (ppm) and the element appears to be essential to metabolism. Zinc and cadmium also accumulate at high levels in tissues. Lead was never found to be lethal in the studies reviewed. Various common contaminants have been reported to be toxic at the following concentrations (ppm): cadmium. 2; copper sulfate, 2 to 18.7; ammonia, 5; potassium. 11; chromium, 12.4; arsenic trioxide, 16; copper, 19; and zinc, 66. In long-term exposures, concentrations of copper as low as 25 parts per billion (ppb) were lethal. Fry of fish infected with 20-35 glochidia were more sensitive than uninfected fish to toluene, naphthalene, and crude oil. Although few specific adverse impacts of contaminants have become clearly evident, circumstantial evidence leaves little doubt that contaminants have been responsible for decreases in population density, range, and diversity. Stresses that have been responsible for the disappearance of naiad mollusks in contaminated areas have not generally been identified, and the components of the stresses have seldom been quantitatively and qualitatively correlated with the composition and size of the naiad fauna. Often two or more factors appear to work in combination to produce the total stress that adversely affects populations. Naiad mollusks are important indio caters of contaminants in the environment; residues in soft tissue indicate recent or current exposure, and residues in shells indicate past exposure.

Effect of Low pH and Aluminum Toxicity on the Photosynthetic Characteristics of Different Fast-Growing Eucalyptus Vegetatively Propagated Clones.

PubMed

Yang, Mei; Tan, Ling; Xu, Yuanyuan; Zhao, Yihui; Cheng, Fei; Ye, Shaoming; Jiang, Weixin

2015-01-01

Knowing how acid soils and aluminum in soils may limit the growth of Eucalyptus trees in plantations is important because these plantations grow in many tropical and subtropical regions. Seedlings of four vegetatively propagated Eucalyptus clones, E. grandis × E. urophylla 'GLGU9'(G9), E. grandis × E. urophylla 'GLGU12' (G12), E. urophylla × E. camaldulensis 'GLUC3' (G3) and E. urophylla 'GLU4'(G4), were subjected to liquid culture with Hoagland nutrient solution for 40 days, then treated with four different treatments of acid and aluminum for 1 day. The four treatments used either pH 3.0 or 4.0 with or without added aluminum (4.4 mM) in all possible combinations; a control used no added aluminum at pH 4.8. Subsequently, the photosynthetic parameters and morphology of leaves from eucalypt seedlings were determined and observed. The results showed that the tested chlorophyll content, net photosynthetic rate, transpiration rate and water use efficiency were apparently inhibited by aluminum. Under uniform Al concentration (4.4 mM), the Al-induced limitation to photosynthetic parameters increased with pH, indicating acid stimulation to Al toxicity. Among all treatments, the most significant reduction was found in the combination of pH 3.0 and 4.4 mM Al. The photosynthetic and transpiration rates showed similar trends with G9 > G12 > G3 > G4, suggesting that G9 and G12 had higher Al-tolerance than other two clones. Microscopic observation revealed changes in leaf morphology when exposed to Al stress; for example, a reduced thickness of leaf epidermis and palisade tissue, the descendant palisade tissue/spongy tissue ratio and leaf tissue looseness. Overall, the acid and aluminum stress exerted negative effects on the photosynthetic activity of eucalypt seedlings, but the differences in tolerance to Al toxicity between the clones were favorable, offering potential to improve Eucalyptus plantation productivity by selecting Al tolerant clones.

Daily fluctuation of hepatic P450 monooxygenase activities in male rats is controlled by the suprachiasmatic nucleus but remains unaffected by adrenal hormones.

PubMed

Furukawa, T; Manabe, S; Watanabe, T; Sehata, S; Sharyo, S; Okada, T; Mori, Y

1999-09-01

Hepatic P450 monooxygenase activities, which strongly influence the efficacy and/or toxicity of drugs, are known to fluctuate daily. We also know that the P450 activities assessed by measurement of 7-alkoxycoumarin O-dealkylase (ACD) activities fluctuate daily, with apparently high values during the dark period in male rats. However, there is little knowledge about the factors that regulate daily fluctuation of P450 monooxygenase activities. In the present study using rats, we induced lesions in the suprachiasmatic nucleus (SCN) of the brain, the known site of the body's internal clock, and examined the effects on the daily fluctuation of the ACD activities to clarify the relationship between the SCN and the daily fluctuation of P450 monooxygenase activities. In addition, adrenalectomy was performed to re-evaluate the influence of adrenal hormones on the P450 activities. Our results indicated that daily fluctuations of the hepatic ACD activities were completely eliminated in the SCN-lesioned rats. However, the ACD activities in the adrenalectomized rats showed apparent daily fluctuations with high values during the dark period and low values during the light period. Therefore, this study demonstrated that the daily fluctuation of the hepatic P450 monooxygenase activities in male rats is controlled by the SCN but remains unaffected by the adrenal hormones.

CdTe/CdSe quantum dots improve the binding affinities between α-amylase and polyphenols.

PubMed

Ni, Xiaoling

2012-03-01

People exposed to engineered nanomaterials have potential health risks associated. Human α-amylase is one of the key enzymes in the digestive system. There are few reports about the influence of quantum dots (QDs) on the digestive enzymes and their inhibition system. This work focused on the toxic effect of CdTe/CdSe QDs on the interactions between α-amylase and its natural inhibitors. Thirty-six dietary polyphenols, natural α-amylase inhibitors from food, were studied for their affinities for α-amylase in the absence and presence of CdTe/CdSe QDs by a fluorescence quenching method. The magnitudes of apparent binding constants of polyphenols for α-amylase were almost in the range of 10(5)-10(7) L mol(-1) in the presence of CdTe/CdSe QDs, which were higher than the magnitudes of apparent binding constants in the absence of CdTe/CdSe QDs (10(4)-10(6) L mol(-1)). CdTe/CdSe QDs obviously improved the affinities of dietary polyphenols for α-amylase up to 389.04 times. It is possible that the binding interaction between polyphenols and α-amylase in the presence of CdTe/CdSe QDs was mainly caused by electrostatic interactions. QDs significantly influence the digestive enzymes and their inhibition system. This journal is © The Royal Society of Chemistry 2012

A comparative approach of methylparaben photocatalytic degradation assisted by UV-C, UV-A and Vis radiations.

PubMed

Doná, Giovanna; Dagostin, João Luiz Andreoti; Takashina, Thiago Atsushi; de Castilhos, Fernanda; Igarashi-Mafra, Luciana

2018-05-01

Due to the widespread use of methylparaben (MEP) and its high chemical stability, it can be found in wastewater treatment plants and can act as an endocrine disrupting compound. In this study, the photocatalytic degradation and mineralization of MEP solutions were evaluated under UV-A, UV-C and Vis radiations in the presence of the photocatalyst TiO 2 . In this sense, the effects of the catalyst load, pH and MEP initial concentration were studied. Remarkably higher reaction rates and total photodegradation were achieved in systems assisted by UV-C radiation. The complete degradation was achieved after 60 min of reaction using the MEP concentration of 30 mg L -1 at pH 9 and 500 mg L -1 TiO 2 . The experimental data apparently followed a Langmuir-Hinshelwood kinetic model, which could predict 88-98% of the reaction behavior. For the best photodegradation condition, the model predicted an apparent reaction rate constant (k app ) equal to 0.0505 min -1 and an initial reaction rate of 1.5641 mg (L min) -1 . Mineralization analyses showed high removal for MEP and derived compounds from the initial solution when using UV-C after 90 min of reaction. The lower toxicity was also confirmed by in vivo tests using MEP solutions previously treated by photocatalysis.

Nosema ceranae escapes fumagillin control in honey bees.

PubMed

Huang, Wei-Fone; Solter, Leellen F; Yau, Peter M; Imai, Brian S

2013-03-01

Fumagillin is the only antibiotic approved for control of nosema disease in honey bees and has been extensively used in United States apiculture for more than 50 years for control of Nosema apis. It is toxic to mammals and must be applied seasonally and with caution to avoid residues in honey. Fumagillin degrades or is diluted in hives over the foraging season, exposing bees and the microsporidia to declining concentrations of the drug. We showed that spore production by Nosema ceranae, an emerging microsporidian pathogen in honey bees, increased in response to declining fumagillin concentrations, up to 100% higher than that of infected bees that have not been exposed to fumagillin. N. apis spore production was also higher, although not significantly so. Fumagillin inhibits the enzyme methionine aminopeptidase2 (MetAP2) in eukaryotic cells and interferes with protein modifications necessary for normal cell function. We sequenced the MetAP2 gene for apid Nosema species and determined that, although susceptibility to fumagillin differs among species, there are no apparent differences in fumagillin binding sites. Protein assays of uninfected bees showed that fumagillin altered structural and metabolic proteins in honey bee midgut tissues at concentrations that do not suppress microsporidia reproduction. The microsporidia, particularly N. ceranae, are apparently released from the suppressive effects of fumagillin at concentrations that continue to impact honey bee physiology. The current application protocol for fumagillin may exacerbate N. ceranae infection rather than suppress it.

Apparent tolerance of turkey vultures (Cathartes aura) to the non-steroidal anti-inflammatory drug diclofenac

USGS Publications Warehouse

Rattner, B.A.; Whitehead, M.A.; Gasper, G.; Meteyer, C.U.; Link, W.A.; Taggart, M.A.; Meharg, A.A.; Pattee, O.H.; Pain, D.J.

2008-01-01

The nonsteroidal anti-inflammatory drug diclofenac is extremely toxic to Old World Gyps vultures (median lethal dose 0.1?0.2 mg/kg), evoking visceral gout, renal necrosis, and mortality within a few days of exposure. Unintentional secondary poisoning of vultures that fed upon carcasses of diclofenac-treated livestock decimated populations in the Indian subcontinent. Because of the widespread use of diclofenac and other cyclooxygenase-2 inhibiting drugs, a toxicological study was undertaken in turkey vultures (Cathartes aura) as an initial step in examining sensitivity of New World scavenging birds. Two trials were conducted entailing oral gavage of diclofenac at doses ranging from 0.08 to 25 mg/kg body weight. Birds were observed for 7 d, blood samples were collected for plasma chemistry (predose and 12, 24, and 48 h and 7 d postdose), and select individuals were necropsied. Diclofenac failed to evoke overt signs of toxicity, visceral gout, renal necrosis, or elevate plasma uric acid at concentrations greater than 100 times the estimated median lethal dose reported for Gyps vultures. For turkey vultures receiving 8 or 25 mg/kg, the plasma half-life of diclofenac was estimated to be 6 h, and it was apparently cleared after several days as no residues were detectable in liver or kidney at necropsy. Differential sensitivity among avian species is a hallmark of cyclooxygenase-2 inhibitors, and despite the tolerance of turkey vultures to diclofenac, additional studies in related scavenging species seem warranted.

Protective Effect of Aronia Melanocarpa Polyphenols on Cadmium Accumulation in the Body: A Study in a Rat Model of Human Exposure to this Metal.

PubMed

Brzoska, Malgorzata M; Galazyn-Sidorczuk, Malgorzata; Jurczuk, Maria; Tomczyk, Michal

2015-01-01

Recently a growing attention has been paid to the possibility of using biologically active compounds, including polyphenols, for the prevention of unfavourable effects of exposure to xenobiotics. The study was aimed to investigate, in a female rat model, whether consumption of Aronia melanocarpa polyphenols (AMP) under chronic exposure to cadmium (Cd) decreases the gastrointestinal absorption and body burden of this heavy metal. For this purpose, Cd turnover (apparent absorption, retention in the body, concentration in the blood, soft tissues and bone tissue, total pool in internal organs, faecal and urinary excretion) was evaluated in the female Wistar rats who were administered only a 0.1% aqueous extract of AMP (prepared from the powdered extract containing 65.74% of polyphenols) as drinking fluid or/and Cd in diet (1 and 5 mg/kg) for up to 24 months. AMP administration under the low Cd treatment (1 mg/kg diet) had only a very slight protective impact against this metal accumulation in the organism, whereas polyphenols application under moderate exposure (5 mg Cd/kg diet) significantly decreased apparent absorption and retention in the body, and increased urinary concentration of this xenobiotic, resulting in its lower concentration in the blood and lower accumulation in soft tissues (mainly in the liver and kidneys) and bone tissue. Based on the study, it can be concluded that consumption of polyphenol- rich products may prevent Cd absorption from the diet polluted by this metal and its accumulation in the females' body, and thus also prevent its toxic action.

Essential oils nanoformulations for stored-product pest control - characterization and biological properties.

PubMed

Werdin González, Jorge Omar; Gutiérrez, María Mercedes; Ferrero, Adriana Alicia; Fernández Band, Beatriz

2014-04-01

The lethal and sublethal activity of poly(ethylene glycol) (PEG) nanoparticles containing essential oils (EO), also the physicochemical characterization, were determined against Tribolium castaneum and Rhizopertha dominica. The 10% ratio EO-PEG nanoparticles showed an average diameter<235 nm (PDI<0.280) and a loading efficacy>75%; after 6 month of storage their size did not change significantly and the amount of the EOs decreased 25%, approximately. Furthermore, during this period, no chemical derivates were observed. The EOs nanoparticles produced a notable increase of the residual contact toxicity apparently due to the slow and persistent release of the active terpenes. In addition, the nanoformulation enhanced the EO contact toxicity and altered the nutritional physiology of both stored product pest. The results indicated that these novel systems could be used in integrated pest management program for T. castaneum and R. dominica control. Copyright © 2013 Elsevier Ltd. All rights reserved.

A technique for extracting blood samples from mice in fire toxicity tests

NASA Technical Reports Server (NTRS)

Bucci, T. J.; Hilado, C. J.; Lopez, M. T.

1976-01-01

The extraction of adequate blood samples from moribund and dead mice has been a problem because of the small quantity of blood in each animal and the short time available between the animals' death and coagulation of the blood. These difficulties are particularly critical in fire toxicity tests because removal of the test animals while observing proper safety precautions for personnel is time-consuming. Techniques for extracting blood samples from mice were evaluated, and a technique was developed to obtain up to 0.8 ml of blood from a single mouse after death. The technique involves rapid exposure and cutting of the posterior vena cava and accumulation of blood in the peritoneal space. Blood samples of 0.5 ml or more from individual mice have been consistently obtained as much as 16 minutes after apparent death. Results of carboxyhemoglobin analyses of blood appeared reproducible and consistent with carbon monoxide concentrations in the exposure chamber.

[Comprehensive analysis on "toxicity and effect" of Chinese pharmaceutical preparations].

PubMed

Hu, Hui-Ling; Fu, Chao-Mei; Zhao, Xuan; Zhang, Jin-Ming; Gao, Fei; He, Yao; Fu, Shu; Li, Ling

2016-09-01

The manufacturing process of Chinese medicines is the significant link to achieve "effect-enhancing and toxicity-reducing", including an interaction between "toxicity and effect". This paper would elucidate the effects of Chinese herbal compound decoction, preparation, dosage forms, route of administration and quality of pharmaceutical excipients on "toxicity-effect" theory from the formulation approaches. The article pointed out that the comprehensive analysis on "toxicity-effect" theory should be strengthened from the aspects of overall manufacturing, fundamental research and modern Chinese preparation, to explore the mechanism of "effect-enhancing and toxicity-reducing" in the manufacturing process, clarify the core status of Chinese preparation in "toxicity-effect" theory, and ensure the security and effectiveness in traditional Chinese medicine clinical application. Copyright© by the Chinese Pharmaceutical Association.

Alcohol enhances oxysterol-induced apoptosis in human endothelial cells by a calcium-dependent mechanism.

PubMed

Spyridopoulos, I; Wischhusen, J; Rabenstein, B; Mayer, P; Axel, D I; Fröhlich, K U; Karsch, K R

2001-03-01

Controversy exists about the net effect of alcohol on atherogenesis. A protective effect is assumed, especially from the tannins and phenolic compounds in red wine, owing to their inhibition of low density lipoprotein (LDL) oxidation. However, increased atherogenesis occurs in subjects with moderate to heavy drinking habits. The purpose of this study was to investigate the influence of alcohol in combination with oxysterols on the endothelium. Cultured human arterial endothelial cells (HAECs) served as an in vitro model to test the cellular effects of various oxysterols. Oxysterols (7beta-hydroxycholesterol, 7-ketocholesterol, and cholesterol-5,6-epoxides), which are assumed to be the most toxic constituents of oxidized LDL, induced apoptosis in HAECs through calcium mobilization followed by activation of caspase-3. Ethanol, methanol, isopropanol, tert-butanol, and red wine all potentiated oxysterol-induced cell death up to 5-fold, paralleled by further induction of caspase-3. The alcohol effect occurred in a dose-dependent manner and reached a plateau at 0.05% concentration. Alcohol itself did not affect endothelial cell viability, nor did other solvents such as dimethyl sulfoxide mimic the alcohol effect. So far as the physiologically occurring oxysterols are concerned, this effect was apparent only for oxysterols oxidized at the steran ring. The possibility of alcohol facilitating the uptake of oxysterols into the cell was not supported by the data from an uptake study with radiolabeled compounds. Finally, alcohol in combination with oxysterols did cause a dramatic increase in cytosolic calcium influx. Blockage of calcium influx by the calcium channel blocker aurintricarboxylic acid or the calcium chelator ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid abrogated the alcohol-mediated enhancement of oxysterol toxicity. We describe for the first time a mechanistic concept explaining possible adverse effects of alcohol in conjunction with physiologically occurring oxysterols on atherogenesis.

Contaminant effects on Great Lakes' fish-eating birds: a population perspective

USGS Publications Warehouse

Heinz, G.H.; Kendall, Ronald J.; Dickerson, Richard L.; Giesy, John P.; Suk, William P.

1998-01-01

Preventing environmental contaminants from reducing wildlife populations is the greatest concern in wildlife toxicology. In the Great Lakes, environmental contaminants have a history of reducing populations of many species of fish-eating birds. Endocrine effects may have contributed to declines in fish-eating bird populations, but the overriding harm was caused by DDE-induced eggshell thinning. Toxic effects may still be occurring today, but apparently they are not of a sufficient magnitude to depress populations of most fish-eating birds. Once DDE levels in the Great Lakes declined, eggshells of birds began to get thicker and reproductive success improved. Populations of double-crested cormorants (Phalacrocorax auritus) and ring-billed gulls (Larus delawarensis) have increased dramatically since the bans on DDT and other organochlorine pesticides. Bald eagles (Haliaeetus leucocephalus) are still not reproducing at a normal rate along the shores of the Great Lakes, but success is much improved compared to earlier records when eggshell thinning was worse. Other species, such as herring gulls (Larus argentatus) and black-crowned night-herons (Nycticorax nycticorax), seem to be having improved reproductive success, but data on Great Lakes'-wide population changes are incomplete. Reproductive success of common terns (Sterna hirundo), Caspian terns (Sterna caspia), and Forster's terns (Sterna forsteri) seems to have improved in recent years, but, again, data on population changes are not very complete, and these birds face many habitat related problems as well as contaminant problems. Although contaminants are still producing toxic effects, and these effects may include endocrine disfunction, fish-eating birds in the Great Lakes seem to be largely weathering these effects, at least as far as populations are concerned. A lack of obvious contaminant effects on populations of fish-eating birds in the Great Lakes, however, should not be equated with a lack of any harm to these birds or with a conclusion that certain contaminants do not need additional control.

75 FR 51869 - CAFTA-DR Consultation Request Regarding Guatemala's Apparent Failure to Effectively Enforce its...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-23

... Request Regarding Guatemala's Apparent Failure to Effectively Enforce its Labor Laws AGENCY: Office of the... (CAFTA-DR), the United States requested consultations with the Government of Guatemala to discuss Guatemala's apparent failure to meet its obligation under Article 16.2.1(a) to effectively enforce its labor...

THE EFFECT OF TUNGSTATE NANOPARTICLES ON REACTIVE OXYGEN SPECIES AND CYTOTOXICITY IN RAW 264.7 MOUSE MONOCYTE MACROPHAGE CELLS

PubMed Central

Dunnick, Katherine M.; Badding, Melissa A.; Schwegler-Berry, Diane; Patete, Jonathan M.; Koenigsmann, Christopher; Wong, Stanislaus S.; Leonard, Stephen S.

2015-01-01

Due to their unique size, surface area, and chemical characteristics, nanoparticles’ use in consumer products has increased. However, the toxicity of nanoparticle (NP) exposure during the manufacturing process has not been fully assessed. Tungstate NP are used in numerous products, including but not limited to scintillator detectors and fluorescent lighting. As with many NP, no apparent toxicity studies have been completed with tungstate NP. The hypothesis that tungstate NP in vitro exposure results in reactive oxygen species (ROS) formation and cytotoxicity was examined. Differences in toxicity based on tungstate NP size, shape (sphere vs. wire), and chemical characteristics were determined. RAW 264.7 mouse monocyte macrophages were exposed to tungstate NP, and ROS formation was assessed via electron spin resonance (ESR), and several assays including hydrogen peroxide, intracellular ROS, and Comet. Results showed ROS production induced by tungstate nanowire exposure, but this exposure did not result in oxidative DNA damage. Nanospheres showed neither ROS nor DNA damage following cellular exposure. Cells were exposed over 72 h to assess cytotoxicity using an MTT (tetrazolium compound) assay. Results showed that differences in cell death between wires and spheres occurred at 24 h but were minimal at both 48 and 72 h. The present results indicate that tungstate nanowires are more reactive and produce cell death within 24 h of exposure, whereas nanospheres are less reactive and did not produce cell death. Results suggest that differences in shape may affect reactivity. However, regardless of the differences in reactivity, in general both shapes produced mild ROS and resulted in minimal cell death at 48 and 72 h in RAW 264.7 cells. PMID:25208664

Safety evaluation of food contact paper and board using chemical tests and in vitro bioassays: role of known and unknown substances.

PubMed

Honkalampi-Hämäläinen, U; Bradley, E L; Castle, L; Severin, I; Dahbi, L; Dahlman, O; Lhuguenot, J-C; Andersson, M A; Hakulinen, P; Hoornstra, D; Mäki-Paakkanen, J; Salkinoja-Salonen, M; Turco, L; Stammati, A; Zucco, F; Weber, A; von Wright, A

2010-03-01

In vitro toxicological tests have been proposed as an approach to complement the chemical safety assessment of food contact materials, particularly those with a complex or unknown chemical composition such as paper and board. Among the concerns raised regarding the applicability of in vitro tests are the effects of interference of the extractables on the outcome of the cytotoxicity and genotoxicity tests applied and the role of known compounds present in chemically complex materials, such as paper and board, either as constituents or contaminants. To answer these questions, a series of experiments were performed to assess the role of natural substances (wood extracts, resin acids), some additives (diisopropylnaphthalene, phthalates, acrylamide, fluorescent whitening agents) and contaminants (2,4-diaminotoluene, benzo[a]pyrene) in the toxicological profile of paper and board. These substances were individually tested or used to spike actual paper and board extracts. The toxic concentrations of diisopropylnaphthalenes and phthalates were compared with those actually detected in paper and board extracts showing conspicuous toxicity. According to the results of the spiking experiments, the extracts did not affect the toxicity of tested chemicals nor was there any significant metabolic interference in the cases where two compounds were used in tests involving xenobiotic metabolism by the target cells. While the identified substances apparently have a role in the cytotoxicity of some of the project samples, their presence does not explain the total toxicological profile of the extracts. In conclusion, in vitro toxicological testing can have a role in the safety assessment of chemically complex materials in detecting potentially harmful activities not predictable by chemical analysis alone.

Assessing potential toxicity of chloride-affected groundwater discharging to an urban stream using juvenile freshwater mussels (Lampsilis siliquoidea).

PubMed

Roy, James W; McInnis, Rodney; Bickerton, Greg; Gillis, Patricia L

2015-11-01

Groundwater contaminants, such as chloride from road salt, pose a threat to aquatic ecosystems when and where they discharge to surface waters. Here we study the application of a laboratory toxicity bioassay to field-collected samples from contaminated groundwater discharging to an urban stream. The objectives were to assess the potential toxicity of the discharging groundwater, while also exploring the suitability of such standard tests to site groundwater. Juvenile freshwater mussels were chosen as a groundwater-appropriate (endobenthic) test organism. Groundwater was sampled from 6 sites at approximate depths of 0, 10, and 50 cm below the sediment. Concentrations of chloride and several metals were above aquatic life guidelines in some samples. Exposure (96-h) to site groundwater resulted in survival of 90-100% and 80-100% for the 0-cm and deeper samples, respectively, indicating that groundwater may pose a toxicological threat to freshwater mussels. Several samples with high chloride had a survival rate of 80%, but generally there was poor correlation between survival and individual contaminants. Parallel juvenile mussel exposures using reconstituted water and NaCl predicted survival in the natural groundwater below 50% based on chloride concentrations. This indicates some protective ability of groundwater, possibly associated with water hardness. Finally, some technical issues with performing bioassays with groundwater were noted. First, aeration of previously anoxic groundwater samples caused marked changes in water quality (especially metal concentrations). Second, calcite crystals formed on the mussel shells in samples with elevated chloride and water hardness, though with no apparent negative effects. Crown Copyright © 2015. Published by Elsevier B.V. All rights reserved.

Tesevatinib ameliorates progression of polycystic kidney disease in rodent models of autosomal recessive polycystic kidney disease

PubMed Central

Sweeney, William E; Frost, Philip; Avner, Ellis D

2017-01-01

AIM To investigate the therapeutic potential of tesevatinib (TSV), a unique multi-kinase inhibitor currently in Phase II clinical trials for autosomal dominant polycystic kidney disease (ADPKD), in well-defined rodent models of autosomal recessive polycystic kidney disease (ARPKD). METHODS We administered TSV in daily doses of 7.5 and 15 mg/kg per day by I.P. to the well characterized bpk model of polycystic kidney disease starting at postnatal day (PN) 4 through PN21 to assess efficacy and toxicity in neonatal mice during postnatal development and still undergoing renal maturation. We administered TSV by oral gavage in the same doses to the orthologous PCK model (from PN30 to PN90) to assess efficacy and toxicity in animals where developmental processes are complete. The following parameters were assessed: Body weight, total kidney weight; kidney weight to body weight ratios; and morphometric determination of a cystic index and a measure of hepatic disease. Renal function was assessed by: Serum BUN; creatinine; and a 12 h urinary concentrating ability. Validation of reported targets including the level of angiogenesis and inhibition of angiogenesis (active VEGFR2/KDR) was assessed by Western analysis. RESULTS This study demonstrates that: (1) in vivo pharmacological inhibition of multiple kinase cascades with TSV reduced phosphorylation of key mediators of cystogenesis: EGFR, ErbB2, c-Src and KDR; and (2) this reduction of kinase activity resulted in significant reduction of renal and biliary disease in both bpk and PCK models of ARPKD. The amelioration of disease by TSV was not associated with any apparent toxicity. CONCLUSION The data supports the hypothesis that this multi-kinase inhibitor TSV may provide an effective clinical therapy for human ARPKD. PMID:28729967

A fully human anti-Ep-CAM scFv-beta-glucuronidase fusion protein for selective chemotherapy with a glucuronide prodrug

PubMed Central

de Graaf, M; Boven, E; Oosterhoff, D; van der Meulen-Muileman, I H; Huls, G A; Gerritsen, W R; Haisma, H J; Pinedo, H M

2002-01-01

Monoclonal antibodies against tumour-associated antigens could be useful to deliver enzymes selectively to the site of a tumour for activation of a non-toxic prodrug. A completely human fusion protein may be advantageous for repeated administration, as host immune responses may be avoided. We have constructed a fusion protein consisting of a human single chain Fv antibody, C28, against the epithelial cell adhesion molecule and the human enzyme β-glucuronidase. The sequences encoding C28 and human enzyme β-glucuronidase were joined by a sequence encoding a flexible linker, and were preceded by the IgGκ signal sequence for secretion of the fusion protein. A CHO cell line was engineered to secrete C28-β-glucuronidase fusion protein. Antibody specificity and enzyme activity were retained in the secreted fusion protein that had an apparent molecular mass of 100 kDa under denaturing conditions. The fusion protein was able to convert a non-toxic prodrug of doxorubicin, N-[4-doxorubicin-N-carbonyl(oxymethyl)phenyl]-O-β-glucuronyl carbamate to doxorubicin, resulting in cytotoxicity. A bystander effect was demonstrated, as doxorubicin was detected in all cells after N-[4-doxorubicin-N-carbonyl(oxymethyl)phenyl]-O-β-glucuronyl carbamate administration when only 10% of the cells expressed the fusion protein. This is the first fully human and functional fusion protein consisting of an scFv against epithelial cell adhesion molecule and human enzyme β-glucuronidase for future use in tumour-specific activation of a non-toxic glucuronide prodrug. British Journal of Cancer (2002) 86, 811–818. DOI: 10.1038/sj/bjc/6600143 www.bjcancer.com © 2002 Cancer Research UK PMID:11875747

A novel dynamic field-matching technique for treatment of patients with para-aortic node-positive cervical cancer: Clinical experience

PubMed Central

Baden, Craig; Whitley, Alexander; López-Araujo, Javier; Popple, Richard; Duan, Jun; Kim, Robert

2016-01-01

Aim To report outcomes for patients with para-aortic lymph node positive cervical cancer treated with a dynamic field-matching technique. Background PET staging of cervical cancer has increased identification of patients with para-aortic lymph node metastasis. IMRT enables dose escalation in this area, but matching IMRT fields with traditional whole pelvis fields presents a challenge. Materials and methods From 2003 to 2012, 20 patients with cervical cancer and para-aortic lymph node metastasis were treated utilizing the dynamic field-matching technique. As opposed to single-isocenter half-beam junction techniques, this technique employs wedge-shaped dose junctions for the abutment of fields. We reviewed the records of all patients who completed treatment with the technique and abstracted treatment, toxicity, and disease-related outcome data for analysis. Results Median prescribed dose to the whole pelvis field was 45 Gy and para-aortic IMRT field 50.4 Gy. All but 3 patients underwent HDR (13 pts) or LDR (4 pts) brachytherapy. All patients developed lower GI toxicity; 10 grade 1, 9 grade 2, and 1 grade 4 (enterovaginal fistula). Median DFS was 12.4 months with 1 and 2-year DFS 60.0% and 38.1%. One-year OS was 83.7% and 2-year OS, 64.4%. A total of 10 patients developed recurrence; none occurred at the matched junction. Conclusions The dynamic field-matching technique provides a means for joining conventional whole pelvis fields and para-aortic IMRT fields that substantially reduces dose deviations at the junction due to field mismatch. Treatment with the dynamic matching technique is simple, effective, and tolerated with no apparent increase in toxicity. PMID:26900356

Developmental toxicity of PCB 126 (3,3',4,4',5-pentachlorobiphenyl) in nestling American kestrels (Falco sparverius)

USGS Publications Warehouse

Hoffman, D.J.; Melancon, M.J.; Klein, P.N.; Rice, C.P.; Eisemann, J.D.; Hines, R.K.; Spann, J.W.; Pendleton, G.W.

1996-01-01

Planar PCB congeners are embryotoxic and teratogenic to birds including American kestrels. The developmental toxicity of 3,3',4,4',5-pentachlorobiphenyl (PCB 126) was studied in the post-hatching kestrel as a model for the eagle. Nestlings were orally dosed for 10 days with 5 ul/g body weight of corn oil (controls) or the planar PCB 126 at concentrations of 50, 250, or 1000 ng/g body weight. Dosing with 50 ng/g of PCB 126 resulted in a hepatic concentration of 156 ng/g w.w., liver enlargement and mild coagulative necrosis, and over ten-fold increases in hepatic microsomal ethoxyresorufin-O-dealkylase (EROD) and benzyloxyresorufin-O-dealkylase (BROD), and approximately a 5-fold increase in methoxyresorufin-O-dealkylase (MROD). At this dose, mild to moderate lymphoid depletion of the spleen was apparent, and decreased follicle size and content of the thyroid. At 250 ng/g, concentration of PCB 126 in the liver was 380 ng/g with increasing multifocal coagulative necrosis, decreased bone growth, decreased spleen weight with lymphocyte depletion of the spleen and bursa, and degenerative lesions of the thyroid. At 1000 ng/g, the liver concentration was 1098 ng/g, accompanied by decreased bursa weight, decreased hepatic thiol concentration and increased plasma enzyme activities (ALT, AST, and LDH-L) in addition to the previous effects. Highly significant positive correlations were noted between liver concentrations of PCB 126 and the ratio of oxidized to reduced glutathone. These findings indicate that nestling kestrels are more susceptible to PCB 126 toxicity than adults, but less sensitive than embryos, and that planar PCBs are of potential hazard to nestling birds.

Withanolide E sensitizes renal carcinoma cells to TRAIL-induced apoptosis by increasing cFLIP degradation.

PubMed

Henrich, C J; Brooks, A D; Erickson, K L; Thomas, C L; Bokesch, H R; Tewary, P; Thompson, C R; Pompei, R J; Gustafson, K R; McMahon, J B; Sayers, T J

2015-02-26

Withanolide E, a steroidal lactone from Physalis peruviana, was found to be highly active for sensitizing renal carcinoma cells and a number of other human cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. Withanolide E, the most potent and least toxic of five TRAIL-sensitizing withanolides identified, enhanced death receptor-mediated apoptotic signaling by a rapid decline in the levels of cFLIP proteins. Other mechanisms by which TRAIL sensitizers have been reported to work: generation of reactive oxygen species (ROS), changes in pro-and antiapoptotic protein expression, death receptor upregulation, activation of intrinsic (mitochondrial) apoptotic pathways, ER stress, and proteasomal inhibition proved to be irrelevant to withanolide E activity. Loss of cFLIP proteins was not due to changes in expression, but rather destabilization and/or aggregation, suggesting impairment of chaperone proteins leading to degradation. Indeed, withanolide E treatment altered the stability of a number of HSP90 client proteins, but with greater apparent specificity than the well-known HSP90 inhibitor geldanamycin. As cFLIP has been reported to be an HSP90 client, this provides a potentially novel mechanism for sensitizing cells to TRAIL. Sensitization of human renal carcinoma cells to TRAIL-induced apoptosis by withanolide E and its lack of toxicity were confirmed in animal studies. Owing to its novel activity, withanolide E is a promising reagent for the analysis of mechanisms of TRAIL resistance, for understanding HSP90 function, and for further therapeutic development. In marked contrast to bortezomib, among the best currently available TRAIL sensitizers, withanolide E's more specific mechanism of action suggests minimal toxic side effects.

Withanolide E sensitizes renal carcinoma cells to TRAIL-induced apoptosis by increasing cFLIP degradation

PubMed Central

Henrich, C J; Brooks, A D; Erickson, K L; Thomas, C L; Bokesch, H R; Tewary, P; Thompson, C R; Pompei, R J; Gustafson, K R; McMahon, J B; Sayers, T J

2015-01-01

Withanolide E, a steroidal lactone from Physalis peruviana, was found to be highly active for sensitizing renal carcinoma cells and a number of other human cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. Withanolide E, the most potent and least toxic of five TRAIL-sensitizing withanolides identified, enhanced death receptor-mediated apoptotic signaling by a rapid decline in the levels of cFLIP proteins. Other mechanisms by which TRAIL sensitizers have been reported to work: generation of reactive oxygen species (ROS), changes in pro-and antiapoptotic protein expression, death receptor upregulation, activation of intrinsic (mitochondrial) apoptotic pathways, ER stress, and proteasomal inhibition proved to be irrelevant to withanolide E activity. Loss of cFLIP proteins was not due to changes in expression, but rather destabilization and/or aggregation, suggesting impairment of chaperone proteins leading to degradation. Indeed, withanolide E treatment altered the stability of a number of HSP90 client proteins, but with greater apparent specificity than the well-known HSP90 inhibitor geldanamycin. As cFLIP has been reported to be an HSP90 client, this provides a potentially novel mechanism for sensitizing cells to TRAIL. Sensitization of human renal carcinoma cells to TRAIL-induced apoptosis by withanolide E and its lack of toxicity were confirmed in animal studies. Owing to its novel activity, withanolide E is a promising reagent for the analysis of mechanisms of TRAIL resistance, for understanding HSP90 function, and for further therapeutic development. In marked contrast to bortezomib, among the best currently available TRAIL sensitizers, withanolide E's more specific mechanism of action suggests minimal toxic side effects. PMID:25719250

Stereotactic body radiation therapy of early-stage non-small-cell lung carcinoma: Phase I study

DOE Office of Scientific and Technical Information (OSTI.GOV)

McGarry, Ronald C.; Papiez, Lech; Williams, Mark

Purpose: A Phase I dose escalation study of stereotactic body radiation therapy to assess toxicity and local control rates for patients with medically inoperable Stage I lung cancer. Methods and Materials: All patients had non-small-cell lung carcinoma, Stage T1a or T1b N0, M0. Patients were immobilized in a stereotactic body frame and treated in escalating doses of radiotherapy beginning at 24 Gy total (3 x 8 Gy fractions) using 7-10 beams. Cohorts were dose escalated by 6.0 Gy total with appropriate observation periods. Results: The maximum tolerated dose was not achieved in the T1 stratum (maximum dose = 60 Gy),more » but within the T2 stratum, the maximum tolerated dose was realized at 72 Gy for tumors larger than 5 cm. Dose-limiting toxicity included predominantly bronchitis, pericardial effusion, hypoxia, and pneumonitis. Local failure occurred in 4/19 T1 and 6/28 T2 patients. Nine local failures occurred at doses {<=}16 Gy and only 1 at higher doses. Local failures occurred between 3 and 31 months from treatment. Within the T1 group, 5 patients had distant or regional recurrence as an isolated event, whereas 3 patients had both distant and regional recurrence. Within the T2 group, 2 patients had solitary regional recurrences, and the 4 patients who failed distantly also failed regionally. Conclusions: Stereotactic body radiation therapy seems to be a safe, effective means of treating early-stage lung cancer in medically inoperable patients. Excellent local control was achieved at higher dose cohorts with apparent dose-limiting toxicities in patients with larger tumors.« less

TOXIC ACTIVITY AND DELAYED EFFECTS OF FIVE BOTANICAL OILS ON THE FOLLOWING GENERATIONS OF AGROTIS IPSILON (HUFNAGEL) (INSECTA: LEPIDOPTERA: NOCTUIDAE) AFTER PARENTS TREATMENT.

PubMed

Mesbah, H A; El-Sayed, N A; El-Kady, M B; Mourad, A K; Kordy, A M; Henaidy, Z M

2014-01-01

The present study is carried out to evaluate the toxic efficiency and delayed effects of five botanical oils on the greasy cut worm Agrotis ipsilon (Lepidoptera: Noctuidae), as a trial for the attainment of a possible use of an alternative safe and effective phytochemicals against the insect-pest. So as to minimize or prevent the repeated usage of conventional insecticides, then reduce the environmental pollution as well as the occurring hazards to man and domestic animal due to the use of the pesticides alone. Four tested concentrations (0.5, 1.0, 1.5 and 2.5% v/v) from each of camphor, red basil, menthol, rose and anise oils, were bioassayed by treating the offered castor oil bean leaves, to the 4th instar larvae along 48h, under the laboratory higrothermic conditions of 25±2 °C and 65±5% R.H. The obtained results showed that the five tested oils were found to have more or less toxic activity and drastic effects on the inspected parameters of fitness components of the treated parent generation of the insect, in particular, pupae, emerged adult moths and laid eggs/female. In this respect camphor and red basil oils were highly effective, followed by menthol oil, anise oil and the least effective one was rose oil. Moreover, the assessed unprofitable delayed effects on the going on of the biological performance within the treated insects showed the adverse effects on the fitness components of the consequent generations (fs) post (p) one treatment with each of the bioassyed oils. The prevalence of adverse effects and disturbance in the going on biological performance through the period of (p) generation; which is followed by the distinct failure of insect development in (f1) generation were recorded for each of the tested menthol oil at 0.5 and 1.5% (v/v); camphor oil at 1.5 and 2.5% and red basil oil at 2.5% (v/v). While anise and rose oils were somewhat less efficient causing the distinct failure of the following generations up to the 3rd and/or the 6th ones. That observed distinct failure of the insect development could be attributed to the rapid or/and slow cumulative effect of the induced recessive lethal genes in both influenced sexes along the interval of the following developed generations (fs) after (p) one treatment, causing apparent adverse disturbance of the normal biological performance, which finally appears at the beginning of the failed generation.

Synthetic retinoids in dermatology

PubMed Central

Heller, Elizabeth H.; Shiffman, Norman J.

1985-01-01

The potential of vitamin A, or retinol, in the treatment of a variety of skin diseases has long been recognized, but because of serious toxic effects this substance generally could not be used. The recent development and marketing of two relatively nontoxic synthetic analogues, which are known as retinoids, has made it possible to treat some of the diseases that are resistant to standard forms of therapy. Isotretinoin is very effective in cystic and conglobate acne, while etretinate is especially useful in the more severe forms of psoriasis. Good results have also been obtained in other disorders of keratinization. Vitamin A and its derivatives apparently have an antineoplastic effect as well and may come to be used in both the prevention and the treatment of epithelial cancer. In many of these diseases the retinoids act by enhancing the normal differentiation and proliferation of epidermal tissues, but the exact mechanisms are not well understood. Their influence on the intracellular polyamines that control the synthesis of nucleic acids and proteins may be an important factor. Although the retinoids have few serious systemic effects, they are teratogenic, and because they persist in the body their use in women of childbearing potential is limited. ImagesFig. 3 PMID:3158386

Selective effect of 2',6'-dihydroxy-4'-methoxychalcone isolated from Piper aduncum on Leishmania amazonensis.

PubMed

Torres-Santos, E C; Moreira, D L; Kaplan, M A; Meirelles, M N; Rossi-Bergmann, B

1999-05-01

2',6'-Dihydroxy-4'-methoxychalcone (DMC) was purified from the dichloromethane extract of Piper aduncum inflorescences. DMC showed significant activity in vitro against promastigotes and intracellular amastigotes of Leishmania amazonensis, with 50% effective doses of 0.5 and 24 micrograms/ml, respectively. Its inhibitory effect on amastigotes is apparently a direct effect on the parasites and is not due to activation of the nitrogen oxidative metabolism of macrophages, since the production of nitric oxide by both unstimulated and recombinant gamma interferon-stimulated macrophages was decreased rather than increased with DMC. The phagocytic activity of macrophages was functioning normally even with DMC concentrations as high as 80 micrograms/ml, as seen by electron microscopy and by the uptake of fluorescein isothiocyanate-labeled beads. Ultrastructural studies also showed that in the presence of DMC the mitochondria of promastigotes were enlarged and disorganized. Despite destruction of intracellular amastigotes, no disarrangement of macrophage organelles were observed, even at 80 micrograms of DMC/ml. These observations suggest that DMC is selectively toxic to the parasites. Its simple structure may well enable it to serve as a new lead compound for the synthesis of novel antileishmanial drugs.

p53 inhibits CRISPR-Cas9 engineering in human pluripotent stem cells.

PubMed

Ihry, Robert J; Worringer, Kathleen A; Salick, Max R; Frias, Elizabeth; Ho, Daniel; Theriault, Kraig; Kommineni, Sravya; Chen, Julie; Sondey, Marie; Ye, Chaoyang; Randhawa, Ranjit; Kulkarni, Tripti; Yang, Zinger; McAllister, Gregory; Russ, Carsten; Reece-Hoyes, John; Forrester, William; Hoffman, Gregory R; Dolmetsch, Ricardo; Kaykas, Ajamete

2018-06-11

CRISPR/Cas9 has revolutionized our ability to engineer genomes and conduct genome-wide screens in human cells 1-3 . Whereas some cell types are amenable to genome engineering, genomes of human pluripotent stem cells (hPSCs) have been difficult to engineer, with reduced efficiencies relative to tumour cell lines or mouse embryonic stem cells 3-13 . Here, using hPSC lines with stable integration of Cas9 or transient delivery of Cas9-ribonucleoproteins (RNPs), we achieved an average insertion or deletion (indel) efficiency greater than 80%. This high efficiency of indel generation revealed that double-strand breaks (DSBs) induced by Cas9 are toxic and kill most hPSCs. In previous studies, the toxicity of Cas9 in hPSCs was less apparent because of low transfection efficiency and subsequently low DSB induction 3 . The toxic response to DSBs was P53/TP53-dependent, such that the efficiency of precise genome engineering in hPSCs with a wild-type P53 gene was severely reduced. Our results indicate that Cas9 toxicity creates an obstacle to the high-throughput use of CRISPR/Cas9 for genome engineering and screening in hPSCs. Moreover, as hPSCs can acquire P53 mutations 14 , cell replacement therapies using CRISPR/Cas9-enginereed hPSCs should proceed with caution, and such engineered hPSCs should be monitored for P53 function.

Continuous 7-Days-A-Week External Beam Irradiation in Locally Advanced Cervical Cancer: Final Results of the Phase I/II Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Serkies, Krystyna, E-mail: kserkies@wp.pl; Dziadziuszko, Rafal; Jassem, Jacek

2012-03-01

Purpose: To evaluate the feasibility and efficacy of definitive continuous 7-days-a-week pelvic irradiation without breaks between external beam radiotherapy and brachytherapy in locally advanced cervical cancer. Methods and Materials: Between November 1998 and December 1999, 30 patients with International Federation of Obstetrics and Gynecology Stage IIB or IIIB cervical cancer were included in a prospective Phase I/II study of continuous 7-days-a-week pelvic irradiation, to the total Manchester point B dose of 40.0-57.6 Gy. The first 13 patients (Group A) were given a daily tumor dose of 1.6 Gy, and the remaining 17 patients (Group B) were given 1.8 Gy. Onemore » or two immediate brachytherapy applications (point A dose 10-20 Gy, each) were performed in 28 cases. Results: Two patients did not complete the irradiation because of apparent early progression of disease during the irradiation. Eleven of the 28 evaluable patients (39%; 45% and 35% in Groups A and B, respectively) completed their treatment within the prescribed overall treatment time. Acute toxicity (including severe European Organisation for Research and Treatment of Cancer/Radiation Therapy Oncology Group Grade 3 and 4 effects in 40%) was experienced by 83% of patients and resulted in unplanned treatment interruptions in 40% of all patients (31% and 47% of patients in Groups A and B, respectively). Severe intestinal side effects occurred in 31% and 41% of Patients in Groups A and B, respectively (p = 0.71). The 5-year overall survival probability was 33%. Cancer recurrence occurred in 63% of patients: 20% inside and 57% outside the pelvis. Cumulative incidence of late severe bowel and urinary bladder toxicity at 24 months was 15%. Conclusion: Continuous irradiation in locally advanced cervical cancer is associated with a high incidence of severe acute toxicity, resulting in unplanned treatment interruptions. Late severe effects and survival after continuous radiotherapy do not substantially differ from those obtained with conventionally fractionated radiotherapy.« less

Endothelial Function and Serum Concentration of Toxic Metals in Frequent Consumers of Fish

PubMed Central

Buscemi, Silvio; Vasto, Sonya; Di Gaudio, Francesca; Grosso, Giuseppe; Bergante, Sonia; Galvano, Fabio; Massenti, Fatima Maria; Amodio, Emanuele; Rosafio, Giuseppe; Verga, Salvatore

2014-01-01

Background Endothelial dysfunction is involved in the pathogenesis of atherosclerosis. Consumption of fish is associated with reduced cardiovascular risk, but there is paucity of data concerning its effect on endothelial function. Furthermore, investigation of the effects of fish consumption on health must take into account the ingestion of contaminants, including transition metals and some metalloids, which may have unfavorable effects on health, including those on the cardiovascular system. We investigated the association between fish consumption, endothelial function (flow mediated dilation of the brachial artery), and serum concentration of some toxic metals in apparently healthy people. Methods Twenty-nine high fish consumers (at least 3 portions a week) were compared with 25 low fish consumers (less than 1 portion a week). All participants were free of diabetes, cardiovascular or other systemic diseases. Serum metal (antimonium, arsenic, mercury, lead, cobalt, copper, zinc, selenium, strontium) concentrations were measured in subgroups of 24 high fish consumers and 19 low fish consumers. Results Both groups exhibited similar habitual dietary patterns, age and anthropometric characteristics. The high fish consumers had higher flow mediated dilation (9.7±1.8 vs. 7.3±1.9%; P<0.001), but also higher serum concentrations of mercury (5.87±2.69 vs. 1.65±1.10 mcg/L; P<0.001) and arsenic (6.04±3.25 vs. 2.30±1.58 mcg/L; P<0.001). The fasting plasma glucose concentrations were significantly correlated with both mercury (r = 0.39; P = 0.01) and arsenic concentrations (r = 0.55; P<0.001). Conclusions Habitual consumption of high amounts of fish is associated with better endothelial function despite higher serum concentrations of mercury and arsenic. PMID:25401695

Protective effects of curcumin and vitamin E against chlorpyrifos-induced lung oxidative damage.

PubMed

Hassani, S; Sepand, M R; Jafari, A; Jaafari, J; Rezaee, R; Zeinali, M; Tavakoli, F; Razavi-Azarkhiavi, K

2015-06-01

There are increasing concerns regarding the toxic effects of chlorpyrifos (CPF) on human health. Curcumin (CUR) is a yellow pigment isolated from turmeric ground rhizome of Curcuma longa Linn., which has been identified as an antioxidant agent. This study was designed to examine the protective effect of CUR and vitamin E (Vit E) on CPF-induced lung toxicity. Rats were divided into seven groups: control, CPF (13.5 mg/kg, orally), CPF + CUR (100 and 300 mg/kg, respectively, orally), CPF + α-tocopherol (Vit E, 150 mg/kg, intraperitoneally), CPF and CUR (100 and 300 mg/kg, respectively) in combination with α-tocopherol. The regimens were administered once daily for 28 days. At the end of the treatment period, lungs were collected for evaluation of oxidative factors and histopathological parameters. CUR and Vit E led to a decrease in lipid peroxidation in the lungs of the CPF-injected animals (48% and 51%, respectively). Glutathione peroxidase inhibited by CPF (91.9 nmol/min/mg protein) was induced again by CUR and Vit E (167.1 and 171.8 nmol/min/mg protein). CUR and Vit E caused a significant induction of superoxide dismutase (103.4 U/mg protein). Catalase activity almost returned to normalcy in CPF-intoxicated rats subjected to CUR + Vit E treatment (p < 0.001). Lung sections from CPF-treated rats displayed histopathological damages, while coadministration of CUR and Vit E resulted in apparently normal morphology with a significant decrease in injuries (p < 0.05). Our findings revealed that coadministration of Vit E and CUR to CPF-treated animals prevents the oxidative damages in the lung tissues. © The Author(s) 2014.

Dual Use of Cigarettes, Little Cigars, Cigarillos, and Large Cigars: Smoking Topography and Toxicant Exposure.

PubMed

Pickworth, Wallace B; Rosenberry, Zachary R; O'Grady, Kevin E; Koszowski, Bartosz

2017-04-01

Smoking topography variables and toxicant exposure (plasma nicotine and exhaled CO) were examined in 3 groups of study participants that smoked both cigarettes and either filtered little cigars (Winchester), cigarillos (Black & Mild), or large cigars (Phillies Blunt). Laboratory ad lib smoking of the cigar products was collected with a smoking puff analyzer; plasma levels of nicotine and exhaled CO were collected before and after smoking. Although there were no statistically significant differences in demographic and cigarette smoking topography among the groups, there were significant differences in how the different cigar products were smoked. Plasma nicotine boost was similar after all products but exhaled CO was greater after the cigarillo and large cigar than the little cigar. Some of the differences were due to the differences in article size but other differences were apparent even after adjustment for the amount of tobacco burned or the mouth intake (puff volume). The topography findings of differences among products challenge the practice of grouping cigars as a single entity in surveys, regulatory decisions, and discussions of toxicant exposure. The results add to the discussion of distinctions among products in the scientific assessment of public health risk and regulatory decisions.

The genomic landscape of rapid repeated evolutionary ...

EPA Pesticide Factsheets

Atlantic killifish populations have rapidly adapted to normally lethal levels of pollution in four urban estuaries. Through analysis of 384 whole killifish genome sequences and comparative transcriptomics in four pairs of sensitive and tolerant populations, we identify the aryl hydrocarbon receptor–based signaling pathway as a shared target of selection. This suggests evolutionary constraint on adaptive solutions to complex toxicant mixtures at each site. However, distinct molecular variants apparently contribute to adaptive pathway modification among tolerant populations. Selection also targets other toxicity-mediatinggenes and genes of connected signaling pathways; this indicates complex tolerance phenotypes and potentially compensatory adaptations. Molecular changes are consistent with selection on standing genetic variation. In killifish, high nucleotide diversityhas likely been a crucial substrate for selective sweeps to propel rapid adaptation. This manuscript describes genomic evaluations that contribute to our understanding of the ecological and evolutionary risks associated with chronic contaminant exposures to wildlife populations. Here, we assessed genetic patterns associated with long-term response to an important class of highly toxic environmental pollutants. Specifically, chemical-specific tolerance has rapidly and repeatedly evolved in an estuarine fish species resident to estuaries of the Atlantic U.S. coast. We used laboratory studies to ch

BioMetals: a historical and personal perspective.

PubMed

Silver, Simon

2011-06-01

Understanding of BioMetals developed basically from a starting point about 60 years ago to current mechanistic understanding of the biological behavior of many metal ions from protein structural and functional studies. Figure 1 shows a Biochemical Periodic Table, element by element, with requirements, roles and biochemistry of the specific ions indicated. With few exceptions, the biology is of the ions formed and not of the elemental state of each. Early BioMetals efforts defined nutritional growth needs for animals, plants and microbes for inorganic "macro-nutrients" such as magnesium, calcium, potassium, sodium, and phosphate and of "micronutrients" such as copper, iron, manganese and zinc. Surprises came early with regard to microbes, for example the finding that Escherichia coli (then and now the standard microbial model) grows happily in the apparent total absence of calcium, sodium, and chloride, which are certainly major animal nutrients. Some elements such as mercury and arsenic are never required by living cells, but are always toxic, often at very low levels. Therefore, the division into nutrient elements and toxic elements came soon. For most inorganic nutrients, excessive amounts can be toxic as well, for example for copper and iron.

Rheological alteration of erythrocytes exposed to carbon nanotubes.

PubMed

Heo, Yujin; Li, Cheng-Ai; Kim, Duckjong; Shin, Sehyun

2017-01-01

Single-walled carbon nanotubes (SWNTs) have been increasingly used in a variety of biomedical applications, such as in vivo delivery of drugs and tumor imaging. Potential exposure of SWNTs to human red blood cells (RBCs) may cause serious toxicity including alteration of mechanical properties of cells. The present study investigated the cellular response to exposure of SWNTs with measuring rheological characteristics of RBCs, including hemolysis, deformability, aggregation, and morphological changes. RBCs were exposed to two different dispersion-state samples (i.e. individual SWNTs and bundled SWNTs) in chitosan hydroxyphenyl acetamide (CHPA) solutions. The concentrations of SWNTs were carefully chosen to avoid any hemorheological alterations due to hemolysis. Rheological characteristics were measured using microfluidic-laser diffractometry and aggregometry. Our results show that the bundled SWNTs had higher hemolytic activity than did the individual SWNTs. RBC aggregation apparently decreased as the concentration of SWNTs or incubation time increased. Additionally, bundled SWNTs caused significant alterations in the shape and fusion of RBCs. In conclusion, bundled SWNTs were found to be more toxic than individual SWNTs. These results provide important insights into the interactions between RBCs and SWNTs and will facilitate assessment of the risk of nanomaterial toxicity of blood.

Sensitivity and Antioxidant Response of Chlorella sp. MM3 to Used Engine Oil and Its Water Accommodated Fraction.

PubMed

Ramadass, Kavitha; Megharaj, Mallavarapu; Venkateswarlu, Kadiyala; Naidu, Ravi

2016-07-01

We exposed the microalgal strain, Chlorella sp. MM3, to unused or used engine oil, or their water accommodated fractions (WAFs) to determine growth inhibition and response of antioxidant enzymes. Oil type and oil concentration greatly affected the microalgal growth. Used oil at 0.04 % (0.4 g L(-1)) resulted in 50 % inhibition in algal growth, measured in terms of chlorophyll-a, while the corresponding concentration of unused oil was nontoxic. Similarly, used oil WAF showed significant toxicity to the algal growth at 10 % level, whereas WAF from unused oil was nontoxic even at 100 % concentration. Peroxidase enzyme in the microalga significantly increased with used oil at concentrations above 0.04 g L(-1) whereas the induction of superoxide dismutase and catalase was apparent only at 0.06 g L(-1). Activities of the antioxidant enzymes increased significantly when the microalga was exposed to 75 and 100 % WAF obtained from used oil. The used oil toxicity on microalga could be due to the presence of toxic soluble mono- and polyaromatic compounds, heavy metals, and other compounds attained by the oil during its use in the motor engines.

Exploring Chemical Routes Relevant to the Toxicity of Paracetamol and Its meta-Analogue at a Molecular Level.

PubMed

Castañeda-Arriaga, Romina; Galano, Annia

2017-06-19

Several chemical routes related to the toxicity of paracetamol (APAP, also known as acetaminophen), its analogue N-acetyl-m-aminophenol (AMAP), and their deacetylated derivatives, were investigated using the density functional theory. It was found that AMAP is more resilient to chemical oxidation than APAP. The chemical degradation of AMAP into radical intermediates is predicted to be significant only when it is induced by strong oxidants. This might explain the apparent contradictions among experimental evidence regarding AMAP toxicity. All of the investigated species are incapable of oxidizing DNA, but they can damage lipids by H atom transfer (HAT) from the bis-allylic site, with the phenoxyl radical of AMAP being the most threatening to the lipids' chemical integrity. Regarding protein damage, Cys residues were identified as the most likely targets. The damage in this case may involve two different routes: (i) HAT from the thiol site by phenoxyl radicals and (ii) protein arylation by the quinone imine (QI) derivatives. Both are not only thermochemically viable, but also are very fast reactions. According to the mechanism identified here as the most likely one for protein arylation, a rather large concentration of QI would be necessary for this damage to be significant. This might explain why APAP is nontoxic in therapeutic doses, while overdoses can result in hepatic toxicity. In addition, the QI derived from both APAP and AMAP were found to be capable of inflicting this kind of damage. In addition, it is proposed that they might increase • OH production via the Fenton reaction, which would contribute to their toxicity.

Relative seed and fruit toxicity of the Australian cycads Macrozamia miquelii and Cycas ophiolitica: further evidence for a megafaunal seed dispersal syndrome in cycads, and its possible antiquity.

PubMed

Hall, J A; Walter, G H

2014-08-01

An apparent contradiction in the ecology of cycad plants is that their seeds are known to be highly poisonous, and yet they seem well adapted for seed dispersal by animals, as shown by their visually conspicuous seed cones and large seeds presented within a brightly colored fleshy "fruit" of sarcotesta. We tested if this sarcotesta could function as a reward for cycad seed dispersal fauna, by establishing if the toxic compound cycasin, known from the seeds, is absent from the sarcotesta. The Australian cycads Macrozamia miquelii and Cycas ophiolitica were tested (N = 10 individuals per species) using gas chromatography / mass spectrometry. Cycasin was detected at 0.34 % (fresh weight) in seed endosperm of M. miquelii and 0.28 % (fresh weight) in seed endosperm of C. ophiolitica. Cycasin was absent from the sarcotesta of the same propagules (none detected in the case of M. miquelii, and trace quantities detected in sarcotesta of only four of the ten C. ophiolitica propagules). This laboratory finding was supported by field observations of native animals eating the sarcotesta of these cycads but discarding the toxic seed intact. These results suggest cycads are adapted for dispersal fauna capable of swallowing the large, heavy propagules whole, digesting the non-toxic sarcotesta flesh internally, and then voiding the toxic seed intact. Megafauna species such as extant emus or cassowaries, or extinct Pleistocene megafauna such as Genyornis, are plausible candidates for such dispersal. Cycads are an ancient lineage, and the possible antiquity of their megafaunal seed dispersal adaptations are discussed.

Atomic charges of individual reactive chemicals in binary mixtures determine their joint effects: an example of cyanogenic toxicants and aldehydes.

PubMed

Tian, Dayong; Lin, Zhifen; Yin, Daqiang; Zhang, Yalei; Kong, Deyang

2012-02-01

Environmental contaminants are usually encountered as mixtures, and many of these mixtures yield synergistic or antagonistic effects attributable to an intracellular chemical reaction that pose a potential threat on ecological systems. However, how atomic charges of individual chemicals determine their intracellular chemical reactions, and then determine the joint effects for mixtures containing reactive toxicants, is not well understood. To address this issue, the joint effects between cyanogenic toxicants and aldehydes on Photobacterium phosphoreum were observed in the present study. Their toxicological joint effects differed from one another. This difference is inherently related to the two atomic charges of the individual chemicals: the oxygen charge of -CHO (O(aldehyde toxicant)) in aldehyde toxicants and the carbon-atom charge of a carbon chain in the cyanogenic toxicant (C(cyanogenic toxicant)). Based on these two atomic charges, the following QSAR (quantitative structure-activity relationship) model was proposed: When (O(aldehyde toxicant) -C(cyanogenic toxicant) )> -0.125, the joint effect of equitoxic binary mixtures at median inhibition (TU, the sum of toxic units) can be calculated as TU = 1.00 ± 0.20; when (O(aldehyde toxicant) -C(cyanogenic toxicant) ) ≤ -0.125, the joint effect can be calculated using TU = - 27.6 x O (aldehyde toxicant) - 5.22 x C (cyanogenic toxicant) - 6.97 (n = 40, r = 0.887, SE = 0.195, F = 140, p < 0.001, q(2) (Loo) = 0.748; SE is the standard error of the regression, F is the F test statistic). The result provides insight into the relationship between the atomic charges and the joint effects for mixtures containing cyanogenic toxicants and aldehydes. This demonstrates that the essence of the joint effects resulting from intracellular chemical reactions depends on the atomic charges of individual chemicals. The present study provides a possible approach for the development of a QSAR model for mixtures containing reactive toxicants based on the atomic charges. Copyright © 2011 SETAC.

Evaluation of dried vegetables residues for poultry: II. Effects of feeding cabbage leaf residues on broiler performance, ileal digestibility and total tract nutrient digestibility.

PubMed

Mustafa, A F; Baurhoo, B

2017-03-01

A study was conducted to investigate the effects of partial replacing corn and soybean meal with dried cabbage leaf residues (DCR) on broiler growth performance, apparent ileal nutrient digestibility, and apparent total tract nutrient utilization. Dietary treatments include 4 levels of DCR (0, 3, 6, and 9%). Two hundred and twenty-four day-old male broilers were randomly assigned to one of 4 groups (8 cage replicates; 7 birds/cage) and grown over a 35-d experimental period. Results showed that feeding DCR had no effects on daily body weigh gain (average 53.4 g/d), daily feed intake (average 94.9 g/d), and feed conversion ratio (average 1.78 g of feed/g of gain). Inclusion of DCR reduced apparent ileal DM (quadratic effect, P < 0.001), OM (linear effect, P = 0.012), and CP (quadratic effect, P = 0.001) digestibility of younger birds (d 21) while incremental levels of DCR had no effect on apparent ileal nutrient digestibilities of older birds (d 35). Apparent total tract digestibility of DM, OM, and CP increased (linear effect, P < 0.001) as the level of DCR increased. It was concluded that the inclusion of DCR in broiler diets up to 9% had no negative impact on bird performance and apparent ileal digestibility of older birds and improved apparent total tract nutrient digestibility. © 2016 Poultry Science Association Inc.

Thiol biochemistry of prokaryotes

NASA Technical Reports Server (NTRS)

Fahey, Robert C.

1986-01-01

The present studies have shown that GSH metabolism arose in the purple bacteria and cyanobacteria where it functions to protect against oxygen toxicity. Evidence was obtained indicating that GSH metabolism was incorporated into eucaryotes via the endosymbiosis giving rise to mitochrondria and chloroplasts. Aerobic bacteria lacking GSH utilize other thiols for apparently similar functions, the thiol being coenzyme A in Gram positive bacteria and chi-glutamylcysteine in the halobacteria. The thiol biochemistry of prokaryotes is thus seen to be much more highly diversified than that of eucaryotes and much remains to be learned about this subject.

Ocular Toxicity Secondary to Asclepias physocarpa: The Balloon Plant

PubMed Central

Pina, Susana; Pedrosa, Catarina; Santos, Cristina; Feijóo, Bernardo; Pego, Peter; Vendrell, Cristina; Santos, Maria João; Prieto, Isabel

2014-01-01

We report a case of a 65-year-old woman with symptoms of blurred vision and ocular irritation a few hours after accidental contact of the right eye with Asclepias physocarpa milky latex. Observation showed a diffuse conjunctival hyperemia and stromal corneal edema with Descemet's membrane folds. Recovery was fast and apparently complete in less than one month. However, specular microscopy at 6-months follow-up showed an abnormal endothelial morphology as sequelae, suggesting this condition is not as innocuous as it has been suggested. PMID:25105044

MUTYH mediates the toxicity of combined DNA 6-thioguanine and UVA radiation.

PubMed

Grasso, Francesca; Ruggieri, Vitalba; De Luca, Gabriele; Leopardi, Paola; Mancuso, Maria Teresa; Casorelli, Ida; Pichierri, Pietro; Karran, Peter; Bignami, Margherita

2015-04-10

The therapeutic thiopurines, including the immunosuppressant azathioprine (Aza) cause the accumulation of the UVA photosensitizer 6-thioguanine (6-TG) in the DNA of the patients' cells. DNA 6-TG and UVA are synergistically cytotoxic and their interaction causes oxidative damage. The MUTYH DNA glycosylase participates in the base excision repair of oxidized DNA bases. Using Mutyh-nullmouse fibroblasts (MEFs) we examined whether MUTYH provides protection against the lethal effects of combined DNA 6-TG/UVA. Surprisingly, Mutyh-null MEFs were more resistant than wild-type MEFs, despite accumulating higher levels of DNA 8-oxo-7,8-dihydroguanine (8-oxoG).Their enhanced 6-TG/UVA resistance reflected the absence of the MUTYH protein and MEFs expressing enzymatically-dead human variants were as sensitive as wild-type cells. Consistent with their enhanced resistance, Mutyh-null cells sustained fewer DNA strand breaks and lower levels of chromosomal damage after 6-TG/UVA. Although 6-TG/UVA treatment caused early checkpoint activation irrespective of the MUTYH status, Mutyh-null cells failed to arrest in S-phase at late time points. MUTYH-dependent toxicity was also apparent in vivo. Mutyh-/- mice survived better than wild-type during a 12-month chronicexposure to Aza/UVA treatments that significantly increased levels of skin DNA 8-oxoG. Two squamous cell skin carcinomas arose in Aza/UVA treated Mutyh-/- mice whereas similarly treated wild-type animals remained tumor-free.

Biotin deprivation impairs mitochondrial structure and function and has implications for inherited metabolic disorders.

PubMed

Ochoa-Ruiz, Estefanía; Díaz-Ruiz, Rodrigo; Hernández-Vázquez, Alaín de J; Ibarra-González, Isabel; Ortiz-Plata, Alma; Rembao, Daniel; Ortega-Cuéllar, Daniel; Viollet, Benoit; Uribe-Carvajal, Salvador; Corella, José Ahmed; Velázquez-Arellano, Antonio

2015-11-01

Certain inborn errors of metabolism result from deficiencies in biotin containing enzymes. These disorders are mimicked by dietary absence or insufficiency of biotin, ATP deficit being a major effect,whose responsible mechanisms have not been thoroughly studied. Here we show that in rats and cultured cells it is the result of reduced TCA cycle flow, partly due to deficient anaplerotic biotin-dependent pyruvate carboxylase. This is accompanied by diminished flow through the electron transport chain, augmented by deficient cytochrome c oxidase (complex IV) activity with decreased cytochromes and reduced oxidative phosphorylation. There was also severe mitochondrial damage accompanied by decrease of mitochondria, associated with toxic levels of propionyl CoA as shown by carnitine supplementation studies, which explains the apparently paradoxical mitochondrial diminution in the face of the energy sensor AMPK activation, known to induce mitochondria biogenesis. This idea was supported by experiments on AMPK knockout mouse embryonic fibroblasts (MEFs). The multifactorial ATP deficit also provides a plausible basis for the cardiomyopathy in patients with propionic acidemia, and other diseases.Additionally, systemic inflammation concomitant to the toxic state might explain our findings of enhanced IL-6, STAT3 and HIF-1α, associated with an increase of mitophagic BNIP3 and PINK proteins, which may further increase mitophagy. Together our results imply core mechanisms of energy deficit in several inherited metabolic disorders.

Immobilized nickel hexacyanoferrate on activated carbons for efficient attenuation of radio toxic Cs(I) from aqueous solutions

NASA Astrophysics Data System (ADS)

Lalhmunsiama; Lalhriatpuia, C.; Tiwari, Diwakar; Lee, Seung-Mok

2014-12-01

The aim of this study is to immobilize nickel hexacyanoferrate onto the large surface of activated carbons (ACs) precursor to rice hulls and areca nut waste materials. These nickel hexacyanoferrate immobilized materials are then assessed in the effective attenuation of radio logically important cesium ions from aqueous solutions. The solid samples are characterized by the XRD analytical method and surface morphology is obtained from the SEM images. The batch reactor experiments show that an increase in sorptive pH (2.0-10.0) apparently not affecting the high percent uptake of Cs(I). Equilibrium modeling studies suggest that the data are reasonably and relatively fitted well to the Langmuir adsorption isotherm. Kinetic studies show that sorption process is fairly rapid and the kinetic data are fitted well to the pseudo-second order rate model. Increasing the background electrolyte concentration from 0.001 to 0.1 mol/L NaCl causes insignificant decrease in Cs(I) removal which infers the higher selectivity of these materials for Cs(I) from aqueous solutions. Further, the column reactor operations enable to obtain the breakthrough data which are then fitted to the Thomas non-linear equation as to obtain the loading capacity of column for Cs(I). The results show that the modified materials show potential applicability in the attenuation of radio toxic cesium from aqueous solution.

The Influence of Hydroxyapatite Nanoparticle Morphology on Embryonic Development in a Zebrafish Exposure Model

PubMed Central

Pujari-Palmer, Shiuli; Lu, Xi; Karlsson Ott, Marjam

2017-01-01

Nanomaterials are used in many different industries such as cosmetics, food, clothing, and electronics. There is increasing concern that exposure to nanoparticles (NPs) during pregnancy can adversely affect fetal development. It is well known that the size, charge, and chemistry of a nanoparticle can modulate embryological development. The role that particle morphology plays on early development, however, is still widely unknown. The present study aims to investigate the effect of hydroxyapatite nanoparticle (HANP) morphology on embryological development in a zebrafish exposure model. Four distinct HANP morphologies (dots, long rods, sheets, and fibers) were fabricated and characterized. Zebrafish embryos were exposed to HANPs (0–100 mg/L), and viability and developmental deformities were evaluated for up to 5 days post-fertilization (dpf). Malformations such as pericardial edema and axial curvature were apparent in embryos as early as 1 dpf, following exposure to the dot and fiber particles, and developed in embryos by 3 dpf in the sheet and long rod particle groups. Minimal death was observed in response to dot, long rod, and sheet particles (≤25%), while fiber particles induced overwhelming toxicity (≤60%) after 1 dpf, and complete toxicity during all subsequent time points. Collectively, these results suggest that nanoparticle morphology can significantly impact embryological development and should be a required consideration when designing nanomaterials for commercial use. PMID:28441729

The fascinating facets of plant selenium accumulation - biochemistry, physiology, evolution and ecology.

PubMed

Schiavon, Michela; Pilon-Smits, Elizabeth A H

2017-03-01

Contents 1582 I. 1582 II. 1583 III. 1588 IV. 1590 V. 1592 1592 References 1592 SUMMARY: The importance of selenium (Se) for medicine, industry and the environment is increasingly apparent. Se is essential for many species, including humans, but toxic at elevated concentrations. Plant Se accumulation and volatilization may be applied in crop biofortification and phytoremediation. Topics covered here include beneficial and toxic effects of Se on plants, mechanisms of Se accumulation and tolerance in plants and algae, Se hyperaccumulation, and ecological and evolutionary aspects of these processes. Plant species differ in the concentration and forms of Se accumulated, Se partitioning at the whole-plant and tissue levels, and the capacity to distinguish Se from sulfur. Mechanisms of Se hyperaccumulation and its adaptive significance appear to involve constitutive up-regulation of sulfate/selenate uptake and assimilation, associated with elevated concentrations of defense-related hormones. Hyperaccumulation has evolved independently in at least three plant families, probably as an elemental defense mechanism and perhaps mediating elemental allelopathy. Elevated plant Se protects plants from generalist herbivores and pathogens, but also gives rise to the evolution of Se-resistant specialists. Plant Se accumulation affects ecological interactions with herbivores, pollinators, neighboring plants, and microbes. Hyperaccumulation tends to negatively affect Se-sensitive ecological partners while facilitating Se-resistant partners, potentially affecting species composition and Se cycling in seleniferous ecosystems. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

Toxic effects of selenium and copper on the planarian, Dugesia dorotocephala

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rauscher, J.D.

1988-01-01

Aquatic toxicologists have become increasingly concerned with the effects of sublethal concentrations of toxicants on aquatic organisms. Sublethal effects of toxicants on freshwater invertebrates were reviewed. Selenium (Se) and copper (Cu) are both essential trace elements and toxicants. Se has been reported to alter the toxicity of heavy metals. Planarians, Dugesia dorotocephala, were used as test animals. The objectives of this study were to determine: (1) acute toxicity of Se on planarians and the effect of the number of planarians per test chamber, (2) interaction of the acute toxicity of Se and Cu on planarians, and (3) sublethal effects ofmore » Se and Cu on planarians.« less

Toxicity interactions between manganese (Mn) and lead (Pb) or cadmium (Cd) in a model organism the nematode C. elegans.

PubMed

Lu, Cailing; Svoboda, Kurt R; Lenz, Kade A; Pattison, Claire; Ma, Hongbo

2018-06-01

Manganese (Mn) is considered as an emerging metal contaminant in the environment. However, its potential interactions with companying toxic metals and the associated mixture effects are largely unknown. Here, we investigated the toxicity interactions between Mn and two commonly seen co-occurring toxic metals, Pb and Cd, in a model organism the nematode Caenorhabditis elegans. The acute lethal toxicity of mixtures of Mn+Pb and Mn+Cd were first assessed using a toxic unit model. Multiple toxicity endpoints including reproduction, lifespan, stress response, and neurotoxicity were then examined to evaluate the mixture effects at sublethal concentrations. Stress response was assessed using a daf-16::GFP transgenic strain that expresses GFP under the control of DAF-16 promotor. Neurotoxicity was assessed using a dat-1::GFP transgenic strain that expresses GFP in dopaminergic neurons. The mixture of Mn+Pb induced a more-than-additive (synergistic) lethal toxicity in the worm whereas the mixture of Mn+Cd induced a less-than-additive (antagonistic) toxicity. Mixture effects on sublethal toxicity showed more complex patterns and were dependent on the toxicity endpoints as well as the modes of toxic action of the metals. The mixture of Mn+Pb induced additive effects on both reproduction and lifespan, whereas the mixture of Mn+Cd induced additive effects on lifespan but not reproduction. Both mixtures seemed to induce additive effects on stress response and neurotoxicity, although a quantitative assessment was not possible due to the single concentrations used in mixture tests. Our findings demonstrate the complexity of metal interactions and the associated mixture effects. Assessment of metal mixture toxicity should take into consideration the unique property of individual metals, their potential toxicity mechanisms, and the toxicity endpoints examined.

Evaluation of Metal Toxicity in Streams Affected by Abandoned Mine Lands, Upper Animas River Watershed, Colorado

USGS Publications Warehouse

Besser, John M.; Allert, Ann L.; Hardesty, Douglas K.; Ingersoll, Christopher G.; May, Thomas W.; Wang, Ning; Leib, Kenneth J.

2001-01-01

Acid drainage from abandoned mines and from naturally-acidic rocks and soil in the upper Animas River watershed of Colorado generates elevated concentrations of acidity and dissolved metals in stream waters and deposition of metal-contaminated particulates in streambed sediments, resulting in both toxicity and habitat degradation for stream biota. High concentrations of iron (Fe), aluminum (Al), zinc (Zn), copper (Cu), cadmium (Cd), and lead (Pb) occur in acid streams draining headwaters of the upper Animas River watershed, and high concentrations of some metals, especially Zn, persist in circumneutral reaches of the Animas River and Mineral Creek, downstream of mixing zones of acid tributaries. Seasonal variation of metal concentrations is reflected in variation in toxicity of stream water. Loadings of dissolved metals to the upper Animas River and tributaries are greatest during summer, during periods of high stream discharge from snowmelt and monsoonal rains, but adverse effects on stream biota may be greater during winter low-flow periods, when stream flows are dominated by inputs of groundwater and contain greatest concentrations of dissolved metals. Fine stream-bed sediments of the upper Animas River watershed also contain elevated concentrations of potentially toxic metals. Greatest sediment metal concentrations occur in the Animas River upstream from Silverton, where there are extensive deposits of mine and mill tailings, and in mixing zones in the Animas River and lower Mineral Creek, where precipitates of Fe and Al oxides also contain high concentrations of other metals. This report summarizes the findings of a series of toxicity studies in streams of the upper Animas River watershed, conducted on-site and in the laboratory between 1998 and 2000. The objectives of these studies were: (1) to determine the relative toxicity of stream water and fine stream-bed sediments to fish and invertebrates; (2) to determine the seasonal range of toxicity in stream water; (3) to develop site-specific thresholds for toxicity of Zn and Cu in stream water; and (4) to develop models of the contributions of Cu and Zn to toxicity of stream water, which may be used to characterize toxicity before and after planned remediation efforts. We evaluated the toxicity of metal-contaminated sediments by conducting sediment toxicity tests with two species of benthic invertebrates, the midge, Chironomus tentans. and the amphipod, Hyalella azteca. Laboratory toxicity tests with both taxa, exposed to fine stream-bed sediments collected in September 1997, showed some evidence of sediment toxicity, as survival of midge larvae in sediments from Cement Creek (C48) and lower Mineral Creek (M34), and growth of amphipods in sediments from these sites and three Animas River sites (A68, Animas at Silverton; A72, Animas below Silverton, and A73, Animas at Elk Park) were significantly reduced compared to a reference site, South Mineral Creek (SMC) . Amphipods were also exposed to site water and fine stream-bed sediment, separately and in combination, during the late summer low flow period (August-September) of 1998. In these studies, stream water, with no sediment present, from all five sites tested (same sites as above, except C48) caused 90% to 100% mortality of amphipods. In contrast, significant reductions in survival of amphipods occurred at two sites (A72 and SMC) in exposures with field-collected sediment plus stream water, and at only one site (A72) in exposures with sediments and clean overlying water. Concentrations of Zn, Pb, Cu, and Cd were high in both sediment and pore water (interstitial water) from most sites tested, but greatest sediment toxicity was apparently associated with greater concentrations of Fe and/or Al in sediments. These results suggest that fine stream-bed sediments of the more contaminated stream reaches of the upper Animas River watershed are toxic to benthic invertebrates, but that these impacts are less serious than tox

Bans of WHO Class I Pesticides in Bangladesh-suicide prevention without hampering agricultural output.

PubMed

Chowdhury, Fazle Rabbi; Dewan, Gourab; Verma, Vasundhara R; Knipe, Duleeka W; Isha, Ishrat Tahsin; Faiz, M Abul; Gunnell, David J; Eddleston, Michael

2018-02-01

Pesticide self-poisoning is a major problem in Bangladesh. Over the past 20-years, the Bangladesh government has introduced pesticide legislation and banned highly hazardous pesticides (HHPs) from agricultural use. We aimed to assess the impacts of pesticide bans on suicide and on agricultural production. We obtained data on unnatural deaths from the Statistics Division of Bangladesh Police, and used negative binomial regression to quantify changes in pesticide suicides and unnatural deaths following removal of WHO Class I toxicity HHPs from agriculture in 2000. We assessed contemporaneous trends in other risk factors, pesticide usage and agricultural production in Bangladesh from 1996 to 2014. Mortality in hospital from pesticide poisoning fell after the 2000 ban: 15.1% vs 9.5%, relative reduction 37.1% [95% confidence interval (CI) 35.4 to 38.8%]. The pesticide poisoning suicide rate fell from 6.3/100 000 in 1996 to 2.2/100 000 in 2014, a 65.1% (52.0 to 76.7%) decline. There was a modest simultaneous increase in hanging suicides [20.0% (8.4 to 36.9%) increase] but the overall incidence of unnatural deaths fell from 14.0/100 000 to 10.5/100 000 [25.0% (18.1 to 33.0%) decline]. There were 35 071 (95% CI 25 959 to 45 666) fewer pesticide suicides in 2001 to 2014 compared with the number predicted based on trends between 1996 to 2000. This reduction in rate of pesticide suicides occurred despite increased pesticide use and no change in admissions for pesticide poisoning, with no apparent influence on agricultural output. Strengthening pesticide regulation and banning WHO Class I toxicity HHPs in Bangladesh were associated with major reductions in deaths and hospital mortality, without any apparent effect on agricultural output. Our data indicate that removing HHPs from agriculture can rapidly reduce suicides without imposing substantial agricultural costs. © The Author 2017. Published by Oxford University Press on behalf of the International Epidemiological Association

Effect of natural and synthetic surfactants on crude oil biodegradation by indigenous strains.

PubMed

Tian, Wei; Yao, Jun; Liu, Ruiping; Zhu, Mijia; Wang, Fei; Wu, Xiaoying; Liu, Haijun

2016-07-01

Hydrocarbon pollution is a worldwide problem. In this study, five surfactants containing SDS, LAS, Brij 30, Tween 80 and biosurfactant were used to evaluate their effect on crude oil biodegradation. Hydrocarbon degrading bacteria were isolated from oil production water. The biosurfactant used was a kind of cyclic lipopeptide produced by Bacillus subtilis strain WU-3. Solubilization test showed all the surfactants could apparently increase the water solubility of crude oil. The microbial adhesion to the hydrocarbon (MATH) test showed surfactants could change cell surface hydrophobicity (CSH) of microbiota, depending on their species and concentrations. Microcalorimetric experiments revealed these surfactants exhibited toxicity to microorganisms at high concentrations (above 1 CMC), except for SDS which showed low antibacterial activity. Surfactant supplementation (about 0.1 and 0.2 CMC) could improve degradation rate of crude oil slightly, while high surfactant concentration (above 1 CMC) may decrease the degradation rate from 50.5% to 28.9%. Those findings of this work could provide guidance for the application of surfactants in bioremediation of oil pollution. Copyright © 2016 Elsevier Inc. All rights reserved.

Amyloid β-Protein as a Substrate Interacts with Extracellular Matrix to Promote Neurite Outgrowth

NASA Astrophysics Data System (ADS)

Koo, Edward H.; Park, Lisa; Selkoe, Dennis J.

1993-05-01

Progressive deposition of amyloid β-protein (Aβ) in brain parenchyma and blood vessels is a characteristic feature of Alzheimer disease. Recent evidence suggests that addition of solubilized synthetic Aβ to medium may produce toxic or trophic effects on cultured hippocampal neurons. Because soluble Aβ may not accumulate in significant quantities in brain, we asked whether immobilized Aβ peptide as a substrate alters neurite outgrowth from cultured rat peripheral sensory neurons. This paradigm may closely mimic the conditions in Alzheimer disease brain tissue, in which neurites contact insoluble, extracellular aggregates of β-amyloid. We detected no detrimental effects of Aβ substrate on neurite outgrowth. Rather, Aβ in combination with low doses of laminin or fibronectin enhanced neurite out-growth from these neuronal explants. Our results suggest that insoluble Aβ in the cerebral neuropil may serve as a neurite-promoting matrix, perhaps explaining the apparent regenerative response of neurites observed around amyloid plaques in Alzheimer disease. Moreover, in concert with the recent discovery of Aβ production by cultured neurons, our data suggest that Aβ plays a normal physiological role in brain by complexing with the extracellular matrix.

Botulinum neurotoxin type A: Actions beyond SNAP-25?

PubMed

Matak, Ivica; Lacković, Zdravko

2015-09-01

Botulinum neurotoxin type A (BoNT/A), the most potent toxin known in nature which causes botulism, is a commonly used therapeutic protein. It prevents synaptic vesicle neuroexocytosis by proteolytic cleavage of synaptosomal-associated protein of 25 kDa (SNAP-25). It is widely believed that BoNT/A therapeutic or toxic actions are exclusively mediated by SNAP-25 cleavage. On the other hand, in vitro and in vivo findings suggest that several BoNT/A actions related to neuroexocytosis, cell cycle and apoptosis, neuritogenesis and gene expression are not necessarily mediated by this widely accepted mechanism of action. In present review we summarize the literature evidence which point to the existence of unknown BoNT/A molecular target(s) and modulation of unknown signaling pathways. The effects of BoNT/A apparently independent of SNAP-25 occur at similar doses/concentrations known to induce SNAP-25 cleavage and prevention of neurotransmitter release. Accordingly, these effects might be pharmacologically significant. Potentially the most interesting are observations of antimitotic and antitumor activity of BoNT/A. However, the exact mechanisms require further studies. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Tris(1,3-dichloro-2-propyl) phosphate perturbs the expression of genes involved in immune response and lipid and steroid metabolism in chicken embryos

DOE Office of Scientific and Technical Information (OSTI.GOV)

Farhat, Amani; National Wildlife Research Centre, Environment Canada, Ottawa, ON K1A 0H3; Buick, Julie K.

We previously demonstrated that in ovo exposure to the flame retardant tris(1,3-dichloro-2-propyl) phosphate (TDCPP) decreased plasma thyroxine levels, reduced growth parameters, and decreased gallbladder size in chicken embryos. In the current study DNA microarrays were used to evaluate global mRNA expression in liver tissue of male chicken embryos that exhibited the above mentioned effects. Injected doses were dimethyl sulfoxide vehicle control, 7.6 or 45 μg TDCPP/g egg. TDCPP caused significant changes in the expression of five genes at the low dose and 47 genes at the high dose (False Discovery Rate p ≤ 0.1, fold change ≥ 1.5). The genemore » expression analysis suggested a compromised immune function, a state of cholestatic liver/biliary fibrosis, and disrupted lipid and steroid metabolism. Circulating bile acid levels were elevated, which is an indication of liver dysfunction, and plasma cholesterol levels were reduced; however, hepatic bile acid and cholesterol levels were unaltered. Interactome analyses identified apolipoprotein E, hepatocyte nuclear factor 4 alpha, and peroxisome proliferator-activated receptor alpha as key regulatory molecules involved in the effects of TDCPP. Our results demonstrate a targeted effect of TDCPP toxicity on lipid metabolism, including cholesterol, that helps explain the aforementioned phenotypic effects, as chicken embryos are highly dependent on yolk lipids for growth and maintenance throughout development. Finally, our results are in concordance with the literature that describes TDCPP as a cancer-causing agent, since the majority of dysregulated genes were involved in cancer pathways. - Highlights: • TDCPP dysregulates genes involved in immune function and lipid metabolism. • A targeted effect of TDCPP toxicity on cholesterol metabolism is apparent. • A state of cholestatic liver fibrosis is suggested by the expression profile. • Elevated plasma bile acids suggest that TDCPP causes liver dysfunction.« less

TOXICITY TESTS FOR SEDIMENT QUALITY ASSESSMENTS

EPA Science Inventory

Toxic sediments have contributed to a wide-variety of environmental problems around the world. The observed effects include direct toxic effects to aquatic life, bio-magnification of toxicants in the food chain, and economic impacts. This chapter discusses the use of toxicity...

Enduring legacy of a toxic fan via episodic redistribution of California gold mining debris

PubMed Central

Singer, Michael Bliss; Aalto, Rolf; James, L. Allan; Kilham, Nina E.; Higson, John L.; Ghoshal, Subhajit

2013-01-01

The interrelationships between hydrologically driven evolution of legacy landscapes downstream of major mining districts and the contamination of lowland ecosystems are poorly understood over centennial time scales. Here, we demonstrate within piedmont valleys of California’s Sierra Nevada, through new and historical data supported by modeling, that anthropogenic fans produced by 19th century gold mining comprise an episodically persistent source of sediment-adsorbed Hg to lowlands. Within the enormous, iconic Yuba Fan, we highlight (i) an apparent shift in the relative processes of fan evolution from gradual vertical channel entrenchment to punctuated lateral erosion of fan terraces, thus enabling entrainment of large volumes of Hg-laden sediment during individual floods, and (ii) systematic intrafan redistribution and downstream progradation of fan sediment into the Central Valley, triggered by terrace erosion during increasingly long, 10-y flood events. Each major flood apparently erodes stored sediment and delivers to sensitive lowlands the equivalent of ∼10–30% of the entire postmining Sierran Hg mass so far conveyed to the San Francisco Bay-Delta (SFBD). This process of protracted but episodic erosion of legacy sediment and associated Hg is likely to persist for >104 y. It creates, within an immense swath of river corridor well upstream of the SFBD, new contaminated floodplain surfaces primed for Hg methylation and augments/replenishes potential Hg sources to the SFBD. Anticipation, prediction, and management of toxic sediment delivery, and corresponding risks to lowland ecology and human society globally, depend on the morphodynamic stage of anthropogenic fan evolution, synergistically coupled to changing frequency of and duration extreme floods. PMID:24167273

Radiotherapy for malignancy in patients with scleroderma: The Mayo Clinic experience

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gold, Douglas G.; Miller, Robert C.; Petersen, Ivy A.

2007-02-01

Purpose: To determine the frequency of acute and chronic adverse effects in patients with scleroderma who receive radiotherapy for treatment of cancer. Methods and Materials: Records were reviewed of 20 patients with scleroderma who received radiotherapy. Acute and chronic toxic effects attributable to radiotherapy were analyzed, and freedom from radiation-related toxicity was calculated. Results: Of the 20 patients, 15 had acute toxic effects, with Grade 3 or higher toxicity for 3 patients. Seven patients had self-limited Grade 1 or 2 radiation dermatitis, and no patient had Grade 3 or higher radiation dermatitis. Thirteen patients had chronic toxic effects, with Grademore » 3 or higher chronic toxicity for 3 patients. The median estimated time to any grade chronic toxicity was 0.4 years, and the median estimated time to Grade 3 or higher chronic toxicity has not been reached. Conclusions: The results suggest that although some patients with scleroderma treated with radiation experience considerable toxic effects, the occurrence of Grade 3 or higher toxicity may be less than previously anticipated.« less

Multi-Toxic Endpoints of the Foodborne Mycotoxins in Nematode Caenorhabditis elegans

PubMed Central

Yang, Zhendong; Xue, Kathy S.; Sun, Xiulan; Tang, Lili; Wang, Jia-Sheng

2015-01-01

Aflatoxins B1 (AFB1), deoxynivalenol (DON), fumonisin B1 (FB1), T-2 toxin (T-2), and zearalenone (ZEA) are the major foodborne mycotoxins of public health concerns. In the present study, the multiple toxic endpoints of these naturally-occurring mycotoxins were evaluated in Caenorhabditis elegans model for their lethality, toxic effects on growth and reproduction, as well as influence on lifespan. We found that the lethality endpoint was more sensitive for T-2 toxicity with the EC50 at 1.38 mg/L, the growth endpoint was relatively sensitive for AFB1 toxic effects, and the reproduction endpoint was more sensitive for toxicities of AFB1, FB1, and ZEA. Moreover, the lifespan endpoint was sensitive to toxic effects of all five tested mycotoxins. Data obtained from this study may serve as an important contribution to knowledge on assessment of mycotoxin toxic effects, especially for assessing developmental and reproductive toxic effects, using the C. elegans model. PMID:26633509

Anti-tumor effect of AZD8055 against neuroblastoma cells in vitro and in vivo.

PubMed

Xu, Dong-Qing; Toyoda, Hidemi; Yuan, Xiao-Jun; Qi, Lei; Chelakkot, Vipin Shankar; Morimoto, Mari; Hanaki, Ryo; Kihira, Kentarou; Hori, Hiroki; Komada, Yoshihiro; Hirayama, Masahiro

2018-04-15

Neuroblastoma (NB) is one of the most common solid tumors in children. High-risk NB remains lethal in about 50% of patients despite comprehensive and intensive treatments. Activation of PI3K/Akt/mTOR signaling pathway correlates with oncogenesis, poor prognosis and chemotherapy resistance in NB. Due to its central role in growth and metabolism, mTOR seems to be an important factor in NB, making it a possible target for NB. In this study, we investigated the effect of AZD8055, a potent dual mTORC1-mTORC2 inhibitor, in NB cell lines. Our data showed that mTOR signaling was extensively activated in NB cells. The activity of mTOR and downstream molecules were down-regulated in AZD8055-treated NB cells. Significantly, AZD8055 effectively inhibited cell growth and induced cell cycle arrest, autophagy and apoptosis in NB cells. Moreover, AZD8055 significantly reduced tumor growth in mice xenograft model without apparent toxicity. Taken together, our results highlight the potential of mTOR as a promising target for NB treatment. Therefore, AZD8055 may be further investigated for treatment in clinical trials for high risk NB. Copyright © 2018 Elsevier Inc. All rights reserved.

Identification of an adenylyl cyclase inhibitor for treating neuropathic and inflammatory pain.

PubMed

Wang, Hansen; Xu, Hui; Wu, Long-Jun; Kim, Susan S; Chen, Tao; Koga, Kohei; Descalzi, Giannina; Gong, Bo; Vadakkan, Kunjumon I; Zhang, Xuehan; Kaang, Bong-Kiun; Zhuo, Min

2011-01-12

Neuropathic pain, often caused by nerve injury, is commonly observed among patients with different diseases. Because its basic mechanisms are poorly understood, effective medications are limited. Previous investigations of basic pain mechanisms and drug discovery efforts have focused mainly on early sensory neurons such as dorsal root ganglion and spinal dorsal horn neurons, and few synaptic-level studies or new drugs are designed to target the injury-related cortical plasticity that accompanies neuropathic pain. Our previous work has demonstrated that calcium-stimulated adenylyl cyclase 1 (AC1) is critical for nerve injury-induced synaptic changes in the anterior cingulate cortex. Through rational drug design and chemical screening, we have identified a lead candidate AC1 inhibitor, NB001, which is relatively selective for AC1 over other adenylate cyclase isoforms. Using a variety of behavioral tests and toxicity studies, we have found that NB001, when administered intraperitoneally or orally, has an analgesic effect in animal models of neuropathic pain, without any apparent side effects. Our study thus shows that AC1 could be a productive therapeutic target for neuropathic pain and describes a new agent for the possible treatment of neuropathic pain.

Protective effects of chlorogenic acid in 3-nitropropionic acid induced toxicity and genotoxicity.

PubMed

Alarcón-Herrera, Norberto; Flores-Maya, Saúl; Bellido, Belén; García-Bores, Ana M; Mendoza, Ernesto; Ávila-Acevedo, Guillermo; Hernández-Echeagaray, Elizabeth

2017-11-01

Mitochondrial inhibition with the toxin 3-Nitropropionic acid (3-NP) has been used to study the underlying mechanisms in striatal neurodegeneration, but few experiments have evaluated its toxicity and genotoxicity of in vivo administration. Furthermore, different antioxidant molecules may prevent degeneration induced by the toxic effects of 3-NP. Therefore, the purpose of this study was to evaluate the toxicity and genotoxicity induced by 3-NP (15 mg/kg) in the micronuclei assay method; also, we assessed chlorogenic acid (CGA, 100 mg/kg) for its anti-toxic and anti-genotoxic effect in damage produced by in vivo treatment with 3-NP. 3-NP induced toxicity and genotoxicity. CGA administered as a co-treatment with 3-NP (3-NP + CA) reduced toxicity by 32.76%, as a pre-treatment for 5 days only, followed by 3-NP treatment (P/CA, 3-NP) inhibiting toxicity by 24.04%, or as a pre-treatment, plus a co-treatment with 3-NP (P/CA, 3-NP + CA) avoided any toxic effect. CGA alone did not exhibit any toxic effect. Only P/CGA, 3-NP + CGA group, avoided toxicity and genotoxicity, suggesting that CGA could be suitable to prevent, reduce or delay toxicity and cell death. Copyright © 2017 Elsevier Ltd. All rights reserved.

Metabolomics reveals the mechanisms for the cardiotoxicity of Pinelliae Rhizoma and the toxicity-reducing effect of processing

NASA Astrophysics Data System (ADS)

Su, Tao; Tan, Yong; Tsui, Man-Shan; Yi, Hua; Fu, Xiu-Qiong; Li, Ting; Chan, Chi Leung; Guo, Hui; Li, Ya-Xi; Zhu, Pei-Li; Tse, Anfernee Kai Wing; Cao, Hui; Lu, Ai-Ping; Yu, Zhi-Ling

2016-10-01

Pinelliae Rhizoma (PR) is a commonly used Chinese medicinal herb, but it has been frequently reported about its toxicity. According to the traditional Chinese medicine theory, processing can reduce the toxicity of the herbs. Here, we aim to determine if processing reduces the toxicity of raw PR, and to explore the underlying mechanisms of raw PR-induced toxicities and the toxicity-reducing effect of processing. Biochemical and histopathological approaches were used to evaluate the toxicities of raw and processed PR. Rat serum metabolites were analyzed by LC-TOF-MS. Ingenuity pathway analysis of the metabolomics data highlighted the biological pathways and network functions involved in raw PR-induced toxicities and the toxicity-reducing effect of processing, which were verified by molecular approaches. Results showed that raw PR caused cardiotoxicity, and processing reduced the toxicity. Inhibition of mTOR signaling and activation of the TGF-β pathway contributed to raw PR-induced cardiotoxicity, and free radical scavenging might be responsible for the toxicity-reducing effect of processing. Our data shed new light on the mechanisms of raw PR-induced cardiotoxicity and the toxicity-reducing effect of processing. This study provides scientific justifications for the traditional processing theory of PR, and should help in optimizing the processing protocol and clinical combinational application of PR.

Effects of lambda-cyhalothrin in two ditch microcosm systems of different trophic status.

PubMed

Roessink, Ivo; Arts, Gertie H P; Belgers, J Dick M; Bransen, Fred; Maund, Steve J; Brock, Theo C M

2005-07-01

The fate and effects of the pyrethroid insecticide lambda-cyhalothrin were compared in mesotrophic (macrophyte-dominated) and eutrophic (phytoplankton-dominated) ditch microcosms (approximately 0.5 m3). Lambda-cyhalothrin was applied three times at one-week intervals at concentrations of 10, 25, 50, 100, and 250 ng/L. The rate of dissipation of lambda-cyhalothrin in the water column of the two types of test systems was similar. After 1 d, only 30% of the amount applied remained in the water phase. Initial, direct effects were observed primarily on arthropod taxa. The most sensitive species was the phantom midge (Chaoborus obscuripes). Threshold levels for slight and transient direct toxic effects were similar (10 ng/L) between types of test systems. At treatment levels of 25 ng/L and higher, apparent population and community responses occurred. At treatments of 100 and 250 ng/L, the rate of recovery of the macroinvertebrate community was lower in the macrophyte-dominated systems, primarily because of a prolonged decline of the amphipod Gammarus pulex. This species occurred at high densities only in the macrophyte-dominated enclosures. Indirect effects (e.g., increase of rotifers and microcrustaceans) were more pronounced in the plankton-dominated test systems, particularly at treatment levels of 25 ng/L and higher.

Potential fluoride toxicity from oral medicaments: A review.

PubMed

Ullah, Rizwan; Zafar, Muhammad Sohail; Shahani, Nazish

2017-08-01

The beneficial effects of fluoride on human oral health are well studied. There are numerous studies demonstrating that a small amount of fluoride delivered to the oral cavity decreases the prevalence of dental decay and results in stronger teeth and bones. However, ingestion of fluoride more than the recommended limit leads to toxicity and adverse effects. In order to update our understanding of fluoride and its potential toxicity, we have described the mechanisms of fluoride metabolism, toxic effects, and management of fluoride toxicity. The main aim of this review is to highlight the potential adverse effects of fluoride overdose and poorly understood toxicity. In addition, the related clinical significance of fluoride overdose and toxicity has been discussed.

Bioaccumulation and toxicity of selenium during a life-cycle exposure with desert pupfish (Cyprinodon macularius)

USGS Publications Warehouse

Besser, John M.; Brumbaugh, William G.; Papoulias, Diana M.; Ivey, Chris D.; Kunz, James L.; Annis, Mandy; Ingersoll, Christopher G.

2012-01-01

Populations of desert pupfish (Cyprinodon macularius; pupfish), a federally-listed endangered species, inhabit irrigation drains in the Imperial Valley agricultural area of southern California. These drains have varying degrees of selenium (Se) contamination of water, sediment, and aquatic biota. Published Se toxicity studies suggest that these levels of Se contamination may pose risk of chronic toxicity to Se-sensitive fish, but until recently there have been no studies of the chronic toxicity of Se to desert pupfish.A life-cycle Se exposure with pupfish was conducted to estimate dietary and tissue thresholds for toxic effects of Se on all life stages. The dietary exposure was based on live oligochaete worms (Lumbriculus variegatus) dosed with Se by a laboratory food chain based on selenized yeast. Oligochaetes readily accumulated Se from mixtures of selenized and control yeasts. The protocol for dosing oligochaetes for pupfish feeding studies included long-term (at least 28 days) feeding of a low-ration of yeast mixtures to large batches of oligochaetes. Oligochaetes were dosed at five Se levels in a 50-percent dilution series. Pupfish were simultaneously fed Se-dosed oligochaetes and exposed to a series of Se concentrations in water (consisting of 85 percent selenate and 15 percent selenite) to produce exposures that were consistent with Se concentrations and speciation in pupfish habitats. The nutritional characteristics of oligochaete diets were consistent across the range of oligochaete Se concentrations tested.The life-cycle exposure started with laboratory-cultured juvenile pupfish that were exposed to Se through sexual maturation and reproduction (150 days; F0 exposure). The Se exposure continued with eggs, larvae, and juveniles produced by Se-exposed parents (79 days; F1 exposure). Selenium exposure (water and diets), Se bioaccumulation (whole-body and eggs), and toxicity endpoints (juvenile and adult survival and growth; egg production and hatching success, larval survival and deformities) were documented throughout the life-cycle study.Selenium concentrations in water (as much as 52 micrograms per liter [μg/L]) and diets (as much as 53 micrograms per gram [μg/g], on a dry weight basis) bracketed concentrations reported in pupfish habitats. Juvenile F0 pupfish rapidly accumulated Se and bioaccumulation models indicated that pupfish had reached more than 97 percent of maximum whole-body Se concentrations by the time they reached reproductive maturity. Adult pupfish accumulated whole-body Se concentrations that averaged about 40 percent of those in the oligochaete diets. Selenium concentrations in eggs and F1 juveniles were similar to or slightly greater than Se concentrations in F0 adults. Juvenile F0 pupfish contained selenomethionine fractions (62–71 percent of whole-body Se) greater than the average reported for wild pupfish from the Imperial Valley (53 percent).Selenium exposure had minimal effects on survival or growth of juvenile and adult pupfish. There was evidence of toxic effects on pupfish in the highest Se treatment (Se–5), including reduced growth of F0 and F1 juvenile pupfish (17–21 percent less than controls) on some sampling dates. These growth reductions did not persist to subsequent sampling dates, but reduced growth of F1 pupfish in the Se–5 treatment was associated with reduced survival (12 percent less than controls).Egg production was greatest in the controls and decreased with increasing Se exposure, reaching a minimum (51 percent less than controls) in the Se–4 treatment, but egg production was reduced by only 24 percent in the Se–5 treatment, a lesser reduction than in other Se treatments except Se–1. There was no statistically significant overall effect of Se treatment on mean pupfish egg production, reflecting large variation among replicates and among sampling dates. However, comparisons of daily mean egg production for 23 sampling dates indicated that egg production in each of 5 Se treatments was significantly less than controls on multiple (3–7) sampling dates, but no mean for any Se treatment was significantly greater than controls on any date. Significant reductions in daily egg production occurred mainly during the middle of the study and egg production increased in several Se treatments during the final 2 weeks of the study. These results suggest that pupfish egg production, although a highly variable endpoint, was adversely affected by elevated Se exposure.Neither egg hatching success nor survival of F1 larvae indicated clear evidence of Se toxicity. Egg hatching success did not differ significantly among treatments, with means ranging from 84–91 percent. The frequency of morphological deformities (primarily spinal deformities) was greater in larvae 10 days post-fertilization (dpf) from a preliminary reproduction study than in older larvae (14 dpf) from the main reproduction study. The frequency of larval deformities was generally greater in Se treatments than controls, but mean frequencies did not differ significantly among treatments. Survival of F1 larvae to 21 dpf was not reduced significantly by parental Se exposure, but the Se–5 treatment had the lowest larval survival (84 percent), and lowest combined egg hatching and larval survival (76 percent).Results of the Se treatments indicate that pupfish were insensitive to Se toxicity through most of their life cycle. Consistent toxic effects on survival and growth of juvenile and adult pupfish (defined as at least 10 percent reduction compared to controls) occurred only in treatment Se–5, which had a mean dietary Se concentration of 52 μg/g and a mean pupfish whole-body Se concentration of 27 μg/g. These apparent toxicity thresholds for growth and survival rank among the least sensitive chronic Se toxicity values reported for nonreproductive endpoints in freshwater fish. Comparisons of these thresholds to surveys of Se concentrations in the Imperial Valley suggest that risks of Se toxicity are low in pupfish habitats. The dietary threshold was about twice as high as the greatest mean Se concentrations reported in midge larvae from seven sites in the Imperial Valley. Whole-body thresholds were greater than mean whole-body Se concentrations reported for field-collected pupfish from three sites and for the sailfin molly (Poecilia latipinna), a potential bioaccumulation surrogate for pupfish, from seven sites.Reduced egg production, although highly variable, was the most sensitive response of pupfish to Se exposure. Toxic effects on egg production (reductions of 24–51 percent relative to controls) occurred in the four highest Se treatments, corresponding to reproductive toxicity thresholds of 7.3 μg/g for Se in diet, 3.4 μg/g in pupfish (whole body), and 4.4 μg/g in pupfish eggs. These thresholds are substantially lower than published Se toxicity values for reproductive effects in other freshwater fish (for example, 17–24 μg/g in eggs). Reduced egg production has not been reported as a sensitive endpoint in Se toxicity studies, although abnormal ovarian development has been reported in Se-exposed fish, and reduced egg production has been reported as a sensitive response of other Cyprinodon pupfish to other environmental stressors.Selenium concentrations in tissues of pupfish, mollies, and diet items from Imperial Valley sites frequently exceeded concentrations associated with reduced pupfish egg production in the laboratory study. Reduced egg production may limit the ability of pupfish populations to persist and recover in Se-contaminated habitats in the Imperial Valley and elsewhere in their limited range. However, these apparent risks of Se toxicity are not supported by recent surveys of desert pupfish populations in the Imperial Valley. These surveys indicated that desert pupfish made up a small, but variable, component of fish communities in Imperial Valley habitats, including sites with increased levels of Se exposure, and that pupfish distribution and population density indicated no clear relationships with Se concentrations in diets or fish tissues. Additional studies could determine the role of egg production in the maintenance and recovery of desert pupfish populations in Se-contaminated habitats.

Adjuvant chemotherapy with 5-fluorouracil, L-folinic acid and levamisole for patients with colorectal cancer: non-randomised comparison of weekly versus four-weekly schedules--less pain, same gain. QUASAR Colorectal Cancer Study Group.

PubMed

Kerr, D J; Gray, R; McConkey, C; Barnwell, J

2000-08-01

QUASAR is a large trial of adjuvant chemotherapy for colorectal cancer in which clinicians could choose to deliver a standard adjuvant cytotoxic chemotherapy regimen, 5-fluorouracil (5-FU) and L-folinic acid (L-FA), in either a once-weekly or a four-weekly schedule. We report results of a non-randomised comparison between these schedules with respect to survival, recurrence and differential toxicity. In a factorial (2 x 2) trial design, QUASAR compared high-dose (175 mg) versus low-dose (25 mg) L-FA and levamisole versus placebo. The dose of 5-FU was fixed at 370 mg/m2 and although the recommended schedule was i.v. bolus delivery, daily for 5 days repeated four-weekly for 6 months, a significant proportion of randomising clinicians were constrained to deliver once-weekly 5-FU-L-FA for 30 weeks. Four thousand nine hundred twenty-seven patients were entered into QUASAR between May 1994 and October 1997, eighteen hundred twenty-nine of whom have recurred and sixteen hundred eighty-nine died. Similar numbers 2370 vs. 2559 were treated with the once-weekly and four-weekly schedules and the demographic features of the 2 groups were well balanced: stage C, 73.3% once-weekly vs. 71.0% four-weekly; colon, 68.0% vs. 68.3%; high-dose FA, 50.1% vs. 49.9%; levamisole, 49.3% vs. 49.3%; females, 40.2% vs. 41.7%; median age (years) 62 vs. 61. The risk of recurrence and survival were similar regardless of schedule: three-year survival was 70.6% once-weekly vs. 71.0% four-weekly; three-year recurrence risk was 35.6% once-weekly vs. 35.5% four-weekly; But, the once-weekly regimen was much less toxic: number of patients for whom toxicity was reported (once-weekly: four-weekly), stomatitis, 37 vs. 337; diarrhoea, 260 vs. 440; neutropenia, 20 vs. 153. The once-weekly regimen is much less toxic than and, apparently, about as effective as the four-weekly schedule. This suggests that the toxicity of 5-FU-L-FA adjuvant chemotherapy could be reduced substantially by weekly scheduling without compromising efficacy. Alternatively, efficacy might be enhanced with equal toxicity by more dose-intense weekly FU-L-FA regimens. However, this conclusion from a non-randomised comparison needs confirmation in prospective randomised studies.

Nature of oxygen-containing radicals in radiation chemistry and photochemistry of aqueous solutions. Annual progress report, July 1981-June 1982

DOE Office of Scientific and Technical Information (OSTI.GOV)

Czapski, G.

During the past years the main emphasis was given to the properties of HO/sub 2/ and O/sub 2//sup -/ and OH, mainly in their role in biological systems. We will continue to study and elucidate how O/sub 2//sup -/ reacts in biological systems. The toxicity of O/sub 2//sup -/ is quite well established but the mechanism is still obscure. One way O/sub 2//sup -/ is toxic, was shown by us and others, that OH is formed from O/sub 2//sup -/ through reduction of Fe/sup 3 +/, and subsequently the reaction of Fe/sup 2 +/ with H/sub 2/O/sub 2/ (Fenton reaction).more » This mechanism is sometimes, unjustifiably, called the Haber Weiss Reaction. In this mechanism Cu(II) can often substitute Fe/sup 3 +/. Our recent results proved that in many cases O/sub 2//sup -/, which in its biological activity and toxicity, reduces Cu(II) or Fe(III) can be replaced by other reductants like Vit. C. The role of oxygen, radiosensitizers in radiation damage of bacteriophages and cells will be further studied, as well as on E. coli and enzymes. We will try to elucidate the formation and role of OH, O/sub 2//sup -/ and O/sub 2/ in these systems as well as the relative contribution of endogenous and exogeneous damage, and the role of direct and indirect radiation damage to cells. Our main emphasis in the near future will concentrate on the effect of copper ions on toxicity of O/sub 2//sup -/. Preliminary results, both with penicillinase as well as with spores and bacteriophages and E. coli, show as if in some of these systems Cu/sup 2 +/ sensitizes the damage caused in the absence of copper by up to one hundred fold. This damage is apparently caused by O/sub 2//sup -/. We found that in this sense, O/sub 2//sup -/ can be often replaced by Vit. C - both are capable of reducing Cu(II) and both form H/sub 2/O/sub 2/ (Vit. C only in the presence of oxygen). In the near future we will concentrate on studying the exact mechanism of toxicity of Vit. C and O/sub 2//sup -/ in the presence of Cu(II) and will compare the toxicity and its mechanism of Vit. C and O/sub 2//sup -/.« less

The Effects of Temperature and Hydrostatic Pressure on Metal Toxicity: Insights into Toxicity in the Deep Sea.

PubMed

Brown, Alastair; Thatje, Sven; Hauton, Chris

2017-09-05

Mineral prospecting in the deep sea is increasing, promoting concern regarding potential ecotoxicological impacts on deep-sea fauna. Technological difficulties in assessing toxicity in deep-sea species has promoted interest in developing shallow-water ecotoxicological proxy species. However, it is unclear how the low temperature and high hydrostatic pressure prevalent in the deep sea affect toxicity, and whether adaptation to deep-sea environmental conditions moderates any effects of these factors. To address these uncertainties we assessed the effects of temperature and hydrostatic pressure on lethal and sublethal (respiration rate, antioxidant enzyme activity) toxicity in acute (96 h) copper and cadmium exposures, using the shallow-water ecophysiological model organism Palaemon varians. Low temperature reduced toxicity in both metals, but reduced cadmium toxicity significantly more. In contrast, elevated hydrostatic pressure increased copper toxicity, but did not affect cadmium toxicity. The synergistic interaction between copper and cadmium was not affected by low temperature, but high hydrostatic pressure significantly enhanced the synergism. Differential environmental effects on toxicity suggest different mechanisms of action for copper and cadmium, and highlight that mechanistic understanding of toxicity is fundamental to predicting environmental effects on toxicity. Although results infer that sensitivity to toxicants differs across biogeographic ranges, shallow-water species may be suitable ecotoxicological proxies for deep-sea species, dependent on adaptation to habitats with similar environmental variability.

Concentration rather than dose defines the local brain toxicity of agents that are effectively distributed by convection-enhanced delivery.

PubMed

Zhang, Rong; Saito, Ryuta; Mano, Yui; Kanamori, Masayuki; Sonoda, Yukihiko; Kumabe, Toshihiro; Tominaga, Teiji

2014-01-30

Convection-enhanced delivery (CED) has been developed as a potentially effective drug-delivery strategy into the central nervous system. In contrast to systemic intravenous administration, local delivery achieves high concentration and prolonged retention in the local tissue, with increased chance of local toxicity, especially with toxic agents such as chemotherapeutic agents. Therefore, the factors that affect local toxicity should be extensively studied. With the assumption that concentration-oriented evaluation of toxicity is important for local CED, we evaluated the appearance of local toxicity among different agents after delivery with CED and studied if it is dose dependent or concentration dependent. Local toxicity profile of chemotherapeutic agents delivered via CED indicates BCNU was dose-dependent, whereas that of ACNU was concentration-dependent. On the other hand, local toxicity for doxorubicin, which is not distributed effectively by CED, was dose-dependent. Local toxicity for PLD, which is extensively distributed by CED, was concentration-dependent. Traditional evaluation of drug induced toxicity was dose-oriented. This is true for systemic intravascular delivery. However, with local CED, toxicity of several drugs exacerbated in concentration-dependent manner. From our study, local toxicity of drugs that are likely to distribute effectively tended to be concentration-dependent. Concentration rather than dose may be more important for the toxicity of agents that are effectively distributed by CED. Concentration-oriented evaluation of toxicity is more important for CED. Copyright © 2013 Elsevier B.V. All rights reserved.

Knowledge and use of edible mushrooms in two municipalities of the Sierra Tarahumara, Chihuahua, Mexico.

PubMed

Quiñónez-Martínez, Miroslava; Ruan-Soto, Felipe; Aguilar-Moreno, Ivonne Estela; Garza-Ocañas, Fortunato; Lebgue-Keleng, Toutcha; Lavín-Murcio, Pablo Antonio; Enríquez-Anchondo, Irma Delia

2014-09-17

The Sierra Madre Occidental of Chihuahua in Northern Mexico is inhabited by indigenous Raramuris, mestizos, and other ethnic groups. The territory consists of canyons and ravines with pine, oak and pine-oak forests in the higher plateaus. A great diversity of potentially edible mushrooms is found in forests of the Municipalities of Bocoyna and Urique. Their residents are the only consumers of wild mushrooms in the Northern Mexico; they have a long tradition of collecting and eating these during the "rainy season." However, despite the wide diversity of edible mushrooms that grow in these areas, residents have a selective preference. This paper aims to record evidence of the knowledge and use of wild potentially edible mushroom species by inhabitants of towns in the Sierra Tarahumara of Chihuahua, Mexico. Using a semi-structured technique, we surveyed 197 habitants from seven locations in Urique, Bocoyna, and the Cusarare area from 2010 to 2012. Known fungi, local nomenclature, species consumed, preparation methods, appreciation of taste, forms of preservation, criteria for differentiating toxic and edible fungi, other uses, economic aspects, and traditional teaching were recorded. To identify the recognized species, photographic stimuli of 22 local edible species and two toxic species were used. The respondents reported preference for five species: Amanita rubescens, Agaricus campestris, Ustilago maydis, Hypomyces lactifluorum, and the Amanita caesarea complex. No apparent differences were found between ethnic groups in terms of preference, although mestizos used other species in Bocoyna (Boletus edulis and B. pinophilus). Some different uses of fungi are recognized by respondents, i.e. home decorations, medicine, as food in breeding rams, etc. The studied population shows a great appreciation towards five species, mainly the A. caesarea complex, and an apparent lack of knowledge of nearly 20 species which are used as food in other areas of Mexico. There are no apparent differences among Sierra inhabitants in terms of gender, occupation, or language regarding the recognition and consumption of species. The rejection of certain species is due mainly to fear of poisoning and the traditional selective teaching of families in the mountain communities of the Sierra Tarahumara.

Are quantum dots toxic? Exploring the discrepancy between cell culture and animal studies.

PubMed

Tsoi, Kim M; Dai, Qin; Alman, Benjamin A; Chan, Warren C W

2013-03-19

Despite significant interest in developing quantum dots (QDs) for biomedical applications, many researchers are convinced that QDs will never be used for treating patients because of their potential toxicity. The perception that QDs are toxic is rooted in two assumptions. Cadmium-containing QDs can kill cells in culture. Many researchers then assume that because QDs are toxic to cells, they must be toxic to humans. In addition, many researchers classify QDs as a homogeneous group of materials. Therefore, if CdSe QDs are harmful, they extrapolate this result to all QDs. Though unsubstantiated, these assumptions continue to drive QD research. When dosing is physiologically appropriate, QD toxicity has not been demonstrated in animal models. In addition, QDs are not uniform: each design is a unique combination of physicochemical properties that influence biological activity and toxicity. In this Account, we summarize key findings from in vitro and in vivo studies, explore the causes of the discrepancy in QD toxicological data, and provide our view of the future direction of the field. In vitro and in vivo QD studies have advanced our knowledge of cellular transport kinetics, mechanisms of QD toxicity, and biodistribution following animal injection. Cell culture experiments have shown that QDs undergo design-dependent intracellular localization and they can cause cytotoxicity by releasing free cadmium into solution and by generating free radical species. In animal experiments, QDs preferentially enter the liver and spleen following intravascular injection, undergo minimal excretion if larger than 6 nm, and appear to be safe to the animal. In vitro and in vivo studies show an apparent discrepancy with regard to toxicity. Dosing provides one explanation for these findings. Under culture conditions, a cell experiences a constant QD dose, but the in vivo QD concentration can vary, and the organ-specific dose may not be high enough to induce detectable toxicity. Because QDs are retained within animals, long-term toxicity may be a problem but has not been established. Future QD toxicity studies should be standardized and systematized because methodological variability in the current body of literature makes it difficult to compare and contrast results. We advocate the following steps for consistent, comparable toxicology data: (a) standardize dose metrics, (b) characterize QD uptake concentration, (c) identify in vitro models that reflect the cells QDs interact with in vivo, and (d) use multiple assays to determine sublethal toxicity and biocompatibility. Finally, we should ask more specific toxicological questions. For example: "At what dose are 5 nm CdSe QDs that are stabilized with mercaptoacetic acid and conjugated to the antibody herceptin toxic to HeLa cells?" rather than "Are QDs toxic?" QDs are still a long way from realizing their potential as a medical technology. Modifying the current QD toxicological research paradigm, investigating toxicity in a case-by-case manner, and improving study quality are important steps in identifying a QD formulation that is safe for human use.

Asbestos as 'toxic short-circuit' optic-fibre for UV within the cell-net: — Likely roles and hazards for secret UV and IR metabolism

NASA Astrophysics Data System (ADS)

Traill, Robert R.

2011-12-01

The most toxic asbestos fibres have widths 250nm-10nm, and this toxicity is "physical", which could mean either mechanical or optical: Tangling with chromosomes is a •mechanical hazard occasionally reported, and fibres <100nm wide would probably be most knife-like. Our other concern here is •optical: Calculations for fibres <=300nm reveal such a transmission possibility, but only when the amphibole fibres (brown and blue asbestos) are >100nm wide — or chrysotile (white asbestos) is >150nm. In both cases, UVA/UVB -transmission would then predominate. (Chrysotile 150nm might be benign — escaping both mechanical and optical!). But what would generate such UV, and why would its transmission be toxic? Thar and Kühl (J.Theor.Biol.:2004) explain that the long mitochondria on microtubules may be able to act as UV-lasers, (and many observers since Gurwitsch 1923 have reported ultraweak UV emissions escaping from all types of living bio-tissue). That all suggests some universal secret role for UV, apparently related to mitosis. Insertion of fibre "short-circuits" could then cause upsets in mitosis-control, and hence DNA irregularities. Such UV-control could parallel similar lower-powered Infra-Red control-systems (as considered elsewhere for coaxial myelin; or as portrayed by G.Albrecht-Buehler's online animations etc.); and the traditional short mitochondria seem better suited for this IR task.

GIS Modeling of Air Toxics Releases from TRI-Reporting and Non-TRI-Reporting Facilities: Impacts for Environmental Justice

PubMed Central

Dolinoy, Dana C.; Miranda, Marie Lynn

2004-01-01

The Toxics Release Inventory (TRI) requires facilities with 10 or more full-time employees that process > 25,000 pounds in aggregate or use > 10,000 pounds of any one TRI chemical to report releases annually. However, little is known about releases from non-TRI-reporting facilities, nor has attention been given to the very localized equity impacts associated with air toxics releases. Using geographic information systems and industrial source complex dispersion modeling, we developed methods for characterizing air releases from TRI-reporting as well as non-TRI-reporting facilities at four levels of geographic resolution. We characterized the spatial distribution and concentration of air releases from one representative industry in Durham County, North Carolina (USA). Inclusive modeling of all facilities rather than modeling of TRI sites alone significantly alters the magnitude and spatial distribution of modeled air concentrations. Modeling exposure receptors at more refined levels of geographic resolution reveals localized, neighborhood-level exposure hot spots that are not apparent at coarser geographic scales. Multivariate analysis indicates that inclusive facility modeling at fine levels of geographic resolution reveals exposure disparities by income and race. These new methods significantly enhance the ability to model air toxics, perform equity analysis, and clarify conflicts in the literature regarding environmental justice findings. This work has substantial implications for how to structure TRI reporting requirements, as well as methods and types of analysis that will successfully elucidate the spatial distribution of exposure potentials across geographic, income, and racial lines. PMID:15579419

Defences against ammonia toxicity in tropical air-breathing fishes exposed to high concentrations of environmental ammonia: a review.

PubMed

Ip, Y K; Chew, S F; Wilson, J M; Randall, D J

2004-10-01

In the tropics, air-breathing fishes can be exposed to environmental ammonia when stranded in puddles of water during the dry season, during a stay inside a burrow, or after agricultural fertilization. At low concentrations of environmental ammonia, NH(3) excretion is impeded, as in aerial exposure, leading to the accumulation of endogenous ammonia. At high concentrations of environmental ammonia, which results in a reversed NH(3) partial pressure gradient (DeltaP(NH3)), there is retention of endogenous ammonia and uptake of exogenous ammonia. In this review, several tropical air-breathing fishes (giant mudskipper, African catfish, oriental weatherloach, swamp eel, four-eyed sleeper, abehaze and slender African lungfish), which can tolerate high environmental ammonia exposure, are used as examples to demonstrate how eight different adaptations can be involved in defence against ammonia toxicity. Four of these adaptations deal with ammonia toxicity at branchial and/or epithelial surfaces: (1) active excretion of NH(4)(+); (2) lowering of environmental pH; (3) low NH(3) permeability of epithelial surfaces; and (4) volatilization of NH(3), while another four adaptations ameliorate ammonia toxicity at the cellular and subcellular levels: (5) high tolerance of ammonia at the cellular and subcellular levels; (6) reduction in ammonia production; (7) glutamine synthesis; and (8) urea synthesis. The responses of tropical air-breathing fishes to high environmental ammonia are determined apparently by behavioural adaptations and the nature of their natural environments.

Metabolites and JAK/STAT pathway were involved in the liver and spleen damage in male Wistar rats fed with mequindox.

PubMed

Wang, Xu; Huang, Xian-Ju; Ihsan, Awais; Liu, Zhao-Ying; Huang, Ling-Li; Zhang, Hua-Hai; Zhang, Hong-Fei; Zhou, Wen; Liu, Qin; Xue, Xi-Juan; Yuan, Zong-Hui

2011-02-27

Mequindox (MEQ) is a novel synthetic quinoxaline 1,4-dioxides antibacterial agent and growth promoter in animal husbandry. This study was to investigate whether reactive oxygen species (ROS), the Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway, suppressors of cytokine signaling (SOCS) and inflammatory cytokines were involved in toxicities of MEQ. Our data demonstrated that high dose of MEQ (275 mg/kg) apparently led to tissue impairment combined with imbalance of redox in liver. In liver and spleen samples, hydroxylation metabolites and desoxymequindox were detected, directly confirming the potential link of N→O group reduction metabolism with its organ toxicity. Moreover, up-regulation of JAK/STAT, SOCS family, tumor necrosis factor (TNF-α) and interleukin-6 (IL-6) were also observed in the high-dose group. Meanwhile, significant changes of oxidative stress indices in liver were observed in the high-dose group. As for NADPH subunit, the mRNA levels of many subunits were significantly up-regulated at low doses but down-regulated in a dose-dependent manner in liver and spleen, suggesting an involvement of NADPH in MEQ metabolism and ROS generation. In conclusion, we reported the dose-dependent long-term toxicity as well as the discussion of the potential mechanism and pathways of MEQ, which raised further awareness of its toxicity following with the dose change. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Adrenergic modulation of hepatotoxicity.

PubMed

Roberts, S M; DeMott, R P; James, R C

1997-01-01

Summaries of the interactions caused by altering adrenoreceptor activity in conjunction with the administration of selected hepatotoxicants are provided in Table 2 and Fig. 1. These hepatotoxicants can be divided into two groups, one whose toxicity is increased by adrenergic agonist drugs (group I) and the other whose toxicity is decreased by adrenergic antagonists (group II). Group I includes carbon tetrachloride, acetaminophen, and methylphenidate. Perhaps the most remarkable aspect these chemicals have in common is the striking potentiation that occurs with cotreatment with certain adrenergic agonist drugs. For each of these, cotreatment with the appropriate adrenergic agent can result in massive hepatocellular necrosis from an otherwise nontoxic dose. In terms of the specific adrenoreceptors involved and mechanisms of potentiation, however, they have little in common. Potentiation of carbon tetrachloride hepatotoxicity appears to be mediated by alpha(2)-adrenoceptor stimulation, acetaminophen is potentiated by alpha(1)-adrenoreceptor agonists, and methylphenidate responds to beta(2)-adrenoreceptor stimulation. Studies of the potentiation of carbon tetrachloride and acetaminophen agree that the timing of adrenergic stimulation relative to the hepatotoxicant dose is critically important to the interaction but markedly different for these two toxicants. Acetaminophen was potentiated only when the adrenergic drug was administered as a 3-h pretreatment. This is apparently a consequence of a mechanism of potentiation that involves adrenergic depression of hepatic glutathione content and a requirement that peak effects on glutathione of both the adrenergic agent and acetaminophen be coincident. The mechanism of potentiation of carbon tetrachloride hepatotoxicity is uncertain but clearly does not involve hepatic glutathione content. In contrast to acetaminophen, adrenergic effects must occur within a time window a few hours after the carbon tetrachloride dose for potentiation to occur. The importance of dose timing has not been evaluated for adrenergic potentiation of methylphenidate hepatotoxicity, but it is clear that this interaction is based on yet a third mechanism. While only three hepatotoxicants of the group I type have been examined in detail, the diversity of receptor types and mechanisms involved suggest that this phenomenon may be relevant for a wide variety of hepatotoxic drugs and chemicals. This interaction is also of interest because factors or events that lead to increased adrenergic stimulation are common in everyday life. Most over-the-counter cold and allergy preparations contain sympathomimetic drugs, and many prescription drugs produce adrenergic effects as either an extension of the intended therapeutic effect or as a side effect. Stress and some disease states can also lead to significant increases in peripheral adrenergic activity, creating the potential for increased susceptibility to hepatic injury from exposure to certain drugs or chemicals. Cocaine and bromobenzene represent group II, chemicals whose hepatotoxicity is diminished by cotreatment with adrenergic antagonist drugs. In the case of cocaine, adrenergic antagonist cotreatment was capable of reducing serum alanine aminotransferase activities by approximately 50%. For bromobenzene, the protection afforded by adrenergic antagonist cotreatment was more profound, with minimal hepatic lesions resulting from doses of bromobenzene that otherwise produced lethal hepatic necrosis. For the chemicals in group II, experimental observations are consistent with a phenomenon in which adrenergic potentiation of toxicity is supplied by the hepatotoxicant itself. Both cocaine and bromobenzene, in hepatotoxic doses increase endogenous catecholamine levels. When the effects of the elevated catecholamines are removed with the appropriate adrenergic antagonist, much lower toxicity (presumably due only to the direct hepatotoxic effects of the drug or chemical) is obse

The Pivotal Role of Aldehyde Toxicity in Autism Spectrum Disorder: The Therapeutic Potential of Micronutrient Supplementation

PubMed Central

Jurnak, Frances

2015-01-01

Autism spectrum disorder (ASD) is characterized by social and communication impairments as well as by restricted, repetitive patterns of behavior and interests. Genomic studies have not revealed dominant genetic errors common to all forms of ASD. So ASD is assumed to be a complex disorder due to mutations in hundreds of common variants. Other theories argue that spontaneous DNA mutations and/or environmental factors contribute to as much as 50% of ASD. In reviewing potential genetic linkages between autism and alcoholism, it became apparent that all theories of ASD are consistent with aldehyde toxicity, in which endogenous and exogenous aldehydes accumulate as a consequence of mutations in key enzymes. Aldehyde toxicity is characterized by cell-localized, micronutrient deficiencies in sulfur-containing antioxidants, thiamine (B1), pyridoxine (B6), folate, Zn2+, possibly Mg2+, and retinoic acid, causing oxidative stress and a cascade of metabolic disturbances. Aldehydes also react with selective cytosolic and membrane proteins in the cell of origin; then some types migrate to damage neighboring cells. Reactive aldehydes also form adducts with DNA, selectively mutating bases and inducing strand breakage. This article reviews the relevant genomic, biochemical, and nutritional literature, which supports the central hypothesis that most ASD symptoms are consistent with symptoms of aldehyde toxicity. The hypothesis represents a paradigm shift in thinking and has profound implications for clinical detection, treatment, and even prevention of ASD. Insight is offered as to which neurologically afflicted children might successfully be treated with micronutrients and which children are unlikely to be helped. The aldehyde toxicity hypothesis likely applies to other neurological disorders. PMID:27330305

Comparative toxicant sensitivity of sexual and asexual reproduction in the rotifer Brachionus calyciflorus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Snell, T.W.; Carmona, M.J.

Cyclically parthenogenetic zooplankters like rotifers are important tools for assessing toxicity in aquatic environments. Sexual reproduction is an essential component of rotifer life cycles, but current toxicity tests utilize only asexual reproduction. The authors compared the effects of four toxicants on asexual and sexual reproduction of the rotifer Brachionus calyciflorus. Toxicants had a differential effect on sexual and asexual reproduction, with sexual reproduction consistently the most sensitive. Concentrations of 0.2 {mu}g/ml PCP (sodium pentachlorophenate) had no effect on the asexual reproductive rate, but significantly reduced sexual reproduction. Likewise, chlorpyrifos concentrations of 0.3 {mu}g/ml had no significant effect on asexual reproduction,more » but sexual reproduction was significantly reduced. There was no difference in NOECs, LOECs, and chronic values for asexual and sexual reproduction for cadmium and naphthol tests. However, comparison of toxicant effect levels revealed that sexual reproduction was more strongly reduced at each toxicant concentration. The four toxicants tested inhibited sexual reproduction 2 to 68 times more than asexual reproduction at the lowest observed effect concentrations. Toxicants inhibited sexual reproduction in its initial step: sexual female production. Because sexual reproduction is more sensitive, toxicity tests based exclusively on asexual reproduction may not be protective of rotifer life cycles.« less

Apparent size contrasts of retinal images and size constancy as determinants of the moon illusion.

PubMed

Smith, O W; Smith, P C; Geist, C C; Zimmermann, R R

1978-06-01

Kaufman and Rock (1962) and Rock and Kaufman (1962) concluded that the moon illusion is a function of and attributable to apparent distance. They also reported a large framing effect as an exception. Analysis of the effect suggests two components which can account for the illusion independently of apparent distance. These are apparent size contrasts of visual images of discriminable features or objects of the earth with the moon's image and size constancy of the features or objects plus the interactions of the two. Apparent distances to horizons are always a consequence of the necessary conditions for the illusion. They are related to the illusion but are not a determinant of it.

Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment: a Delphi consensus.

PubMed

Schmiegelow, Kjeld; Attarbaschi, Andishe; Barzilai, Shlomit; Escherich, Gabriele; Frandsen, Thomas Leth; Halsey, Christina; Hough, Rachael; Jeha, Sima; Kato, Motohiro; Liang, Der-Cherng; Mikkelsen, Torben Stamm; Möricke, Anja; Niinimäki, Riitta; Piette, Caroline; Putti, Maria Caterina; Raetz, Elizabeth; Silverman, Lewis B; Skinner, Roderick; Tuckuviene, Ruta; van der Sluis, Inge; Zapotocka, Ester

2016-06-01

Although there are high survival rates for children with acute lymphoblastic leukaemia, their outcome is often counterbalanced by the burden of toxic effects. This is because reported frequencies vary widely across studies, partly because of diverse definitions of toxic effects. Using the Delphi method, 15 international childhood acute lymphoblastic leukaemia study groups assessed acute lymphoblastic leukaemia protocols to address toxic effects that were to be considered by the Ponte di Legno working group. 14 acute toxic effects (hypersensitivity to asparaginase, hyperlipidaemia, osteonecrosis, asparaginase-associated pancreatitis, arterial hypertension, posterior reversible encephalopathy syndrome, seizures, depressed level of consciousness, methotrexate-related stroke-like syndrome, peripheral neuropathy, high-dose methotrexate-related nephrotoxicity, sinusoidal obstructive syndrome, thromboembolism, and Pneumocystis jirovecii pneumonia) that are serious but too rare to be addressed comprehensively within any single group, or are deemed to need consensus definitions for reliable incidence comparisons, were selected for assessment. Our results showed that none of the protocols addressed all 14 toxic effects, that no two protocols shared identical definitions of all toxic effects, and that no toxic effect definition was shared by all protocols. Using the Delphi method over three face-to-face plenary meetings, consensus definitions were obtained for all 14 toxic effects. In the overall assessment of outcome of acute lymphoblastic leukaemia treatment, these expert opinion-based definitions will allow reliable comparisons of frequencies and severities of acute toxic effects across treatment protocols, and facilitate international research on cause, guidelines for treatment adaptation, preventive strategies, and development of consensus algorithms for reporting on acute lymphoblastic leukaemia treatment. Copyright © 2016 Elsevier Ltd. All rights reserved.

Spectrofluorimetric assay method for glutathione and glutathione transferase using monobromobimane.

PubMed

Yakubu, S I; Yakasai, I A; Musa, A

2011-06-01

The primary role of glutathione transferase is to defend an organism from toxicities through catalyzing the reaction of glutathione (GSH) with potentially toxic compounds or metabolites to their chemically and biologically inert conjugates. The objective of the study was to develop a simple and sensitive spectrofluorimetric assay method for glutathione transferase using monobromobimane (MBB), a non fluorescent compound with electrophilic site. MBB slowly reacted with glutathione to form fluorescent glutathione conjugate and that the reaction was catalysed by glutathione transferase. Both non-enzymatic and enzymatic reaction products of MBB, in presence of GSH in phosphate buffer (pH 6.5), were measured by following increase of fluorescence at wavelength of 475nm. For validation of the assay method, the kinetic parameters such as the apparent Michaelis-Mente constants and maximum rates of conjugate formation as well as the specific activity of rat hepatic glutathione transferase were determined. The method was found to be sensitive, thus, applied to measure glutathione contents of crude preparation of rat hepatic cytosol fraction.

EPA's proposed land ban regulations. Hearing before the Subcommittee on Commerce, Transportation, and Tourism of the Committee on Energy and Commerce, House of Representatives, Ninety-Ninth Congress, Second Session, February 19, 1986

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

1986-01-01

Three representatives of the Environmental Protection Agency (EPA) testified in response to questions over the agency's apparent approval of the land disposal of toxic materials in contradiction to the ban implicit in the Hazardous and Solid Waste Amendments of 1984. In new regulations, EPA interprets the ban as applying only when migration of toxic materials exceeds its screening levels. EPA also cites its screening levels to place a cap on waste treatment. At issue was EPA's effort to avoid the mandate of the 1984 legislation and its acceptance of screening levels which may assume a lower threat than actually exists.more » EPA representatives explained the rulemaking, and defended the use of screening levels as a basis for treatment and exemption. Additional material submitted for the record by the agency and by the House committee follows the testimony.« less

The Effect of Toxic Leadership

DTIC Science & Technology

2012-03-15

traits) and not the disease (culture, climate, outcomes ).3 Several researchers agree that the long-term negative effect that toxic leaders have on an...The Effect of Toxic Leadership by Lieutenant Colonel Darrell W. Aubrey United States Army United States Army War...The Effect of Toxic Leadership 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Lieutenant

Kawasaki disease and toxic shock syndrome--at last the etiology is clear?

PubMed

Curtis, Nigel

2004-01-01

A decade after the superantigen hypothesis for KD was first suggested, it has still not been either proven or refuted conclusively. Although initial optimism for the hypothesis was quashed by a series of published papers apparently refuting the idea, in the last few years there have been a number of good studies providing evidence in support of the superantigen hypothesis. Whether this renewed enthusiasm is justified will hopefully become clear in the near future. Ultimately, accurate diagnosis, more targeted treatment, and preventative strategies depend on the unraveling of the immunopathogenesis of this disease.

Results of a randomized comparison of radiotherapy and bromodeoxyuridine with radiotherapy alone for brain metastases: Report of RTOG trial 89-05

DOE Office of Scientific and Technical Information (OSTI.GOV)

Phillips, T.L.; Scott, C.B.; Leibel, S.A.

1995-09-30

The purpose of this trial was to determine if the addition of bromodeoxyuridine (BrdUrd) to radiotherapy prolongs survival when compared to radiotherapy alone in patients with brain metastases. Seventy-two patients with brain metastases were randomized to 37.5 Gy in 15 fractions of 2.5 Gy or to the same dose with BrdUrd 0.8 g/m{sup 2} per day for 4 days of each of 3 weeks. Patients were stratified by primary site (breast, lung or other), number of metastases (single or multiple) and age (<60 vs. >60). There was no significant difference between the two treatment arms (p = 0.904). The studymore » was open from October 1989 to March 1993 and accrued 72 patients. Only one patient in the RT only arm remains alive. The two treatment arms were balanced with respect to all stratification variables. Toxicity due to radiotherapy was similar in both arms. BrdUrd caused significant Grade 4 and 5 hematologic and skin toxicity in five patients. Two patients died due to hematologic toxicity and one from a Stevens-Johnson type skin reaction. Phenytoin played a role in the skin reactions and ranitidine was associated with the hematologic deaths. Ranitidine was eliminated, BrdUrd was discontinued after any hematologic toxicity, and no further Grade 4 or 5 toxicities were seen. The median survival was 6.12 months in the radiotherapy group and 4.3 in the BrdUrd group (p = 0.904). Patients with solitary brain metastases had significantly better survival (p = 0.031). BrdUrd did not enhance the efficacy of the radiotherapy regiment tested, in spite of the fact that brain metastases have shown high labeling indices. The toxicity of this schedule of BrdUrd administration was apparently increased by ranitidine and phenytoin. 16 refs., 4 figs., 13 tabs.« less

Inhibition of GSK-3 Ameliorates Aβ Pathology in an Adult-Onset Drosophila Model of Alzheimer's Disease

PubMed Central

Killick, Richard; Augustin, Hrvoje; Gandy, Carina; Allen, Marcus J.; Hardy, John; Lovestone, Simon; Partridge, Linda

2010-01-01

Aβ peptide accumulation is thought to be the primary event in the pathogenesis of Alzheimer's disease (AD), with downstream neurotoxic effects including the hyperphosphorylation of tau protein. Glycogen synthase kinase-3 (GSK-3) is increasingly implicated as playing a pivotal role in this amyloid cascade. We have developed an adult-onset Drosophila model of AD, using an inducible gene expression system to express Arctic mutant Aβ42 specifically in adult neurons, to avoid developmental effects. Aβ42 accumulated with age in these flies and they displayed increased mortality together with progressive neuronal dysfunction, but in the apparent absence of neuronal loss. This fly model can thus be used to examine the role of events during adulthood and early AD aetiology. Expression of Aβ42 in adult neurons increased GSK-3 activity, and inhibition of GSK-3 (either genetically or pharmacologically by lithium treatment) rescued Aβ42 toxicity. Aβ42 pathogenesis was also reduced by removal of endogenous fly tau; but, within the limits of detection of available methods, tau phosphorylation did not appear to be altered in flies expressing Aβ42. The GSK-3–mediated effects on Aβ42 toxicity appear to be at least in part mediated by tau-independent mechanisms, because the protective effect of lithium alone was greater than that of the removal of tau alone. Finally, Aβ42 levels were reduced upon GSK-3 inhibition, pointing to a direct role of GSK-3 in the regulation of Aβ42 peptide level, in the absence of APP processing. Our study points to the need both to identify the mechanisms by which GSK-3 modulates Aβ42 levels in the fly and to determine if similar mechanisms are present in mammals, and it supports the potential therapeutic use of GSK-3 inhibitors in AD. PMID:20824130

Evidence of low toxicity of oil sands process-affected water to birds invites re-evaluation of avian protection strategies

PubMed Central

Beck, Elizabeth M.; Smits, Judit E. G.; St Clair, Colleen Cassady

2015-01-01

Exposure to water containing petroleum waste products can generate both overt and subtle toxicological responses in wildlife, including birds. Such exposure can occur in the tailings ponds of the mineable oil sands, which are located in Alberta, Canada, under a major continental flyway for waterfowl. Over the 40 year history of the industry, a few thousand bird deaths have been reported following contact with bitumen on the ponds, but a new monitoring programme demonstrated that many thousands of birds land annually without apparent harm. This new insight creates an urgent need for more information on the sublethal effects on birds from non-bitumen toxicants that occur in the water, including naphthenic acids, polycyclic aromatic hydrocarbons, heavy metals and salts. Ten studies have addressed the effects of oil sands process-affected water (OSPW), and none reported acute or substantial adverse health effects. Interpretive caution is warranted, however, because nine of the studies addressed reclaimed wetlands that received OSPW, not OSPW ponds per se, and differences between experimental and reference sites may have been reduced by shared sources of pollution in the surrounding air and water. Two studies examined eggs of birds nesting >100 km from the mine sites. Only one study exposed birds directly and repeatedly to OSPW and found no consistent differences between treated and control birds in blood-based health metrics. If it is true that aged forms of OSPW do not markedly affect the health of birds that land briefly on the ponds, then the extensiveness of current bird-deterrent programmes is unwarranted and could exert negative net environmental effects. More directed research on bird health is urgently needed, partly because birds that land on these ponds subsequently migrate to destinations throughout North America where they are consumed by both humans and wildlife predators. PMID:27293723

Effects of methomyl on steroidogenic gene transcription of the hypothalamic-pituitary-gonad-liver axis in male tilapia.

PubMed

Meng, ShunLong; Qiu, LiPing; Hu, GengDong; Fan, LiMin; Song, Chao; Zheng, Yao; Wu, Wei; Qu, JianHong; Li, DanDan; Chen, JiaZhang; Xu, Pao

2016-12-01

Male tilapia were exposed to sub-lethal methomyl concentrations of 0, 0.2, 2, 20 or 200 μg/L for 30 d, and were subsequently cultured in methomyl-free water for 18 d. Relative transcript abundance of steroidogenic genes involved in the HPGL axis of male tilapia was examined at 30 d in the exposure test and at 18 d in the recovery test. The results revealed that low concentrations of methomyl (0.2 and 2 μg/L) did not cause significant changes in gene mRNA levels in the HPGL axis of male tilapia; thus, we considered 2 μg/L concentrations as the level that showed no apparent adverse endocrine disruption effects. However, higher concentrations of methomyl (20 and 200 μg/L) disrupted the endocrine system and caused significant increase in the levels of GnRH2, GnRH3, ERα, and ERβ genes in the hypothalamus, GnRHR and FSHβ genes in the pituitary, CYP19a, FSHR, and ERα genes in the testis, and VTG and ERα genes in the liver, and significantly decreased the levels of LHR, StAR, 3β-HSD, and ARα genes in the testis and LHβ gene in the pituitary, leading to changes in sex steroid hormone and vitellogenin levels in the serum and ultimately resulting in reproductive dysfunction in male tilapia. The recovery tests showed that the toxicity effect caused by 20 μg/L methomyl was reversible; however, the toxicity effect at 200 μg/L of methomyl was irreversible after 18 d. Therefore, we concluded that 200 μg/L was the threshold concentration for methomyl-induced irreversible endocrine disruption in male tilapia. Copyright © 2016 Elsevier Ltd. All rights reserved.

Evidence of low toxicity of oil sands process-affected water to birds invites re-evaluation of avian protection strategies.

PubMed

Beck, Elizabeth M; Smits, Judit E G; St Clair, Colleen Cassady

2015-01-01

Exposure to water containing petroleum waste products can generate both overt and subtle toxicological responses in wildlife, including birds. Such exposure can occur in the tailings ponds of the mineable oil sands, which are located in Alberta, Canada, under a major continental flyway for waterfowl. Over the 40 year history of the industry, a few thousand bird deaths have been reported following contact with bitumen on the ponds, but a new monitoring programme demonstrated that many thousands of birds land annually without apparent harm. This new insight creates an urgent need for more information on the sublethal effects on birds from non-bitumen toxicants that occur in the water, including naphthenic acids, polycyclic aromatic hydrocarbons, heavy metals and salts. Ten studies have addressed the effects of oil sands process-affected water (OSPW), and none reported acute or substantial adverse health effects. Interpretive caution is warranted, however, because nine of the studies addressed reclaimed wetlands that received OSPW, not OSPW ponds per se, and differences between experimental and reference sites may have been reduced by shared sources of pollution in the surrounding air and water. Two studies examined eggs of birds nesting >100 km from the mine sites. Only one study exposed birds directly and repeatedly to OSPW and found no consistent differences between treated and control birds in blood-based health metrics. If it is true that aged forms of OSPW do not markedly affect the health of birds that land briefly on the ponds, then the extensiveness of current bird-deterrent programmes is unwarranted and could exert negative net environmental effects. More directed research on bird health is urgently needed, partly because birds that land on these ponds subsequently migrate to destinations throughout North America where they are consumed by both humans and wildlife predators.

Translation of Toxicity Data into CW Agent Toxicity Estimates

DTIC Science & Technology

2003-07-01

UNLIMITED UNCLASSIFIED/UNLIMITEDPrepared by Douglas R. Sommerville, PE US Army ECBC, APG, MD Dependence of Toxic Effect on Exposure Time Inhalation (IH...to longer exposure durations. Toxicity estimates for exposure durations ranging from 2 to 360 minutes have been derived for six agents (GA, GB, GD...individuals having effects greater in severity than the defining effect of the ECTYY Cn T = k Toxic load equation 5 6 Edgewood Chemical Biological Center

Inhibition of DNA replication in Saccharomyces cerevisiae by araCMP.

PubMed

McIntosh, E M; Kunz, B A; Haynes, R H

1986-01-01

Cytosine arabinoside (araC), a potent inhibitor of DNA replication in mammalian cells, was found to be completely ineffective in Saccharomyces cerevisiae. The 5' monophosphate derivative, araCMP, is toxic and effectively inhibits both nuclear and mitochondrial DNA synthesis in this organism. Although wild-type strains can be inhibited by araCMP, dTMP permeable (tup-) strains were found to be much more sensitive to the analogue. In vivo labelling experiments indicate that araC enters yeast cells; however, it is extensively catabolized by deamination and breakage of the glycosidic bond. In addition, the analogue is not efficiently phosphorylated in S. cerevisiae owing to an apparent lack of deoxynucleoside kinase activity. These results provide further evidence that deoxyribonucleotides can be synthesized only through de novo pathways in this organism. Finally, araCMP was found to be recombinagenic in S. cerevisiae which suggests, together with other previous studies, that, in general, inhibition of DNA synthesis in yeast promotes mitotic recombination events.

Results from the NOAA National Status and Trends Program on distribution and effects of chemical contamination in the coastal and estuarine United States.

PubMed

O'Connor, T P; Ehler, C N

1991-04-01

The NOAA National Status and Trends (NS&T) Program has been monitoring chemical contamination in fish livers, and surface sediments since 1984 and in molluscan tissue and sediments since 1986. Data from fine-grained sediment at 175 sites are used to describe the spatial distribution of contamination throughout the coastal and estuarine United States. Highest levels are generally found in, and considered representative of, urban areas. It should be noted, however, that these levels are not as high as have been found near discharge pipes or in isolated industrial areas through other monitoring efforts. Dramatic biological responses, such as liver tumors in fish or apparently toxic contaminant levels in sediment, are found infrequently. Subtle biological changes, especially those that affect reproductive ability, are being sought. Data from three annual collections of mollusks have been used to identify early signals of temporal trends in contamination at NS&T sites.

The biodistribution and toxicity of plutonium, americium and neptunium.

PubMed

Taylor, D M

1989-07-15

In the nuclear fuel cycle the transuranic radionuclides plutonium-239, americium-241 and neptunium-237 would probably present the most serious hazard to human health if released into the environment. Despite differences in their solution chemistry the three elements exhibit remarkable similarity in their biochemical behaviour, apparently sharing similar transport pathways in blood and cells. After entering the blood the elements deposit predominantly in liver and skeleton, where retention appears to be prolonged, with half-times of the order of years. The principal late effects of all three radionuclides are the induction of cancers of bone, lung or liver. For the latter tumours the induction risk per unit radiation dose appears similar for the three radionuclides. But in bone there are indications that, due to microscopic differences in the distribution of the alpha-particle radiation dose, the efficiency of bone cancer induction may increase in the order americium-241 less than plutonium-239 less than neptunium-237. No case of human cancer induced by these radionuclides is known.

Dual Use of Cigarettes, Little Cigars, Cigarillos, and Large Cigars: Smoking Topography and Toxicant Exposure

PubMed Central

Pickworth, Wallace B.; Rosenberry, Zachary R.; O’Grady, Kevin E.; Koszowski, Bartosz

2017-01-01

Objective Smoking topography variables and toxicant exposure (plasma nicotine and exhaled CO) were examined in 3 groups of study participants that smoked both cigarettes and either filtered little cigars (Winchester), cigarillos (Black & Mild), or large cigars (Phillies Blunt). Methods Laboratory ad lib smoking of the cigar products was collected with a smoking puff analyzer; plasma levels of nicotine and exhaled CO were collected before and after smoking. Results Although there were no statistically significant differences in demographic and cigarette smoking topography among the groups, there were significant differences in how the different cigar products were smoked. Plasma nicotine boost was similar after all products but exhaled CO was greater after the cigarillo and large cigar than the little cigar. Some of the differences were due to the differences in article size but other differences were apparent even after adjustment for the amount of tobacco burned or the mouth intake (puff volume). Conclusions The topography findings of differences among products challenge the practice of grouping cigars as a single entity in surveys, regulatory decisions, and discussions of toxicant exposure. The results add to the discussion of distinctions among products in the scientific assessment of public health risk and regulatory decisions. PMID:28966952

Preventive effects of phytoestrogens against postmenopausal osteoporosis as compared to the available therapeutic choices: An overview

PubMed Central

Al-Anazi, Abdullah Foraih; Qureshi, Viquar Fatima; Javaid, Khalida; Qureshi, Shoeb

2011-01-01

Estrogen deficiency is a major risk factor for osteoporosis in postmenopausal women. Although hormone replacement therapy (HRT) has been rampantly used to recompense for the bone loss, but the procedure is coupled with severe adverse effects. Hence, there is a boost in the production of newer synthetic products to ward off the effects of menopause-related osteoporosis. As of today, there are several prescription products available for the treatment of postmenopause osteoporosis; most of these are estrogenic agents and combination products. Nevertheless, in view of the lack of effect and/or toxicity of these products, majority of the postmenopausal women are now fascinated by highly publicized natural products. This is an offshoot of the generalized consensus that these products are more effective and free from any adverse effects. Recently, certain plant-derived natural products, mostly phytoestrogens (isoflavones, lignans, coumestanes, stilbenes, flavonoids) and many more novel estrogen-like compounds in plants have been immensely used to prevent menopause-related depletion in bone mineral density (BMD). Although, a number of papers are published on menopause-related general symptoms, sexual dysfunction, cardiovascular diseases, Alzheimer's disease, diabetes, colon, and breast cancers, there is paucity of literature on the accompanying osteoporosis and its treatment. In view of the controversies on synthetic hormones and drugs and drift of a major population of patients toward natural drugs, it was found worthwhile to investigate if these drugs are suitable to be used in the treatment of postmenopausal osteoporosis. Preparation of this paper is an attempt to review the (a) epidemiology of postmenopausal osteoporosis, (b) treatment modalities of postmenopausal osteoporosis by hormones and synthetic drugs and the associated drawbacks and adverse effects, and (c) prevention and treatment of postmenopausal osteoporosis by phytoestrogens, their drawbacks and toxicity. It is apparent that both the categories of treatment are useful and both have adverse effects, but the plant products are nonscientific and hence are not advised to be used till more studies are undertaken to ensure that the benefits clearly outweigh the risk, in addition to recognition by Food and Drug Administration. PMID:22346228

Ecological impacts of lead mining on Ozark streams: toxicity of sediment and pore water.

PubMed

Besser, John M; Brumbaugh, William G; Allert, Ann L; Poulton, Barry C; Schmitt, Christopher J; Ingersoll, Christopher G

2009-02-01

We studied the toxicity of sediments downstream of lead-zinc mining areas in southeast Missouri, using chronic sediment toxicity tests with the amphipod, Hyalella azteca, and pore-water toxicity tests with the daphnid, Ceriodaphnia dubia. Tests conducted in 2002 documented reduced survival of amphipods in stream sediments collected near mining areas and reduced survival and reproduction of daphnids in most pore waters tested. Additional amphipod tests conducted in 2004 documented significant toxic effects of sediments from three streams downstream of mining areas: Strother Creek, West Fork Black River, and Bee Fork. Greatest toxicity occurred in sediments from a 6-km reach of upper Strother Creek, but significant toxic effects occurred in sediments collected at least 14 km downstream of mining in all three watersheds. Toxic effects were significantly correlated with metal concentrations (nickel, zinc, cadmium, and lead) in sediments and pore waters and were generally consistent with predictions of metal toxicity risks based on sediment quality guidelines, although ammonia and manganese may also have contributed to toxicity at a few sites. Responses of amphipods in sediment toxicity tests were significantly correlated with characteristics of benthic invertebrate communities in study streams. These results indicate that toxicity of metals associated with sediments contributes to adverse ecological effects in streams draining the Viburnum Trend mining district.

Ecological impacts of lead mining on Ozark streams: Toxicity of sediment and pore water

USGS Publications Warehouse

Besser, J.M.; Brumbaugh, W.G.; Allert, A.L.; Poulton, B.C.; Schmitt, C.J.; Ingersoll, C.G.

2009-01-01

We studied the toxicity of sediments downstream of lead-zinc mining areas in southeast Missouri, using chronic sediment toxicity tests with the amphipod, Hyalella azteca, and pore-water toxicity tests with the daphnid, Ceriodaphnia dubia. Tests conducted in 2002 documented reduced survival of amphipods in stream sediments collected near mining areas and reduced survival and reproduction of daphnids in most pore waters tested. Additional amphipod tests conducted in 2004 documented significant toxic effects of sediments from three streams downstream of mining areas: Strother Creek, West Fork Black River, and Bee Fork. Greatest toxicity occurred in sediments from a 6-km reach of upper Strother Creek, but significant toxic effects occurred in sediments collected at least 14 km downstream of mining in all three watersheds. Toxic effects were significantly correlated with metal concentrations (nickel, zinc, cadmium, and lead) in sediments and pore waters and were generally consistent with predictions of metal toxicity risks based on sediment quality guidelines, although ammonia and manganese may also have contributed to toxicity at a few sites. Responses of amphipods in sediment toxicity tests were significantly correlated with characteristics of benthic invertebrate communities in study streams. These results indicate that toxicity of metals associated with sediments contributes to adverse ecological effects in streams draining the Viburnum Trend mining district.

Selective Effect of 2′,6′-Dihydroxy-4′-Methoxychalcone Isolated from Piper aduncum on Leishmania amazonensis

PubMed Central

Torres-Santos, Eduardo Caio; Moreira, Davyson Lima; Kaplan, Maria Auxiliadora C.; Meirelles, Maria Nazareth; Rossi-Bergmann, Bartira

1999-01-01

2′,6′-Dihydroxy-4′-methoxychalcone (DMC) was purified from the dichloromethane extract of Piper aduncum inflorescences. DMC showed significant activity in vitro against promastigotes and intracellular amastigotes of Leishmania amazonensis, with 50% effective doses of 0.5 and 24 μg/ml, respectively. Its inhibitory effect on amastigotes is apparently a direct effect on the parasites and is not due to activation of the nitrogen oxidative metabolism of macrophages, since the production of nitric oxide by both unstimulated and recombinant gamma interferon-stimulated macrophages was decreased rather than increased with DMC. The phagocytic activity of macrophages was functioning normally even with DMC concentrations as high as 80 μg/ml, as seen by electron microscopy and by the uptake of fluorescein isothiocyanate-labeled beads. Ultrastructural studies also showed that in the presence of DMC the mitochondria of promastigotes were enlarged and disorganized. Despite destruction of intracellular amastigotes, no disarrangement of macrophage organelles were observed, even at 80 μg of DMC/ml. These observations suggest that DMC is selectively toxic to the parasites. Its simple structure may well enable it to serve as a new lead compound for the synthesis of novel antileishmanial drugs. PMID:10223942

The impact of zero-valent iron nanoparticles upon soil microbial communities is context dependent.

PubMed

Pawlett, Mark; Ritz, Karl; Dorey, Robert A; Rocks, Sophie; Ramsden, Jeremy; Harris, Jim A

2013-02-01

Nanosized zero-valent iron (nZVI) is an effective land remediation tool, but there remains little information regarding its impact upon and interactions with the soil microbial community. nZVI stabilised with sodium carboxymethyl cellulose was applied to soils of three contrasting textures and organic matter contents to determine impacts on soil microbial biomass, phenotypic (phospholipid fatty acid (PLFA)), and functional (multiple substrate-induced respiration (MSIR)) profiles. The nZVI significantly reduced microbial biomass by 29 % but only where soil was amended with 5 % straw. Effects of nZVI on MSIR profiles were only evident in the clay soils and were independent of organic matter content. PLFA profiling indicated that the soil microbial community structure in sandy soils were apparently the most, and clay soils the least, vulnerable to nZVI suggesting a protective effect imparted by clays. Evidence of nZVI bactericidal effects on Gram-negative bacteria and a potential reduction of arbuscular mycorrhizal fungi are presented. Data imply that the impact of nZVI on soil microbial communities is dependent on organic matter content and soil mineral type. Thereby, evaluations of nZVI toxicity on soil microbial communities should consider context. The reduction of AM fungi following nZVI application may have implications for land remediation.

The Read-Across Hypothesis and Environmental Risk Assessment of Pharmaceuticals

PubMed Central

2013-01-01

Pharmaceuticals in the environment have received increased attention over the past decade, as they are ubiquitous in rivers and waterways. Concentrations are in sub-ng to low μg/L, well below acute toxic levels, but there are uncertainties regarding the effects of chronic exposures and there is a need to prioritise which pharmaceuticals may be of concern. The read-across hypothesis stipulates that a drug will have an effect in non-target organisms only if the molecular targets such as receptors and enzymes have been conserved, resulting in a (specific) pharmacological effect only if plasma concentrations are similar to human therapeutic concentrations. If this holds true for different classes of pharmaceuticals, it should be possible to predict the potential environmental impact from information obtained during the drug development process. This paper critically reviews the evidence for read-across, and finds that few studies include plasma concentrations and mode of action based effects. Thus, despite a large number of apparently relevant papers and a general acceptance of the hypothesis, there is an absence of documented evidence. There is a need for large-scale studies to generate robust data for testing the read-across hypothesis and developing predictive models, the only feasible approach to protecting the environment. PMID:24006913

Evaluation of five antibiotics on larval gut bacterial diversity of Plutella xylostella (Lepidoptera: Plutellidae).

PubMed

Lin, Xiao-Li; Kang, Zhi-Wei; Pan, Qin-Jian; Liu, Tong-Xian

2015-10-01

Larvae of the diamondback moth, Plutella xylostella L. (Lepidoptera: Plutellidae), have rich microbial communities inhabiting the gut, and these bacteria contribute to the fitness of the pest. In this study we evaluated the effects of five antibiotics (rifampicin, ampicillin, tetracycline, streptomycin sulfate and chloramphenicol) on the gut bacterial diversity of P. xylostella larvae. We screened five different concentrations for each antibiotic in a leaf disc assay, and found that rifampicin and streptomycin sulfate at 3 mg/mL significantly reduced the diversity of the bacterial community, and some bacterial species could be rapidly eliminated. The number of gut bacteria in the rifampicin group and streptomycin sulfate group decreased more rapidly than the others. With the increase of antibiotic concentration, the removal efficiency was improved, whereas toxic effects became more apparent. All antibiotics reduced larval growth and development, and eventually caused high mortality, malformation of the prepupae, and hindered pupation and adult emergence. Among the five antibiotics, tetracycline was the most toxic and streptomycin sulfate was a relatively mild one. Some dominant bacteria were not affected by feeding antibiotics alone. Denaturing gradient gel electrophoresis graph showed that the most abundant and diverse bacteria in P. xylostella larval gut appeared in the cabbage feeding group, and diet change and antibiotics intake influenced gut flora abundance. Species diversity was significantly reduced in the artificial diet and antibiotics treatment groups. After feeding on the artificial diet with rifampicin, streptomycin sulfate and their mixture for 10 days, larval gut bacteria could not be completely removed as detected with the agarose gel electrophoresis method. © 2014 Institute of Zoology, Chinese Academy of Sciences.

Ochratoxin A induces rat renal carcinogenicity with limited induction of oxidative stress responses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Qi, Xiaozhe; Yu, Tao; Zhu, Liye

Ochratoxin A (OTA) has displayed nephrotoxicity and renal carcinogenicity in mammals, however, no clear mechanisms have been identified detailing the relationship between oxidative stress and these toxicities. This study was performed to clarify the relationship between oxidative stress and the renal carcinogenicity induced by OTA. Rats were treated with 70 or 210 μg/kg b.w. OTA for 4 or 13 weeks. In the rats administrated with OTA for 13 weeks, the kidney was damaged seriously. Cytoplasmic vacuolization was observed in the outer stripe of the outer medulla. Karyomegaly was prominent in the tubular epithelium. Kidney injury molecule-1 (Kim-1) was detected inmore » the outer stripe of the outer medulla in both low- and high-dose groups. OTA increased the mRNA levels of clusterin in rat kidneys. Interestingly, OTA did not significantly alter the oxidative stress level in rat liver and kidney. Yet, some indications related to proliferation and carcinogenicity were observed. A dose-related increase in proliferating cell nuclear antigen (PCNA) was observed at 4 weeks in both liver and kidney, but at 13 weeks, only in the kidney. OTA down-regulated reactive oxygen species (ROS) and up-regulated vimentin and lipocalin 2 in rat kidney at 13 weeks. The p53 gene was decreased in both liver and kidney at 13 weeks. These results suggest that OTA caused apparent kidney damage within 13 weeks but exerted limited effect on oxidative stress parameters. It implies that cell proliferation is the proposed mode of action for OTA-induced renal carcinogenicity. - Highlights: • We studied OTA toxicities in both the rat liver and kidney for 13 weeks. • OTA exerts limited effects on oxidative stress in the rat liver and kidney. • OTA induced renal carcinogenicity resulting from cell proliferation.« less

High-Throughput Library Screening Identifies Two Novel NQO1 Inducers in Human Lung Cells

PubMed Central

Marquardt, Gaby; Massimi, Aldo B.; Shi, Miao; Han, Weiguo; Spivack, Simon D.

2012-01-01

Many phytochemicals possess antioxidant and cancer-preventive properties, some putatively through antioxidant response element–mediated phase II metabolism, entailing mutagen/oxidant quenching. In our recent studies, however, most candidate phytochemical agents were not potent in inducing phase II genes in normal human lung cells. In this study, we applied a messenger RNA (mRNA)–specific gene expression–based high throughput in vitro screening approach to discover new, potent plant-derived phase II inducing chemopreventive agents. Primary normal human bronchial epithelial (NHBE) cells and immortalized human bronchial epithelial cells (HBECs) were exposed to 800 individual compounds in the MicroSource Natural Products Library. At a level achievable in humans by diet (1.0 μM), 2,3-dihydroxy-4-methoxy-4′-ethoxybenzophenone (DMEBP), triacetylresveratrol (TRES), ivermectin, sanguinarine sulfate, and daunorubicin induced reduced nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1 (NQO1) mRNA and protein expression in NHBE cells. DMEBP and TRES were the most attractive agents as coupling potency and low toxicity for induction of NQO1 (mRNA level, ≥3- to 10.8-fold that of control; protein level, ≥ two- to fourfold that of control). Induction of glutathione S-transferase pi mRNA expression was modest, and none was apparent for glutathione S-transferase pi protein expression. Measurements of reactive oxygen species and glutathione/oxidized glutathione ratio showed an antioxidant effect for DMEBP, but no definite effect was found for TRES in NHBE cells. Exposure of NHBE cells to H2O2 induced nuclear translocation of nuclear factor erythroid 2–related factor 2, but this translocation was not significantly inhibited by TRES and DMEBP. These studies show that potency and low toxicity may align for two potential NQO1-inducing agents, DMEBP and TRES. PMID:22021338

Cardiopulmonary responses of intratracheally instilled tire particles and constituent metal components

USGS Publications Warehouse

Gottipolu, R.R.; Landa, E.R.; Schladweiler, M.C.; McGee, J.K.; Ledbetter, A.D.; Richards, J.H.; Wallenborn, G.J.; Kodavanti, U.P.

2008-01-01

Tire and brake wear particles contain transition metals, and contribute to near-road PM. We hypothesized that acute cardiopulmonary injury from respirable tire particles (TP) will depend on the amount of soluble metals. Respirable fractions of two types of TP (TP1 and TP2) were analyzed for water and acid-leachable metals using ICP-AES. Both TP types contained a variety of transition metals, including zinc (Zn), copper (Cu), aluminum, and iron. Zn and Cu were detected at high levels in water-soluble fractions (TP2 > TP1). Male Wistar Kyoto rats (12-14 wk) were intratracheally instilled, in the first study, with saline, TP1 or TP2 (5 mg/kg), and in the second study, with soluble Zn, Cu (0.5 ??mol/kg), or both. Pulmonary toxicity and cardiac mitochondrial enzymes were analyzed 1 d, 1 wk, or 4 wk later for TP and 4 or 24 h later for metals. Increases in lavage fluid markers of inflammation and injury were observed at d 1 (TP2 > TP1), but these changes reversed by wk 1. No effects on cardiac enzymes were noted with either TP. Exposure of rats to soluble Zn and Cu caused marked pulmonary inflammation and injury but temporal differences were apparent (Cu effects peaked at 4 h and Zn at 24 h). Instillation of Zn, Cu, and Zn+ Cu decreased the activity of cardiac aconitase, isocitrate dehydrogenase, succinate dehydrogenase, cytochrome-c-oxidase and superoxide dismutase suggesting mitochondrial oxidative stress. The observed acute pulmonary toxicity of TP could be due to the presence of water soluble Zn and Cu. At high concentrations these metals may induce cardiac oxidative stress. Copyright ?? Informa Healthcare USA, Inc.

Dual-modality, fluorescent, PLGA encapsulated bismuth nanoparticles for molecular and cellular fluorescence imaging and computed tomography.

PubMed

Swy, Eric R; Schwartz-Duval, Aaron S; Shuboni, Dorela D; Latourette, Matthew T; Mallet, Christiane L; Parys, Maciej; Cormode, David P; Shapiro, Erik M

2014-11-07

Reports of molecular and cellular imaging using computed tomography (CT) are rapidly increasing. Many of these reports use gold nanoparticles. Bismuth has similar CT contrast properties to gold while being approximately 1000-fold less expensive. Herein we report the design, fabrication, characterization, and CT and fluorescence imaging properties of a novel, dual modality, fluorescent, polymer encapsulated bismuth nanoparticle construct for computed tomography and fluorescence imaging. We also report on cellular internalization and preliminary in vitro and in vivo toxicity effects of these constructs. 40 nm bismuth(0) nanocrystals were synthesized and encapsulated within 120 nm Poly(dl-lactic-co-glycolic acid) (PLGA) nanoparticles by oil-in-water emulsion methodologies. Coumarin-6 was co-encapsulated to impart fluorescence. High encapsulation efficiency was achieved ∼70% bismuth w/w. Particles were shown to internalize within cells following incubation in culture. Bismuth nanocrystals and PLGA encapsulated bismuth nanoparticles exhibited >90% and >70% degradation, respectively, within 24 hours in acidic, lysosomal environment mimicking media and both remained nearly 100% stable in cytosolic/extracellular fluid mimicking media. μCT and clinical CT imaging was performed at multiple X-ray tube voltages to measure concentration dependent attenuation rates as well as to establish the ability to detect the nanoparticles in an ex vivo biological sample. Dual fluorescence and CT imaging is demonstrated as well. In vivo toxicity studies in rats revealed neither clinically apparent side effects nor major alterations in serum chemistry and hematology parameters. Calculations on minimal detection requirements for in vivo targeted imaging using these nanoparticles are presented. Indeed, our results indicate that these nanoparticles may serve as a platform for sensitive and specific targeted molecular CT and fluorescence imaging.

Effect of soil cadmium on growth, photosynthesis and quality of Raphanus sativus and Lactuca sativa.

PubMed

Kaur, Navjyot; Jhanji, Shalini

2016-09-01

Cadmium (Cd) raises serious concerns as its accumulation in the plant not only affect the growth and quality of plant but also threaten the health of consumers. In this research, two vegetables, i.e., radish (Raphanus sativus L.) and lettuce (Lactuca sativa L), were planted in pots having soil treated with Cd as Cd (NO3)2 at different doses (25, 50, 100 and 200 mg Cd kg-1 soil ) to investigate the influence of cadmium on their growth, photosynthetic attributes and quality. Cadmium retarded plant growth as dry weight of radish roots decline by 87% and leaves by 83% following 200 mg Cd kg-1 soil application and the corresponding values for lettuce were 64 and 69% respectively. Significant reductions in various photosynthetic parameters viz., leaf area per plant, total chlorophyll, Chl a and Chl b content were also recorded with Cd applications. The Cd treatments resulted in loss of membrane integrity as revealed by significant increase in electrolyte leakage in leaves of both vegetables. There was significant increase in Cd accumulation in radish and lettuce with all applications but no visual symptoms of Cd toxicity were noticed with 25 and 50 mg Cd kg-1 soil application except for yield differences, illustrating that Cd accumulate in this crop without visual evidence of its presence. However, toxicity symptoms in the form of interveinal chlorosis of the leaf lamina, followed by necrosis and leaf rolling, were clearly evident with 100 and 200 mg Cd kg-1 soil application. Apparently, Cd causes harm due to its phytotoxic effects and high accumulation in edible parts of radish and lettuce without any visible symptoms that constitutes a substantial hazard to human health.

Effect of Low pH and Aluminum Toxicity on the Photosynthetic Characteristics of Different Fast-Growing Eucalyptus Vegetatively Propagated Clones

PubMed Central

Yang, Mei; Tan, Ling; Xu, Yuanyuan; Zhao, Yihui; Cheng, Fei; Ye, Shaoming; Jiang, Weixin

2015-01-01

Knowing how acid soils and aluminum in soils may limit the growth of Eucalyptus trees in plantations is important because these plantations grow in many tropical and subtropical regions. Seedlings of four vegetatively propagated Eucalyptus clones, E. grandis × E. urophylla ‘GLGU9’(G9), E. grandis × E. urophylla ‘GLGU12’ (G12), E. urophylla × E. camaldulensis ‘GLUC3’ (G3) and E. urophylla ‘GLU4’(G4), were subjected to liquid culture with Hoagland nutrient solution for 40 days, then treated with four different treatments of acid and aluminum for 1 day. The four treatments used either pH 3.0 or 4.0 with or without added aluminum (4.4 mM) in all possible combinations; a control used no added aluminum at pH 4.8. Subsequently, the photosynthetic parameters and morphology of leaves from eucalypt seedlings were determined and observed. The results showed that the tested chlorophyll content, net photosynthetic rate, transpiration rate and water use efficiency were apparently inhibited by aluminum. Under uniform Al concentration (4.4 mM), the Al-induced limitation to photosynthetic parameters increased with pH, indicating acid stimulation to Al toxicity. Among all treatments, the most significant reduction was found in the combination of pH 3.0 and 4.4 mM Al. The photosynthetic and transpiration rates showed similar trends with G9 > G12 > G3 > G4, suggesting that G9 and G12 had higher Al-tolerance than other two clones. Microscopic observation revealed changes in leaf morphology when exposed to Al stress; for example, a reduced thickness of leaf epidermis and palisade tissue, the descendant palisade tissue/spongy tissue ratio and leaf tissue looseness. Overall, the acid and aluminum stress exerted negative effects on the photosynthetic activity of eucalypt seedlings, but the differences in tolerance to Al toxicity between the clones were favorable, offering potential to improve Eucalyptus plantation productivity by selecting Al tolerant clones. PMID:26090998

Antibacterial mechanisms of a novel type picosecond laser-generated silver-titanium nanoparticles and their toxicity to human cells

PubMed Central

Korshed, Peri; Li, Lin; Liu, Zhu; Mironov, Aleksandr; Wang, Tao

2018-01-01

In this study, we explored the antibacterial mechanisms for a novel type of Ag-TiO2 compound nanoparticles (NPs) produced from an Ag-TiO2 alloy using a picosecond laser and evaluated the toxicity of the Ag-TiO2 NPs to a range of human cell types. Transmission electron microscopy was used to determine the morphology, shapes, and size distribution of the laser-generated Ag-TiO2 NPs. UV-visible spectrometer was used to confirm the shift of light absorbance of the NPs toward visible light wavelength. Results showed that the laser-generated Ag-TiO2 NPs had significant antibacterial activities against both Gram-negative and Gram-positive bacterial strains, including Escherichia coli, Pseudomonas aeruginosa, and the methicillin-resistant Staphylococcus aureus. Increased level of reactive oxygen species was produced by E. coli after exposure to the Ag-TiO2 NPs, which was accompanied with lipid peroxidation, glutathione depletion, disintegration of cell membrane and protein leakage, leading to the cell death. Five types of human cells originated from lung (A549), liver (HePG2), kidney (HEK293), endothelium cells (human coronary artery endothelial cells [hCAECs]), and skin (human dermal fibroblast cells [HDFc]) were used to evaluate the cytotoxicity of the laser-generated Ag-TiO2 NPs. A weak but statistically significant decrease in cell proliferation was observed for hCAECs, A549 and HDFc cells when co-cultured with 2.5 µg/mL or 20 µg/mL of the laser-generated Ag-TiO2 NPs for 48 hours. However, this effect was no longer apparent when a higher concentration of NPs (20 µg/mL) was used after 72 hours of co-culture with human cells, suggesting a possible adaptive process in the cells had occurred. We conclude that picosecond laser-generated Ag-TiO2 NPs have a broad spectrum of antibacterial effect, including against the drug-resistant strain, with multiple underlying molecular mechanisms and low human cell toxicity. The antimicrobial properties of the new type of picoseconds laser-generated Ag-TiO2 compound NPs could have potential biomedical applications. PMID:29317818

Antibacterial mechanisms of a novel type picosecond laser-generated silver-titanium nanoparticles and their toxicity to human cells.

PubMed

Korshed, Peri; Li, Lin; Liu, Zhu; Mironov, Aleksandr; Wang, Tao

2018-01-01

In this study, we explored the antibacterial mechanisms for a novel type of Ag-TiO 2 compound nanoparticles (NPs) produced from an Ag-TiO 2 alloy using a picosecond laser and evaluated the toxicity of the Ag-TiO 2 NPs to a range of human cell types. Transmission electron microscopy was used to determine the morphology, shapes, and size distribution of the laser-generated Ag-TiO 2 NPs. UV-visible spectrometer was used to confirm the shift of light absorbance of the NPs toward visible light wavelength. Results showed that the laser-generated Ag-TiO 2 NPs had significant antibacterial activities against both Gram-negative and Gram-positive bacterial strains, including Escherichia coli, Pseudomonas aeruginosa , and the methicillin-resistant Staphylococcus aureus . Increased level of reactive oxygen species was produced by E. coli after exposure to the Ag-TiO 2 NPs, which was accompanied with lipid peroxidation, glutathione depletion, disintegration of cell membrane and protein leakage, leading to the cell death. Five types of human cells originated from lung (A549), liver (HePG2), kidney (HEK293), endothelium cells (human coronary artery endothelial cells [hCAECs]), and skin (human dermal fibroblast cells [HDFc]) were used to evaluate the cytotoxicity of the laser-generated Ag-TiO 2 NPs. A weak but statistically significant decrease in cell proliferation was observed for hCAECs, A549 and HDFc cells when co-cultured with 2.5 µg/mL or 20 µg/mL of the laser-generated Ag-TiO 2 NPs for 48 hours. However, this effect was no longer apparent when a higher concentration of NPs (20 µg/mL) was used after 72 hours of co-culture with human cells, suggesting a possible adaptive process in the cells had occurred. We conclude that picosecond laser-generated Ag-TiO 2 NPs have a broad spectrum of antibacterial effect, including against the drug-resistant strain, with multiple underlying molecular mechanisms and low human cell toxicity. The antimicrobial properties of the new type of picoseconds laser-generated Ag-TiO 2 compound NPs could have potential biomedical applications.

Promising new technology for managing diamondback moth (Lepidoptera: Plutellidae) in cabbage with pheromone.

PubMed

Mitchell, Everett R

2002-05-01

Experiments were conducted in plantings of cabbage in spring 1999 and 2000 to evaluate a novel, new matrix system for delivering sex pheromone to suppress sexual communication by diamondback moth, Plutella xylostella (L.). The liquid, viscous, slow-release formulation contained a combination of diamondback moth pheromone, a blend of Z-11-hexadecenyl acetate, 27%:Z-11-hexadecen-1-ol, 1%:Z-11-tetradecen-1-ol, 9%:Z-11-hexadecenal, 63%, and the insecticide permethrin (0.16% and 6% w/w of total formulated material, respectively). Field trapping experiments showed that the lure-toxicant combination was highly attractive to male moths for at least four weeks using as little as a 0.05 g droplet of formulated material per trap; and the permethrin insecticide had no apparent influence on response of moths to lure baited traps. Small field plots of cabbage were treated with the lure-toxicant-matrix combination using droplets of 0.44 and 0.05 g each applied to cabbage in a grid pattern at densities ranging from 990 to 4396 droplets/ha to evaluate the potential for disrupting sexual communication of diamondback moth. There was no significant difference in the level of suppression of sexual communication of diamondback moth, as measured by captures of males in pheromone-baited traps located in the treated plots, versus moths captured in untreated control plots, among the treatments regardless of droplet size (0.05 or 0.44 g) or number of droplets applied per ha. Plots treated with the smallest droplet size (0.05 g) and with the fewest number of droplets per ha (990) suppressed captures of male diamondback moths > 90% for up to 3 weeks post treatment. Although laboratory assays showed that the lure-toxicant combination was 100% effective at killing the diamondback moth, the mode of action in the field trials was not determined. The results indicate that the liquid, viscous, slow release formulation containing diamondback moth pheromone could be used to effectively suppress sexual communication of this pest in cabbage and other crucifers, although as many as three applications probably would be required for suppression over an entire growing season.

A chromogranin A ELISA absent of an apparent high-dose hook effect observed in other chromogranin A ELISAs.

PubMed

Erickson, J Alan; Grenache, David G

2016-01-15

Routine testing for chromogranin A (CgA) using an established commercial ELISA revealed an apparent high-dose hook effect in approximately 15% of specimens. Investigations found the same effect in two additional ELISAs. We hypothesized that a CgA derived peptide(s) at high concentrations was responsible but experiments were inconclusive. Here we describe the analytical performance characteristics of the Chromoa™ CgA ELISA that did not display the apparent high-dose hook effect. Performance characteristics of the Chromoa ELISA were assessed. The reference interval was established utilizing healthy volunteers. Specimens producing the apparent high-dose hook effect in other assays were evaluated using the Chromoa ELISA. The limit of detection was 8ng/ml. Linearity was acceptable (slope=1.04, intercept=18.1 and r(2)=0.997). CVs were ≤4.6 and ≤9.3% for repeatability and within-laboratory imprecision, respectively. CgA was stable at ambient and refrigerated temperatures for a minimum of two and 14days, respectively. An upper reference interval limit of 95ng/ml was established. Specimens demonstrating the apparent high-dose hook effect in other ELISAs did not exhibit the phenomenon using the Chromoa ELISA. The Chromoa ELISA demonstrates acceptable performance for quantifying serum CgA. The apparent high-dose hook effect exhibited in other ELISAs was absent using the Chromoa assay. Copyright © 2015 Elsevier B.V. All rights reserved.

[ERGOGENIC SPORT SUPPLEMENTS FOR ATHLETES].

PubMed

Arieli, Rakefet; Lahav, Yair

2016-06-01

Use of performance-enhancing supplements occurs at all levels of sports, from recreational athletes to professional athletes. Although some supplements do enhance athletic performance, many have no proven benefits and have adverse effects. Nutritional supplements are categorized into the following categories: I. Apparently Effective. II. Possibly Effective. III. Too Early To Tell. IV. Apparently Ineffective. This article will review 4 ergogenic supplements which are categorized in the first category--"Apparently Effective"--1) Buffer agents 2) Creatine 3) Caffeine and 4 Nitric Oxide. Given the widespread use of performance enhancing supplements, physicians, and dietitians should be prepared to counsel athletes about their effectiveness, safety and legality.

Developmental neurotoxicity of succeeding generations of insecticides

PubMed Central

Abreu-Villaça, Yael; Levin, Edward D.

2016-01-01

Insecticides are by design toxic. They must be toxic to effectively kill target species of insects. Unfortunately, they also have off-target toxic effects that can harm other species, including humans. Developmental neurotoxicity is one of the most prominent off-target toxic risks of insecticides. Over the past seven decades several classes of insecticides have been developed, each with their own mechanisms of effect and toxic side effects. This review covers the developmental neurotoxicity of the succeeding generations of insecticides including organochlorines, organophosphates, pyrethroids, carbamates and neonicotinoids. The goal of new insecticide development is to more effectively kill target species with fewer toxic side effects on non-target species. From the experience with the developmental neurotoxicity caused by the generations of insecticides developed in the past advice is offered how to proceed with future insecticide development to decrease neurotoxic risk. PMID:27908457

MUTYH mediates the toxicity of combined DNA 6-thioguanine and UVA radiation

PubMed Central

De Luca, Gabriele; Leopardi, Paola; Mancuso, Maria Teresa; Casorelli, Ida; Pichierri, Pietro; Karran, Peter; Bignami, Margherita

2015-01-01

The therapeutic thiopurines, including the immunosuppressant azathioprine (Aza) cause the accumulation of the UVA photosensitizer 6-thioguanine (6-TG) in the DNA of the patients' cells. DNA 6-TG and UVA are synergistically cytotoxic and their interaction causes oxidative damage. The MUTYH DNA glycosylase participates in the base excision repair of oxidized DNA bases. Using Mutyh-nullmouse fibroblasts (MEFs) we examined whether MUTYH provides protection against the lethal effects of combined DNA 6-TG/UVA. Surprisingly, Mutyh-null MEFs were more resistant than wild-type MEFs, despite accumulating higher levels of DNA 8-oxo-7,8-dihydroguanine (8-oxoG). Their enhanced 6-TG/UVA resistance reflected the absence of the MUTYH protein and MEFs expressing enzymatically-dead human variants were as sensitive as wild-type cells. Consistent with their enhanced resistance, Mutyh-null cells sustained fewer DNA strand breaks and lower levels of chromosomal damage after 6-TG/UVA. Although 6-TG/UVA treatment caused early checkpoint activation irrespective of the MUTYH status, Mutyh-null cells failed to arrest in S-phase at late time points. MUTYH-dependent toxicity was also apparent in vivo. Mutyh−/−mice survived better than wild-type during a 12-month chronicexposure to Aza/UVA treatments that significantly increased levels of skin DNA 8-oxoG. Two squamous cell skin carcinomas arose in Aza/UVA treated Mutyh−/− mice whereas similarly treated wild-type animals remained tumor-free. PMID:25638157

Fabrication of environmentally biodegradable lignin nanoparticles.

PubMed

Frangville, Camille; Rutkevičius, Marius; Richter, Alexander P; Velev, Orlin D; Stoyanov, Simeon D; Paunov, Vesselin N

2012-12-21

We developed a method for the fabrication of novel biodegradable nanoparticles (NPs) from lignin which are apparently non-toxic for microalgae and yeast. We compare two alternative methods for the synthesis of lignin NPs which result in particles of very different stability upon change of pH. The first method is based on precipitation of low-sulfonated lignin from an ethylene glycol solution by using diluted acidic aqueous solutions, which yields lignin NPs that are stable over a wide range of pH. The second approach is based on the acidic precipitation of lignin from a high-pH aqueous solution which produces NPs stable only at low pH. Our study reveals that lignin NPs from the ethylene glycol-based precipitation contain densely packed lignin domains which explain the stability of the NPs even at high pH. We characterised the properties of the produced lignin NPs and determined their loading capacities with hydrophilic actives. The results suggest that these NPs are highly porous and consist of smaller lignin domains. Tests with microalgae like Chlamydomonas reinhardtii and yeast incubated in lignin NP dispersions indicated that these NPs lack measurable effect on the viability of these microorganisms. Such biodegradable and environmentally compatible NPs can find applications as drug delivery vehicles, stabilisers of cosmetic and pharmaceutical formulations, or in other areas where they may replace more expensive and potentially toxic nanomaterials. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Ultra-small iron-gallic acid coordination polymer nanoparticles for chelator-free labeling of 64Cu and multimodal imaging-guided photothermal therapy.

PubMed

Jin, Qiutong; Zhu, Wenjun; Jiang, Dawei; Zhang, Rui; Kutyreff, Christopher J; Engle, Jonathan W; Huang, Peng; Cai, Weibo; Liu, Zhuang; Cheng, Liang

2017-08-31

Cancer nanotechnology has become the hot topic nowadays. While various kinds of nanomaterials have been widely explored for innovative cancer imaging and therapy applications, safe multifunctional nano-agents without long-term retention and toxicity are still demanded. Herein, iron-gallic acid coordination nanoparticles (Fe-GA CPNs) with ultra-small sizes are successfully synthesized by a simple method for multimodal imaging-guided cancer therapy. After surface modification with polyethylene glycol (PEG), the synthesized Fe-GA-PEG CPNs show high stability in various physiological solutions. Taking advantage of high near-infrared (NIR) absorbance as well as the T 1 -MR contrasting ability of Fe-GA-PEG CPNs, in vivo photoacoustic tomography (PAT) and magnetic resonance (MR) bimodal imaging are carried out, revealing the efficient passive tumor targeting of these ultra-small CPNs after intravenous (i.v.) injection. Interestingly, such Fe-GA-PEG CPNs could be labeled with the 64 Cu isotope via a chelator-free method for in vivo PET imaging, which also illustrates the high tumor uptake of Fe-GA CPNs. We further utilize Fe-GA-PEG CPNs for in vivo photothermal therapy and achieve highly effective tumor destruction after i.v. injection of Fe-GA-PEG CPNs and the following NIR laser irradiation of the tumors, without observing any apparent toxicity of such CPNs to the treated animals. Our work highlights the promise of ultra-small iron coordination nanoparticles for imaging-guided cancer therapy.

Changes in ultrastructure and expression of steroidogenic factor-1 in ovaries of zebrafish Danio rerio exposed to glyphosate.

PubMed

Armiliato, Neide; Ammar, Dib; Nezzi, Luciane; Straliotto, Marcos; Muller, Yara M R; Nazari, Evelise M

2014-01-01

Glyphosate is a broad-spectrum organophosphate (OP) herbicide, highly soluble in water, and when applied in terrestrial systems it penetrates into soil, eventually reaching the aquatic community and affecting nontarget organisms. The aim of this study was to evaluate the toxicity of glyphosate on ovaries of zebrafish (Danio rerio). Ovaries (n = 18 per triplicate) were exposed to 65 μg/L of glyphosate [N-(phosphonomethyl) glycine] for 15 d. This concentration was determined according to Resolution 357/2005/CONAMA/Brazil, which establishes the permissible concentration of glyphosate in Brazilian inland waters. Nonexposed ovaries (n = 18 per triplicate) were used as control. Subsequently, morphology and expression of steroidogenic factor-1 (SF-1) of exposed and nonexposed ovaries was determined. No apparent changes were noted in general morphology of exposed and nonexposed ovaries. However, a significant increase in diameter of oocytes was observed after exposure to glyphosate. When ovarian ultrastructure was examined the presence of concentric membranes, appearing as myelin-like structures, associated with the external membranes of mitochondria and with yolk granules was found. After glyphosate exposure, immunohistochemistry and immunoblotting revealed greater expression of SF-1 in the oocytes, which suggests a relationship between oocyte growth and SF-1 expression. These subtle adverse effects of glyphosate on oocytes raised a potential concern for fish reproduction. These results contribute to understanding glyphosate-induced toxicity to nontarget organisms, showing subcellular and molecular impairments that may affect reproduction in +female fish.

Stable disease and improved health-related quality of life (HRQoL) following fractionated low dose 131I-metaiodobenzylguanidine (MIBG) therapy in metastatic paediatric paraganglioma: observation on false "reverse" discordance during pre-therapy work up and its implication for patient selection for high dose targeted therapy.

PubMed

Basu, S; Nair, N

2006-08-01

The incidence of paraganglioma in the paediatric population is exceedingly rare, accounting for < 0.1% of childhood cancers. We report here the response and toxicity profile in a case of malignant paraganglioma which was treated with what is currently perceived as an unconventional and non-standard approach, using three consecutive low doses of 131I-MIBG (a cumulative dose of 11 647.6 MBq). The patient had a stable disease at the end of 42 months follow-up following the first treatment with 131I-MIBG. Excellent symptomatic and hormonal responses were observed. The only adverse effect was mild nausea in the first 24 h after therapy. In addition to the potentially primary end point of radiological and biochemical response measurement, we, in this paper, endeavoured to look for a quality of life evaluation for this form of treatment. Given the rarity of this condition, the experience gained by this therapeutic approach is intriguing from response and toxicity standpoints and may be extrapolated to malignant pheochromocytoma as well. An apparent "reverse discordance" between 131I-MIBG scintigraphy and 99Tc(m)-MDP bone scan encountered during pre-therapy work up is also described with possible explanations. This draws attention to an important clinical issue in selecting patients for high dose targeted therapy.

Reproductive toxicity: Male and female reproductive systems as targets for chemical injury

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mattison, D.R.; Plowchalk, D.R.; Meadows, M.J.

On the basis of current knowledge of reproductive biology and toxicology, it is apparent that chemicals affecting reproduction may elicit their effects at a number of sites in both the male and the female reproductive system. This multiplicity of targets is attributable to the dynamic nature of the reproductive system, in which the hypothalamic-pituitary-gonadal axis is controlled by precise positive and negative feedback mechanisms among its components. Interference by a xenobiotic at any level in either the male or the female reproductive system may ultimately impair hypothalamic or pituitary function. Normal gonadal processes such as spermatogenesis or oogenesis, ejaculation ormore » ovulation, hormone production by Leydig or granulosa cells, and the structure or function of the accessory reproductive structures (e.g., epididymis, fallopian tube) also appear vulnerable to xenobiotics. The reproductive system is a complex one that requires local and circulating hormones for control. This brief review illustrates a system for characterizing the mechanism of action of reproductive toxicants, as well as for defining the sites available for disruption of reproduction. Unfortunately, at present, data addressing the actual vulnerability of reproduction are sorely lacking. However, when experiments have been conducted and combined with epidemiologic data or clinical observation, it has been possible to demonstrate impairment of reproductive processes by xenobiotics. The role of environmental exposure to xenobiotics in the increase in infertility that has been observed remains to be defined. 87 references.« less

Predicting toxic effects of copper on aquatic biota in mineralized areas by using the Biotic Ligand Model

USGS Publications Warehouse

Smith, Kathleen S.; Ranville, James F.; Adams, M.; Choate, LaDonna M.; Church, Stan E.; Fey, David L.; Wanty, Richard B.; Crock, James G.

2006-01-01

The chemical speciation of metals influences their biological effects. The Biotic Ligand Model (BLM) is a computational approach to predict chemical speciation and acute toxicological effects of metals on aquatic biota. Recently, the U.S. Environmental Protection Agency incorporated the BLM into their regulatory water-quality criteria for copper. Results from three different laboratory copper toxicity tests were compared with BLM predictions for simulated test-waters. This was done to evaluate the ability of the BLM to accurately predict the effects of hardness and concentrations of dissolved organic carbon (DOC) and iron on aquatic toxicity. In addition, we evaluated whether the BLM and the three toxicity tests provide consistent results. Comparison of BLM predictions with two types of Ceriodaphnia dubia toxicity tests shows that there is fairly good agreement between predicted LC50 values computed by the BLM and LC50 values determined from the two toxicity tests. Specifically, the effect of increasing calcium concentration (and hardness) on copper toxicity appears to be minimal. Also, there is fairly good agreement between the BLM and the two toxicity tests for test solutions containing elevated DOC, for which the LC50 is 3-to-5 times greater (less toxic) than the LC50 for the lower-DOC test water. This illustrates the protective effects of DOC on copper toxicity and demonstrates the ability of the BLM to predict these protective effects. In contrast, for test solutions with added iron there is a decrease in LC50 values (increase in toxicity) in results from the two C. dubia toxicity tests, and the agreement between BLM LC50 predictions and results from these toxicity tests is poor. The inability of the BLM to account for competitive iron binding to DOC or DOC fractionation may be a significant shortcoming of the BLM for predicting site- specific water-quality criteria in streams affected by iron-rich acidic drainage in mined and mineralized areas.

A variable parameter single degree-of-freedom model for predicting the effects of sitting posture and vibration magnitude on the vertical apparent mass of the human body.

PubMed

Toward, Martin G R; Griffin, Michael J

2010-01-01

Models of the vertical apparent mass of the human body are mostly restricted to a sitting posture unsupported by a backrest and ignore the variations in apparent mass associated with changes in posture and changes in the magnitude of vibration. Using findings from experimental research, this study fitted a single degree-of-freedom lumped parameter model to the measured vertical apparent mass of the body measured with a range of sitting postures and vibration magnitudes. The resulting model reflects the effects of reclining a rigid backrest or reclining a foam backrest (from 0 to 30 degrees), the effects of moving the hands from the lap to a steering wheel, the effects of moving the horizontal position of the feet, and the effects of vibration magnitude (from 0.125 to 1.6 ms(-2) r.m.s.). The error between the modelled and the measured apparent mass was minimised, for both the apparent masses of individual subjects and the median apparent masses of groups of 12 subjects, for each sitting posture and each vibration magnitude. Trends in model parameters, the damping ratios, and the damped natural frequencies were identified as a function of the model variables and show the effects of posture and vibration magnitude on body dynamics. For example, contact with a rigid backrest increased the derived damped natural frequency of the principal resonance as a result of reduced moving mass and increased stiffness. When the rigid backrest was reclined from 0 to 30º, the damping decreased and the resonance frequency increased as a result of reduced moving mass. It is concluded that, by appropriate variations in model parameters, a single degree-of-freedom model can provide a useful fit to the vertical apparent mass of the human body over a wide range of postures and vibration magnitudes. When measuring or modelling seat transmissibility, it may be difficult to justify an apparent mass model with more than a single degree-of-freedom if it does not reflect the large influences of vibration magnitude, body posture, and individual variability.

Development of biotic ligand models for chronic manganese toxicity to fish, invertebrates, and algae.

PubMed

Peters, Adam; Lofts, Stephen; Merrington, Graham; Brown, Bruce; Stubblefield, William; Harlow, Keven

2011-11-01

Ecotoxicity tests were performed with fish, invertebrates, and algae to investigate the effect of water quality parameters on Mn toxicity. Models were developed to describe the effects of Mn as a function of water quality. Calcium (Ca) has a protective effect on Mn toxicity for both fish and invertebrates, and magnesium (Mg) also provides a protective effect for invertebrates. Protons have a protective effect on Mn toxicity to algae. The models derived are consistent with models of the toxicity of other metals to aquatic organisms in that divalent cations can act as competitors to Mn toxicity in fish and invertebrates, and protons act as competitors to Mn toxicity in algae. The selected models are able to predict Mn toxicity to the test organisms to within a factor of 2 in most cases. Under low-pH conditions invertebrates are the most sensitive taxa, and under high-pH conditions algae are most sensitive. The point at which algae become more sensitive than invertebrates depends on the Ca concentration and occurs at higher pH when Ca concentrations are low, because of the sensitivity of invertebrates under these conditions. Dissolved organic carbon concentrations have very little effect on the toxicity of Mn to aquatic organisms. Copyright © 2011 SETAC.

Toxicity of cobalt-complexed cyanide to Oncorhynchus mykiss, Daphnia magna, and Ceriodaphnia dubia: Potentiation by ultraviolet radiation and attenuation by dissolved organic carbon and adaptive UV tolerance

USGS Publications Warehouse

Little, Edward E.; Calfee, Robin D.; Theodorakos, Peter M.; Brown, Zoe Ann; Johnson, Craig A.

2007-01-01

BackgroundCobalt cyanide complexes often result when ore is treated with cyanide solutions to extract gold and other metals. These have recently been discovered in low but significant concentrations in effluents from gold leach operations. This study was conducted to determine the potential toxicity of cobalt-cyanide complexes to freshwater organisms and the extent to which ultraviolet radiation (UV) potentiates this toxicity. Tests were also conducted to determine if humic acids or if adaptation to UV influenced sensitivity to the cyanide complexes.MethodsRainbow trout (Oncorhynchus mykiss), Daphnia magna, and Ceriodaphnia dubia were exposed to potassium hexacyanocobaltate in the presence and absence of UV radiation, in the presence and absence of humic acids. Cyano-cobalt exposures were also conducted with C. dubia from cultures adapted to elevated UV.ResultsWith an LC50 concentration of 0.38 mg/L, cyanocobalt was over a 1000 times more toxic to rainbow trout in the presence of UV at a low, environmentally relevant irradiance level (4 μW/cm2 as UVB) than exposure to this compound in the absence of UV with an LC50 of 112.9 mg/L. Toxicity was immediately apparent, with mortality occurring within an hour of the onset of exposure at the highest concentration. Fish were unaffected by exposure to UV alone. Weak-acid dissociable cyanide concentrations were observed in irradiated aqueous solutions of cyanocobaltate within hours of UV exposure and persisted in the presence of UV for at least 96 hours, whereas negligible concentrations were observed in the absence of UV. The presence of humic acids significantly diminished cyanocobalt toxicity to D. magna and reduced mortality from UV exposure. Humic acids did not significantly influence survival among C. dubia. C. dubia from UV-adapted populations were less sensitive to metallocyanide compounds than organisms from unadapted populations.ConclusionsThe results indicate that metallocyanide complexes may pose a hazard to aquatic life through photochemically induced processes. Factors that decrease UV exposure such as dissolved organic carbon or increased pigmentation would diminish toxicity.

Elemental selenium at nano size possesses lower toxicity without compromising the fundamental effect on selenoenzymes: comparison with selenomethionine in mice.

PubMed

Wang, Huali; Zhang, Jinsong; Yu, Hanqing

2007-05-15

Glutathione peroxidase and thioredoxin reductase are major selenoenzymes through which selenium exerts powerful antioxidant effects. Selenium also elicits pro-oxidant effects at toxic levels. The antioxidant and pro-oxidant effects, or bioavailability and toxicity, of selenium depend on its chemical form. Selenomethionine is considered to be the most appropriate supplemental form due to its excellent bioavailability and lower toxicity compared to various selenium compounds. The present studies reveal that, compared with selenomethionine, elemental selenium at nano size (Nano-Se) possesses equal efficacy in increasing the activities of glutathione peroxidase and thioredoxin reductase but has much lower toxicity as indicated by median lethal dose, acute liver injury, and short-term toxicity. Our results suggest that Nano-Se can serve as an antioxidant with reduced risk of selenium toxicity.

Investigation of anti-oxidative stress in vitro and water apparent diffusion coefficient in MRI on rat after spinal cord injury in vivo with Tithonia diversifolia ethanolic extracts treatment.

PubMed

Juang, Chi-Long; Yang, Fei Shish; Hsieh, Ming Shuang; Tseng, Hu-Yi; Chen, Su-Chiu; Wen, Hsiao-Chuan

2014-11-18

Spinal cord injury (SCI)-induced secondary oxidative stress associates with a clinical complication and high mortality. Treatments to improve the neurological outcome of secondary injury are considered as important issues. The objective of the current study is to evaluate the anti-oxidative effect of Tithonia diversifolia ethanolic extracts (TDE) on cells and apply the pharmacological effect to SCI model using a MRI imaging algorism. The anti-oxidation properties were tested in a 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. Rat liver cells (clone-9) were treated with various doses of TDE (0 ~ 50 μg/ml) before exposed to 250 μM H2O2 and cell survival was determined by MTT and LDH assays. We performed water apparent diffusion coefficient (ADC) map in MR techniques to investigate the efficacy of TDE treatment on SCI animal model. We performed T5 laminectomy and compression (50 g, 1 min) to induce SCI. PHILIP 3.0 T MRI was used to image 24 male Sprague-Dawley rats weighing 280-320 g. Rats were randomly divided into three groups: sham group, SCI group, SCI treated with TDE group. The MRI images were taken and ADC were acquired before and after of treatment of TDE (50 mg/kg B. W. orally, 5 days) in SCI model. TDE protected clone-9 cells against H2O2-induced toxicity through DPPH scavenging mechanism. In addition, SCI induced the increase in ADC after 6 hours. TDE treatment slightly decreased the ADC level after 1-week SCI compared with control animals. Our studies have proved that the cytoprotection effect of TDE, at least in part, is through scavenging ROS to eliminate intracellular oxidative stress and highlight a potential therapeutic consideration of TDE in alternative and complementary medicine.

Subchronic oral toxicity and metabolite profiling of the p53 stabilizing agent, CP-31398, in rats and dogs.

PubMed

Johnson, William D; Muzzio, Miguel; Detrisac, Carol J; Kapetanovic, Izet M; Kopelovich, Levy; McCormick, David L

2011-11-18

CP-31398 (N'-[2-[2-(4-methoxyphenyl)ethenyl]-4-quinazolinyl]-N,N-dimethyl-1,3-propanediamine dihydrochloride) is a styrylquinazoline that stabilizes the DNA binding conformation of p53, thereby maintaining the activity of p53 as a transcription factor and tumor suppressor. In consideration of the potential use of p53 stabilizers for cancer prevention and therapy, 28-day studies (with recovery) were performed to characterize the toxicity of CP-31398 in rats and dogs. In the rat study, groups of 15 CD rats/sex received daily gavage exposure to CP-31398 at 0, 40, 80, or 160mg/kg/day (0, 240, 480, or 960mg/m(2)/day). In the dog study, groups of five beagle dogs received daily gavage exposure to CP-31398 at 0, 10, 20, or 40mg/kg/day (0, 200, 400, or 800mg/m(2)/day). The high dose of CP-31398 induced mortality in both species: seven male rats and four female rats died as a result of hepatic infarcts, and two female dogs died as a result of hepatic necrosis without evidence of thrombosis. No deaths were seen in the mid- or low-dose groups in either species. In dogs, sporadic emesis was seen in the high dose and mid dose groups, and reductions in body weight gain were observed in all drug-exposed groups. CP-31398 induced mild anemia in both species; clinical pathology data also demonstrated hepatic toxicity, renal toxicity, inflammatory reactions, and coagulopathies in rats in the high dose and mid dose groups. Treatment-related microscopic changes in high dose and mid dose rats were identified in the liver, kidney, heart, bone marrow, lung, adrenals, spleen, thymus, skeletal muscle, and ovary; microscopic changes in the liver, heart, lung, and adrenals persisted through the recovery period. In dogs, microscopic changes were identified in the central nervous system, lung, and liver; changes in all tissues remained at the end of the recovery period. The liver is the primary site of limiting toxicity for CP-31398 in rats, and is also a key site of toxicity in dogs. The maximum tolerated dose (MTD) for subchronic oral administration of CP-31398 is 80mg/kg/day (480mg/m(2)/day) in rats and 20mg/kg/day (400mg/m(2)/day) in dogs. Although only modest and apparently reversible toxicities (microscopic changes in rats; reductions in body weight gain and alterations in red cell parameters in dogs) were seen in the low dose groups, no observed adverse effect levels (NOAELs) for CP-31398 could not be established for either species. The toxicity of CP-31398 suggests that this agent may not be suitable for use in cancer prevention. However, should in vivo antitumor efficacy be achievable at doses that do not induce limiting toxicity, CP-31398 may have utility as a cancer therapeutic. Modification of the primary sites of CP-31398 metabolism (N-demethylation of the alkyl side chain; hydroxylation and O-demethylation of the styryl benzene group) may result in the development of CP-31398 analogs with comparable pharmacologic activity and reduced toxicity. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Subchronic oral toxicity and metabolite profiling of the p53 stabilizing agent, CP-31398, in rats and dogs

PubMed Central

Johnson, William D.; Muzzio, Miguel; Detrisac, Carol J.; Kapetanovic, Izet M.; Kopelovich, Levy; McCormick, David L.

2011-01-01

CP-31398 (N′-[2-[2-(4-methoxyphenyl)ethenyl]-4-quinazolinyl]-N,N-dimethyl-1,3-propanediamine dihydrochloride) is a styrylquinazoline that stabilizes the DNA binding conformation of p53, thereby maintaining the activity of p53 as a transcription factor and tumor suppressor. In consideration of the potential use of p53 stabilizers for cancer prevention and therapy, 28-day studies (with recovery) were performed to characterize the toxicity of CP-31398 in rats and dogs. In the rat study, groups of 15 CD rats/sex received daily gavage exposure to CP-31398 at 0, 40, 80, or 160 mg/kg/day (0, 240, 480, or 960 mg/m2/day). In the dog study, groups of five beagle dogs received daily gavage exposure to CP-31398 at 0, 10, 20, or 40 mg/kg/day (0, 200, 400, or 800 mg/m2/day). The high dose of CP-31398 induced mortality in both species: seven male rats and four female rats died as a result of hepatic infarcts, and two female dogs died as a result of hepatic necrosis without evidence of thrombosis. No deaths were seen in the mid- or low dose groups in either species. In dogs, sporadic emesis was seen in the high dose and mid dose groups, and reductions in body weight gain were observed in all drug-exposed groups. CP-31398 induced mild anemia in both species; clinical pathology data also demonstrated hepatic toxicity, renal toxicity, inflammatory reactions, and coagulopathies in rats in the high dose and mid dose groups. Treatment-related microscopic changes in high dose and mid dose rats were identified in the liver, kidney, heart, bone marrow, lung, adrenals, spleen, thymus, skeletal muscle, and ovary; microscopic changes in the liver, heart, lung, and adrenals persisted through the recovery period. In dogs, microscopic changes were identified in the central nervous system, lung, and liver; changes in all tissues remained at the end of the recovery period. The liver is the primary site of limiting toxicity for CP-31398 in rats, and is also a key site of toxicity in dogs. The Maximum Tolerated Dose (MTD) for subchronic oral administration of CP-31398 is 80 mg/kg/day (480 mg/m2/day) in rats and 20 mg/kg/day (400 mg/m2/day) in dogs. Although only modest and apparently reversible toxicities (microscopic changes in rats; reductions in body weight gain and alterations in red cell parameters in dogs) were seen in the low dose groups, No Observed Adverse Effect Levels (NOAELs) for CP-31398 could not be established for either species. The toxicity of CP-31398 suggests that this agent may not be suitable for use in cancer prevention. However, should in vivo antitumor efficacy be achievable at doses that do not induce limiting toxicity, CP-31398 may have utility as a cancer therapeutic. Modification of the primary sites of CP-31398 metabolism (N-demethylation of the alkyl side chain; hydroxylation and O-demethylation of the styryl benzene group) may result in the development of CP-31398 analogs with comparable pharmacologic activity and reduced toxicity. PMID:21864638

Aqueous Stability and Oral Pharmacokinetics of Meloxicam and Carprofen in Male C57BL/6 Mice

PubMed Central

Ingrao, Joelle C; Johnson, Ron; Tor, Elizabeth; Gu, Yu; Litman, Marcus; Turner, Patricia V

2013-01-01

We found that carprofen and meloxicam under 3 environmental conditions (ambient dark, ambient light, and 4 °C) remained stable for at least 7 d. We then evaluated the oral pharmacokinetics of meloxicam (20 mg/kg) and carprofen (10 mg/kg) in male C57BL/6 mice after oral gavage or administration in the drinking water. Mice did not drink meloxicam-medicated water but readily consumed carprofen-medicated water, consuming an average of 14.19 mL carprofen-medicated water per 100 g body weight daily; mice drank more during the dark phase than during the light phase. Plasma analyzed by HPLC (meloxicam) and tandem mass spectrometry (carprofen) revealed that the peak meloxicam and carprofen concentrations were 16.7 and 20.3 μg/mL and occurred at 4 and 2 h after oral gavage, respectively. Similar blood levels were achieved after 12 h access to the carprofen-medicated water bottle. At 24 h after oral gavage, the drugs were not detectable in plasma. Meloxicam plasma AUC, elimination half-life, apparent volume of distribution, and apparent oral clearance were 160.4 mg/L × h, 7.4 h, 0.36 L/kg, and 0.125 mL/h × kg, respectively. Carprofen plasma AUC, elimination half-life, apparent volume of distribution, and apparent oral clearance were 160.8 mg/L × h, 7.4 h, 0.42 L/kg, and 0.062 mL/h × kg, respectively. No gross or microscopic evidence of toxicity was seen in any mouse. Our findings indicate that carprofen can be administered in drinking water to mice and that medicated water bottles should be placed 12 to 24 h prior to painful procedures. PMID:24041210

Elimination Rates of Dioxin Congeners in Former Chlorophenol Workers from Midland, Michigan

PubMed Central

Collins, James J.; Bodner, Kenneth M.; Wilken, Michael; Bodnar, Catherine M.

2012-01-01

Background: Exposure reconstructions and risk assessments for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other dioxins rely on estimates of elimination rates. Limited data are available on elimination rates for congeners other than TCDD. Objectives: We estimated apparent elimination rates using a simple first-order one-compartment model for selected dioxin congeners based on repeated blood sampling in a previously studied population. Methods: Blood samples collected from 56 former chlorophenol workers in 2004–2005 and again in 2010 were analyzed for dioxin congeners. We calculated the apparent elimination half-life in each individual for each dioxin congener and examined factors potentially influencing elimination rates and the impact of estimated ongoing background exposures on rate estimates. Results: Mean concentrations of all dioxin congeners in the sampled participants declined between sampling times. Median apparent half-lives of elimination based on changes in estimated mass in the body were generally consistent with previous estimates and ranged from 6.8 years (1,2,3,7,8,9-hexachlorodibenzo-p-dioxin) to 11.6 years (pentachlorodibenzo-p-dioxin), with a composite half-life of 9.3 years for TCDD toxic equivalents. None of the factors examined, including age, smoking status, body mass index or change in body mass index, initial measured concentration, or chloracne diagnosis, was consistently associated with the estimated elimination rates in this population. Inclusion of plausible estimates of ongoing background exposures decreased apparent half-lives by approximately 10%. Available concentration-dependent toxicokinetic models for TCDD underpredicted observed elimination rates for concentrations < 100 ppt. Conclusions: The estimated elimination rates from this relatively large serial sampling study can inform occupational and environmental exposure and serum evaluations for dioxin compounds. PMID:23063871

Aqueous stability and oral pharmacokinetics of meloxicam and carprofen in male C57BL/6 mice.

PubMed

Ingrao, Joelle C; Johnson, Ron; Tor, Elizabeth; Gu, Yu; Litman, Marcus; Turner, Patricia V

2013-09-01

We found that carprofen and meloxicam under 3 environmental conditions (ambient dark, ambient light, and 4 °C) remained stable for at least 7 d. We then evaluated the oral pharmacokinetics of meloxicam (20 mg/kg) and carprofen (10 mg/kg) in male C57BL/6 mice after oral gavage or administration in the drinking water. Mice did not drink meloxicam-medicated water but readily consumed carprofen-medicated water, consuming an average of 14.19 mL carprofen-medicated water per 100 g body weight daily; mice drank more during the dark phase than during the light phase. Plasma analyzed by HPLC (meloxicam) and tandem mass spectrometry (carprofen) revealed that the peak meloxicam and carprofen concentrations were 16.7 and 20.3 μg/mL and occurred at 4 and 2 h after oral gavage, respectively. Similar blood levels were achieved after 12 h access to the carprofen-medicated water bottle. At 24 h after oral gavage, the drugs were not detectable in plasma. Meloxicam plasma AUC, elimination half-life, apparent volume of distribution, and apparent oral clearance were 160.4 mg/L × h, 7.4 h, 0.36 L/kg, and 0.125 mL/h × kg, respectively. Carprofen plasma AUC, elimination half-life, apparent volume of distribution, and apparent oral clearance were 160.8 mg/L × h, 7.4 h, 0.42 L/kg, and 0.062 mL/h × kg, respectively. No gross or microscopic evidence of toxicity was seen in any mouse. Our findings indicate that carprofen can be administered in drinking water to mice and that medicated water bottles should be placed 12 to 24 h prior to painful procedures.

Toxicity of benthic dinoflagellates on grazing, behavior and survival of the brine shrimp Artemia salina

PubMed Central

Neves, Raquel A. F.; Fernandes, Tainá; dos Santos, Luciano Neves; Nascimento, Silvia M.

2017-01-01

Harmful algae may differently affect their primary grazers, causing sub-lethal effects and/or leading to their death. The present study aim to compare the effects of three toxic benthic dinoflagellates on clearance and grazing rates, behavioral changes, and survival of Artemia salina. Feeding assays consisted in 1-h incubations of brine shrimps with the toxic Prorocentrum lima, Gambierdiscus excentricus and Ostreopsis cf. ovata and the non-toxic Tetraselmis sp. Brine shrimps fed unselectively on all toxic and non-toxic algal preys, without significant differences in clearance and ingestion rates. Acute toxicity assays were performed with dinoflagellate cells in two growth phases during 7-h to assess differences in cell toxicity to A. salina. Additionally, exposure to cell-free medium was performed to evaluate its effects on A. salina survival. The behavior of brine shrimps significantly changed during exposure to the toxic dinoflagellates, becoming immobile at the bottom by the end of the trials. Dinoflagellates significantly affected A. salina survival with 100% mortality after 7-h exposure to cells in exponential phase (all treatments) and to P. lima in stationary phase. Mortality rates of brine shrimps exposed to O. cf. ovata and G. excentricus in stationary phase were 91% and 75%, respectively. However, incubations of the brine shrimps with cell-free medium did not affect A. salina survivorship. Significant differences in toxic effects between cell growth phases were only found in the survival rates of A. salina exposed to G. excentricus. Acute exposure to benthic toxic dinoflagellates induced harmful effects on behavior and survival of A. salina. Negative effects related to the toxicity of benthic dinoflagellates are thus expected on their primary grazers making them more vulnerable to predation and vectors of toxins through the marine food webs. PMID:28388672

Toxicity of benthic dinoflagellates on grazing, behavior and survival of the brine shrimp Artemia salina.

PubMed

Neves, Raquel A F; Fernandes, Tainá; Santos, Luciano Neves Dos; Nascimento, Silvia M

2017-01-01

Harmful algae may differently affect their primary grazers, causing sub-lethal effects and/or leading to their death. The present study aim to compare the effects of three toxic benthic dinoflagellates on clearance and grazing rates, behavioral changes, and survival of Artemia salina. Feeding assays consisted in 1-h incubations of brine shrimps with the toxic Prorocentrum lima, Gambierdiscus excentricus and Ostreopsis cf. ovata and the non-toxic Tetraselmis sp. Brine shrimps fed unselectively on all toxic and non-toxic algal preys, without significant differences in clearance and ingestion rates. Acute toxicity assays were performed with dinoflagellate cells in two growth phases during 7-h to assess differences in cell toxicity to A. salina. Additionally, exposure to cell-free medium was performed to evaluate its effects on A. salina survival. The behavior of brine shrimps significantly changed during exposure to the toxic dinoflagellates, becoming immobile at the bottom by the end of the trials. Dinoflagellates significantly affected A. salina survival with 100% mortality after 7-h exposure to cells in exponential phase (all treatments) and to P. lima in stationary phase. Mortality rates of brine shrimps exposed to O. cf. ovata and G. excentricus in stationary phase were 91% and 75%, respectively. However, incubations of the brine shrimps with cell-free medium did not affect A. salina survivorship. Significant differences in toxic effects between cell growth phases were only found in the survival rates of A. salina exposed to G. excentricus. Acute exposure to benthic toxic dinoflagellates induced harmful effects on behavior and survival of A. salina. Negative effects related to the toxicity of benthic dinoflagellates are thus expected on their primary grazers making them more vulnerable to predation and vectors of toxins through the marine food webs.

Impacts of the phenylpyrazole insecticide fipronil on larval fish: time-series gene transcription responses in fathead minnow (Pimephales promelas) following short-term exposure.

PubMed

Beggel, Sebastian; Werner, Inge; Connon, Richard E; Geist, Juergen P

2012-06-01

The utilization of molecular endpoints in ecotoxicology can provide rapid and valuable information on immediate organismal responses to chemical stressors and is increasingly used for mechanistic interpretation of effects at higher levels of biological organization. This study contributes knowledge on the sublethal effects of a commonly used insecticide, the phenylpyrazole fipronil, on larval fathead minnow (Pimephales promelas), utilizing a quantitative transcriptomic approach. Immediately after 24h of exposure to fipronil concentrations of ≥31 μg.L(-1), highly significant changes in gene transcription were observed for aspartoacylase, metallothionein, glucocorticoid receptor, cytochrome P450 3A126 and vitellogenin. Different mechanisms of toxicity were apparent over the course of the experiment, with short-term responses indicating neurotoxic effects. After 6 days of recovery, endocrine effects were observed with vitellogenin being up-regulated 90-fold at 61 μg.L(-1) fipronil. Principal component analysis demonstrated a significant increase in gene transcription changes over time and during the recovery period. In conclusion, multiple mechanisms of action were observed in response to fipronil exposure, and unknown delayed effects would have been missed if transcriptomic responses had only been measured at a single time-point. These challenges can be overcome by the inclusion of multiple endpoints and delayed effects in experimental designs. Copyright © 2012 Elsevier B.V. All rights reserved.

Genome of Enterobacteriophage Lula/phi80 and Insights into Its Ability To Spread in the Laboratory Environment

PubMed Central

Rotman, Ella; Kouzminova, Elena; Plunkett, Guy

2012-01-01

The novel temperate bacteriophage Lula, contaminating laboratory Escherichia coli strains, turned out to be the well-known lambdoid phage phi80. Our previous studies revealed that two characteristics of Lula/phi80 facilitate its spread in the laboratory environment: cryptic lysogen productivity and stealthy infectivity. To understand the genetics/genomics behind these traits, we sequenced and annotated the Lula/phi80 genome, encountering an E. coli-toxic gene revealed as a gap in the sequencing contig and analyzing a few genes in more detail. Lula/phi80's genome layout copies that of lambda, yet homology with other lambdoid phages is mostly limited to the capsid genes. Lula/phi80's DNA is resistant to cutting with several restriction enzymes, suggesting DNA modification, but deletion of the phage's damL gene, coding for DNA adenine methylase, did not make DNA cuttable. The damL mutation of Lula/phi80 also did not change the phage titer in lysogen cultures, whereas the host dam mutation did increase it almost 100-fold. Since the high phage titer in cultures of Lula/phi80 lysogens is apparently in response to endogenous DNA damage, we deleted the only Lula/phi80 SOS-controlled gene, dinL. We found that dinL mutant lysogens release fewer phage in response to endogenous DNA damage but are unchanged in their response to external DNA damage. The toxic gene of Lula/phi80, gamL, encodes an inhibitor of the host ATP-dependent exonucleases, RecBCD and SbcCD. Its own antidote, agt, apparently encoding a modifier protein, was found nearby. Interestingly, Lula/phi80 lysogens are recD and sbcCD phenocopies, so GamL and Agt are part of lysogenic conversion. PMID:23042999

Safety and side effects of ayahuasca in humans--an overview focusing on developmental toxicology.

PubMed

dos Santos, Rafael Guimarães

2013-01-01

Despite being relatively well studied from a botanical, chemical, and (acute) pharmacological perspective, little is known about the possible toxic effects of ayahuasca (an hallucinogenic brew used for magico-ritual purposes) in pregnant women and in their children, and the potential toxicity of long-term ayahuasca consumption. It is the main objective of the present text to do an overview of the risks and possible toxic effects of ayahuasca in humans, reviewing studies on the acute ayahuasca administration to humans, on the possible risks associated with long-term consumption by adults and adolescents, and on the possible toxic effects on pregnant animals and in their offspring. Acute ayahuasca administration, as well as long-term consumption of this beverage, does not seem to be seriously toxic to humans. Although some nonhuman developmental studies suggested possible toxic effects of ayahuasca or of some of its alkaloids, the limited human literature on adolescents exposed to ayahuasca as early as in the uterus reports no serious toxic effects of the ritual consumption of the brew. Researchers must take caution when extrapolating nonhuman data to humans and more data are needed in basic and human research before a definite opinion can be made regarding the possible toxic effects of ayahuasca in pregnant women and in their children.

The acute toxic effects of 1-alkyl-3-methylimidazolium nitrate ionic liquids on Chlorella vulgaris and Daphnia magna.

PubMed

Zhang, Cheng; Zhang, Shuai; Zhu, Lusheng; Wang, Jinhua; Wang, Jun; Zhou, Tongtong

2017-10-01

Given their increasingly widespread application, the toxic effects of ionic liquids (ILs) have become the subject of significant attention in recent years. Therefore, the present study assessed the acute toxic effects of 1-alkyl-3-methylimidazolium nitrate ([C n mim]NO 3 (n = 2, 4, 6, 8, 10, 12)) on Chlorella vulgaris and Daphnia magna. The sensitivity of the tested organism Daphnia magna and the investigated IL concentrations in water using high-performance liquid chromatography (HPLC) were also evaluated to demonstrate the reliability of the present study. The results illustrated that Daphnia magna is indeed sensitive to the reference toxicant and the investigated ILs were stable in the aquatic environment. The 50% effect concentration (EC 50 ) was used to represent the acute toxic effects on Chlorella vulgaris and Daphnia magna. With the increasing alkyl-chain lengths, the toxicity of the investigated ILs increased in both the test organisms. Accordingly, the alkyl-chain lengths can cause significantly toxic effects on aquatic organisms, and Daphnia magna are much more sensitive than Chlorella vulgaris to the imidazolium-based ILs used in the present study. Furthermore, the present study provides more information on the acute toxic effects of 1-alkyl-3-methylimidazolium nitrate. Copyright © 2017 Elsevier Ltd. All rights reserved.

Toxicology

NASA Technical Reports Server (NTRS)

Macewen, J. W.

1973-01-01

Oxygen toxicity is examined, including the effects of oxygen partial pressure variations on toxicity and oxygen effects on ozone and nitrogen dioxide toxicity. Toxicity of fuels and oxidizers, such as hydrazines, are reported. Carbon monoxide, spacecraft threshold limit values, emergency exposure limits, spacecraft contaminants, and water quality standards for space missions are briefly summarized.

Effect of feeding fescue seed containing ergot alkaloid toxins on stallion spermatogenesis and sperm cells.

PubMed

Fayrer-Hosken, R; Stanley, A; Hill, N; Heusner, G; Christian, M; De La Fuente, R; Baumann, C; Jones, L

2012-12-01

The cellular effects of tall fescue grass-associated toxic ergot alkaloids on stallion sperm and colt testicular tissue were evaluated. This was a continuation of an initial experiment where the effects of toxic ergot alkaloids on the stallion spermiogram were investigated. The only spermiogram parameter in exposed stallions that was affected by the toxic ergot alkaloids was a decreased gel-free volume of the ejaculate. This study examined the effect of toxic ergot alkaloids on chilling and freezing of the stallion sperm cells. The effect of toxic ergot alkaloids on chilled extended sperm cells for 48 h at 5°C was to make the sperm cells less likely to undergo a calcium ionophore-induced acrosome reaction. The toxic ergot alkaloids had no effect on the freezability of sperm cells. However, if yearling colts were fed toxic ergot alkaloids, then the cytological analysis of meiotic chromosome synapsis revealed a significant increase in the proportion of pachytene spermatocytes showing unpaired sex chromosomes compared to control spermatocytes. There was little effect of ergot alkaloids on adult stallions, but there might be a significant effect on yearling colts. © 2012 Blackwell Verlag GmbH.

Effect of Feeding Fescue Seed Containing Ergot Alkaloid Toxins on Stallion Spermatogenesis and Sperm Cells

PubMed Central

Fayrer-Hosken, R; Stanley, A; Hill, N; Heusner, G; Christian, M; Fuente, R De La; Baumann, C; Jones, L

2012-01-01

Contents The cellular effects of tall fescue grass–associated toxic ergot alkaloids on stallion sperm and colt testicular tissue were evaluated. This was a continuation of an initial experiment where the effects of toxic ergot alkaloids on the stallion spermiogram were investigated. The only spermiogram parameter in exposed stallions that was affected by the toxic ergot alkaloids was a decreased gel-free volume of the ejaculate. This study examined the effect of toxic ergot alkaloids on chilling and freezing of the stallion sperm cells. The effect of toxic ergot alkaloids on chilled extended sperm cells for 48 h at 5 °C was to make the sperm cells less likely to undergo a calcium ionophore–induced acrosome reaction. The toxic ergot alkaloids had no effect on the freezability of sperm cells. However, if yearling colts were fed toxic ergot alkaloids, then the cytological analysis of meiotic chromosome synapsis revealed a significant increase in the proportion of pachytene spermatocytes showing unpaired sex chromosomes compared to control spermatocytes. There was little effect of ergot alkaloids on adult stallions, but there might be a significant effect on yearling colts. PMID:22524585

Apparent resistivity for transient electromagnetic induction logging and its correction in radial layer identification

NASA Astrophysics Data System (ADS)

Meng, Qingxin; Hu, Xiangyun; Pan, Heping; Xi, Yufei

2018-04-01

We propose an algorithm for calculating all-time apparent resistivity from transient electromagnetic induction logging. The algorithm is based on the whole-space transient electric field expression of the uniform model and Halley's optimisation. In trial calculations for uniform models, the all-time algorithm is shown to have high accuracy. We use the finite-difference time-domain method to simulate the transient electromagnetic field in radial two-layer models without wall rock and convert the simulation results to apparent resistivity using the all-time algorithm. The time-varying apparent resistivity reflects the radially layered geoelectrical structure of the models and the apparent resistivity of the earliest time channel follows the true resistivity of the inner layer; however, the apparent resistivity at larger times reflects the comprehensive electrical characteristics of the inner and outer layers. To accurately identify the outer layer resistivity based on the series relationship model of the layered resistance, the apparent resistivity and diffusion depth of the different time channels are approximately replaced by related model parameters; that is, we propose an apparent resistivity correction algorithm. By correcting the time-varying apparent resistivity of radial two-layer models, we show that the correction results reflect the radially layered electrical structure and the corrected resistivities of the larger time channels follow the outer layer resistivity. The transient electromagnetic fields of radially layered models with wall rock are simulated to obtain the 2D time-varying profiles of the apparent resistivity and corrections. The results suggest that the time-varying apparent resistivity and correction results reflect the vertical and radial geoelectrical structures. For models with small wall-rock effect, the correction removes the effect of the low-resistance inner layer on the apparent resistivity of the larger time channels.

An assessment of stressor extent and biological condition in the North American mid-continent great rivers (USA)

USGS Publications Warehouse

Angradi, Ted R.; Bolgriend, David W.; Jicha, Terri M.; Pearson, Mark S.; Taylor, Debra L.; Moffett, Mary F.; Blocksom, Karen A.; Walters, David M.; Elonen, Colleen M.; Anderson, Leroy E.; Lazorchak, James M.; Reavie, Euan D.; Kireta, Amy R.; Hill, Brian H.

2011-01-01

We assessed the North American mid-continent great rivers (Upper Mississippi, Missouri, and Ohio). We estimated the extent of each river in most- (MDC) or least-disturbed condition (LDC) based on multiple biological response indicators: fish and macroinvertebrate, trophic state based on chlorophyll a, macrophyte cover, and exposure of fish-eating wildlife to toxic contaminants in fish tissue (Hg, total chlordane, total DDT, PCBs). We estimated the extent of stressors on each river including nutrients, suspended solids, sediment toxicity, invasive species, and land use (agriculture and impervious surface). All three rivers had a greater percent of their river length in MDC than in LDC based on fish assemblages. The Upper Mississippi River had the greatest percent of river length with eutrophic status. The Ohio River had the greatest percent of river length with fish with tissue contaminant levels toxic to wildlife. Overall, condition indices based on fish assemblages were more sensitive to stress than macroinvertebrate indices. Compared to the streams in its basin, more of the Upper Mississippi and Missouri Rivers were in MDC for nutrients than the Ohio River. Invasive species (Asian carp and Dreissenid mussels) were less widespread and less abundant on the Missouri River than on the other great rivers. The Ohio River had the most urbanized floodplains (greatest percent impervious surface). The Missouri River had the most floodplain agriculture. The effect of large urban areas on river condition was apparent for several indicators. Ecosystem condition based in fish assemblages, trophic state, and fish tissue contamination was related to land use on the floodplain and at the subcatchment scale. This is the first unbiased bioassessment of the mid-continent great rivers in the United States. The indicators, condition thresholds, results, and recommendations from this program are a starting point for improved future great river assessments.

Implicit Versus Explicit Applications of the Tissue Residue Approach, Oral Presentation

EPA Science Inventory

Toxic effect models based on the relationship of toxic effects to chemical concentrations within receptor organism tissues can often be reformulated to describe the relationship of toxic effects to exposure concentrations without actual specification of the tissue concentrations....

Toxicity of star fruit (Averrhoa carambola) in renal patients: A systematic review of the literature.

PubMed

Aranguren, Camilo; Vergara, Camila; Rosselli, Diego

2017-01-01

Several reports have discussed the neurotoxic effects of star fruit (Averrhoa carambola) in patients with chronic kidney disease (CKD). There is also some evidence highlighting the potentially harmful effects on patients with apparently normal renal function, who after consuming this fruit, developed acute renal injury. We performed a systematic review of the literature in the two main global databases (PubMed and Embase) as well as in Lilacs, for Latin American publications. We also included case reports, case series, or review articles which presented individual patient data. Animal or in vitro studies were excluded. We initially screened 259 references, of which 42 were selected for full-text review and 26 were finally selected for data extraction. A total of 123 patients from eight countries were documented: Brazil, with 47 cases, had the highest reported incidence, followed by Taiwan (36), Bangladesh (20), China and France (8 each), Sri Lanka (2), and Thailand and Colombia (1 each); 28 (22%) of the patients died. Despite the relatively low frequency of star fruit consumption, it has become a global issue. Patients with already diagnosed CKD are the obvious target for preventive measures, but persons with undiagnosed kidney conditions could also be at risk.

Infertility in Men with Spinal Cord Injury: Research and Treatment

PubMed Central

Brackett, Nancy L.

2012-01-01

Spinal cord injury (SCI) occurs most often to young men. Following SCI, most men are infertile due to a combination of erectile dysfunction, ejaculatory dysfunction and semen abnormalities. Erectile dysfunction may be treated by the same therapies that are used in the general population. Similarly, the same treatments that are effective to assist conception in couples with non-SCI male factor patients are effective in assisting conception in SCI male-factor patients. The most apparent differences in male-factor symptoms between SCI and non-SCI patients are the high occurrences of anejaculation and atypical semen profiles in men with SCI. Methods available to assist ejaculation in men with SCI include penile vibratory stimulation and EEJ. Use of surgical sperm retrieval as the first line of treatment for anejaculation in men with SCI is controversial. Most men with SCI have a unique semen profile characterized by normal sperm concentration, but abnormally low sperm motility. Toxic substances in the semen contribute to this problem. Despite impaired sperm parameters, pregnancy outcomes using sperm from men with SCI are similar to pregnancy outcomes using sperm from non-SCI men. Future studies should focus on improving natural ejaculation and improving semen quality in these men. PMID:24278717

Emissions from small-scale burns of simulated deployed U.S. military waste.

PubMed

Woodall, Brian D; Yamamoto, Dirk P; Gullett, Brian K; Touati, Abderrahmane

2012-10-16

U.S. military forces have historically relied on open burning as an expedient method of volume reduction and treatment of solid waste during the conflicts in Afghanistan and Iraq. This study is the first effort to characterize a broad range of pollutants and their emission factors during the burning of military waste and the effects that recycling efforts, namely removing plastics, might have on emissions. Piles of simulated military waste were constructed, burned, and emissions sampled at the U.S. Environmental Protection Agency (EPA) Open Burn Testing Facility (OBTF), Research Triangle Park, NC. Three tests contained polyethylene terephthalate (PET #1 or PET) plastic water bottles and four did not. Emission factors for polycyclic aromatic hydrocarbons (PAHs), volatile organic compounds (VOCs), particulate matter (PM(10), PM(2.5)), polychlorinated and polybrominated dioxins/furans (PCDD/F and PBDD/F), and criteria pollutants were determined and are contained within. The average PCDD/F emission factors were 270 ng-toxic equivalency (TEQ) per kg carbon burned (ng-TEQ/kg Cb), ranging from 35 to 780 ng-TEQ/kg Cb. Limited testing suggests that targeted removal of plastic water bottles has no apparent effect on reducing pollutants and may even promote increased emissions.

How air pollution alters brain development: the role of neuroinflammation.

PubMed

Brockmeyer, Sam; D'Angiulli, Amedeo

2016-01-01

The present review synthesizes lines of emerging evidence showing how several samples of children populations living in large cities around the world suffer to some degree neural, behavioral and cognitive changes associated with air pollution exposure. The breakdown of natural barriers warding against the entry of toxic particles, including the nasal, gut and lung epithelial barriers, as well as widespread breakdown of the blood-brain barrier facilitatethe passage of airborne pollutants into the body of young urban residents. Extensive neuroinflammation contributes to cell loss within the central nervous system, and likely is a crucial mechanism by which cognitive deficits may arise. Although subtle, neurocognitive effects of air pollution are substantial, apparent across all populations, and potentially clinically relevant as early evidence of evolving neurodegenerative changes. The diffuse nature of the neuroinflammation risk suggests an integrated neuroscientific approach incorporating current clinical, cognitive, neurophysiological, radiological and epidemiologic research. Neuropediatric air pollution research requires extensive multidisciplinary collaborations to accomplish the goal of protecting exposed children through multidimensional interventions having both broad impact and reach. While intervening by improving environmental quality at a global scale is imperative, we also need to devise efficient strategies on how the neurocognitive effects on local pediatric populations should be monitored.

Pharmacokinetics of vephylline--a new N-substituted theophylline derivative.

PubMed

Staneva, D; Mihailova, D; Astroug, H; Prodanova, K; Micheva, M

1988-01-01

Vephylline (7,2-bis-2-hydroxyethylamino-1, 3-dimethylxanthine tartarate) is a xanthine derivative with high bronchodilating activity, low toxicity, and weak effects on the central nervous system. The aim of this study is to determine the pharmacokinetic parameters of vephylline after intravenous and oral (in solution and in tablets) administration to rabbits. Vephylline (dose 50 mg/kg b.w. intravenousely and orally in solution and dose 53.5 mg/kg b.w. in the form of tablets) is administered to the rabbits in an autocontrol crossover design at 7-days intervals. After the intravenous administration the distribution is relatively fast (t1/2 alpha = 3.28h). High values of the apparent volume of distribution--12.15 1/kg suggest tissue accumulation. Elimination is considerably slower (t1/2 beta = 19,00 h) than distribution. After oral administration of the drug in solution the absorption half-life is short and the bioavailability is relatively high. Peak plasma levels are attained at the first hour. The differences in the distribution and elimination patterns for vephylline and theophyline could determine a longer effect for the new bronchodilating drug. The results are discussed in regard to the future clinical application of vephylline.

How air pollution alters brain development: the role of neuroinflammation

PubMed Central

Brockmeyer, Sam

2016-01-01

Abstract The present review synthesizes lines of emerging evidence showing how several samples of children populations living in large cities around the world suffer to some degree neural, behavioral and cognitive changes associated with air pollution exposure. The breakdown of natural barriers warding against the entry of toxic particles, including the nasal, gut and lung epithelial barriers, as well as widespread breakdown of the blood-brain barrier facilitatethe passage of airborne pollutants into the body of young urban residents. Extensive neuroinflammation contributes to cell loss within the central nervous system, and likely is a crucial mechanism by which cognitive deficits may arise. Although subtle, neurocognitive effects of air pollution are substantial, apparent across all populations, and potentially clinically relevant as early evidence of evolving neurodegenerative changes. The diffuse nature of the neuroinflammation risk suggests an integrated neuroscientific approach incorporating current clinical, cognitive, neurophysiological, radiological and epidemiologic research. Neuropediatric air pollution research requires extensive multidisciplinary collaborations to accomplish the goal of protecting exposed children through multidimensional interventions having both broad impact and reach. While intervening by improving environmental quality at a global scale is imperative, we also need to devise efficient strategies on how the neurocognitive effects on local pediatric populations should be monitored. PMID:28123818

Report on Region III's asbestos hotline. Technical report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lubick, L.

1989-01-01

The report is part of the National Network for Environmental Management Studies under the auspices of the Office of Cooperative Environmental Management of the U.S. Environmental Protection Agency. The research project studies the effectiveness of an asbestos hotline that was created by Reg. III in June, 1989 through the cooperative efforts of the Air Enforcement Branch and Toxics and Pesticides Branch in Region III for use in the Annapolis, MD area. The hotline enables public officials to act upon confidential tips provided by citizens who are aware of potential asbestos violations. The major thrust of the NNEMS project focuses onmore » outreach activities-making the public aware of asbestos problems and of the Annapolis hotline as a tool to address their concerns. Diverse groups were targeted through press, radio, Congress and the public school system explaining the role citizens play in the control of asbestos. Subsequent citizen use of the hotline cited violations in public offices and manufacturing buildings, but did not produce reports of violations in school facilities. Apparently, school fliers failed to reach their target audience. Preliminary analysis indicates that the most effective method to publicize the hotline is through public service announcements on radio and in newspapers.« less

The inhibition of postinfarct ventricle remodeling without polycythaemia following local sustained intramyocardial delivery of erythropoietin within a supramolecular hydrogel.

PubMed

Wang, Tao; Jiang, Xue-Jun; Lin, Tao; Ren, Shan; Li, Xiao-Yan; Zhang, Xian-Zheng; Tang, Qi-zhu

2009-09-01

Erythropoietin (EPO) can protect myocardium from ischemic injury, but it also plays an important role in promoting polycythaemia, the potential for thrombo-embolic complications. Local sustained delivery of bioactive agents directly to impaired tissues using biomaterials is an approach to limit systemic toxicity and improve the efficacy of therapies. The present study was performed to investigate whether local intramyocardial injection of EPO with hydrogel could enhance cardioprotective effect without causing polycythaemia after myocardial infarction (MI). To test the hypothesis, phosphate buffered solution (PBS), alpha-cyclodextrin/MPEG-PCL-MPEG hydrogel, recombined human erythropoietin (rhEPO) in PBS, or rhEPO in hydrogel were injected into the infarcted area immediately after MI in rats. The hydrogel allowed a sustained release of EPO, which inhibited cell apoptosis and increased neovasculature formation, and subsequently reduced infarct size and improved cardiac function compared with other groups. Notably, there was no evidence of polycythaemia from this therapy, with no differences in erythrocyte count and hematocrit compared with the animals received PBS or hydrogel blank injection. In conclusion, intramyocardial delivery of rhEPO with alpha-cyclodextrin/MPEG-PCL-MPEG hydrogel may lead to cardiac performance improvement after MI without apparent adverse effect.

Impact of the Clean Water Act on the levels of toxic metals in urban estuaries: The Hudson River estuary revisited

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sanudo-Wilhelmy, S.A.; Gill, G.A.

1999-10-15

To establish the impact of the Clean Water Act on the water quality of urban estuaries, dissolved trace metals and phosphate concentrations were determined in surface waters collected along the Hudson River estuary between 1995 and 1997 and compared with samples collected in the mid-1970s by Klinkhammer and Bender. The median concentrations along the estuary have apparently declined 36--56% for Cu, 55--89% for Cd, 53--85% for Ni, and 53--90% for Zn over a period of 23 years. These reductions appear to reflect improvements in controlling discharges from municipal and industrial wastewater treatment plants since the Clean Water Act was enactedmore » in 1972. In contrast, levels of dissolved nutrients (PO{sub 4}) have remained relatively constant during the same period of time, suggesting that wastewater treatment plant improvements in the New York/New Jersey Metropolitan area have not been as effective at reducing nutrient levels within the estuary. While more advanced wastewater treatment could potentially reduce the levels of Ag and PO{sub 4} along the estuary, these improvements would have a more limited effect on the levels of other trace metals.« less

Effects of oxamyl on the citrus nematode, Tylenchulus semipenetrans, and on infection of sweet orange.

PubMed

Baines, R C; Small, R H

1976-04-01

Foliar sprays of 4 microg/ml oxamyl on sweet orange trees in a greenhouse slightly depressed the number of Tylenchulus semipenetrans larvae obtained from roots and soil, but similar treatments were not effective in two orchards. Soil drench treatments decreased the number of citrus nematode larvae obtained from roots or soil of citrus plants grown itt a greenhouse and in orchards. Exposure to 5-10 microg/ml of oxamyl in water was lethal to only a few second-stage larvae treated 10 days, and many second-stage larvae in 2.0 microg/ml oxamyl recovered motility when transferred to fresh water. Aqueous solutions of 50 and 100 microg/ml of oxamyl were toxic to citrus nematode larvae. Additional observations indicate that oxamyl interfered with hatch of citrus nematode larvae and was nematistatic and/or protected sweet orange roots from infection. Oxamyl degraded at different rates in two soils. The number of citrus nematode larvae that infected and developed on sweet orange roots was increased by an undetermined product of the degradation of oxamyl in soil, water, and possibly within plants. This product apparently was translocated in roots.

Elucidating mechanisms of toxic action of dissolved organic chemicals in oil sands process-affected water (OSPW).

PubMed

Morandi, Garrett D; Wiseman, Steve B; Guan, Miao; Zhang, Xiaowei W; Martin, Jonathan W; Giesy, John P

2017-11-01

Oil sands process-affected water (OSPW) is generated during extraction of bitumen in the surface-mining oil sands industry in Alberta, Canada, and is acutely and chronically toxic to aquatic organisms. It is known that dissolved organic compounds in OSPW are responsible for most toxic effects, but knowledge of the specific mechanism(s) of toxicity, is limited. Using bioassay-based effects-directed analysis, the dissolved organic fraction of OSPW has previously been fractionated, ultimately producing refined samples of dissolved organic chemicals in OSPW, each with distinct chemical profiles. Using the Escherichia coli K-12 strain MG1655 gene reporter live cell array, the present study investigated relationships between toxic potencies of each fraction, expression of genes and characterization of chemicals in each of five acutely toxic and one non-toxic extract of OSPW derived by use of effects-directed analysis. Effects on expressions of genes related to response to oxidative stress, protein stress and DNA damage were indicative of exposure to acutely toxic extracts of OSPW. Additionally, six genes were uniquely responsive to acutely toxic extracts of OSPW. Evidence presented supports a role for sulphur- and nitrogen-containing chemical classes in the toxicity of extracts of OSPW. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effect of temperature and heating rate on apparent lethal concentrations of pyrolysis products

NASA Technical Reports Server (NTRS)

Hilado, C. J.; Solis, A. N.; Marcussen, W. H.; Furst, A.

1976-01-01

The apparent lethal concentrations for 50 percent of the test animals of the pyrolysis products from twelve polymeric materials were studied as a function of temperature and heating rate. The materials were polyethylene, nylon 6, ABS, polycarbonate, polyether sulfone, polyaryl sulfone, wool fabric, aromatic polyamide fabric, polychloroprene foam, polyvinyl fluoride film, Douglas fir, and red oak. The apparent lethal concentration values of most materials vary significantly with temperature and heating rate. The apparent lethal concentration values, based on weight of sample charged, appears to effectively integrate the thermophysical, thermochemical, and physiological responses from a known quantity of material under specified imposed conditions.

Does plant apparency matter? Thirty years of data provide limited support but reveal clear patterns of the effects of plant chemistry on herbivores.

PubMed

Smilanich, Angela M; Fincher, R Malia; Dyer, Lee A

2016-05-01

According to the plant-apparency hypothesis, apparent plants allocate resources to quantitative defenses that negatively affect generalist and specialist herbivores, while unapparent plants invest more in qualitative defenses that negatively affect nonadapted generalists. Although this hypothesis has provided a useful framework for understanding the evolution of plant chemical defense, there are many inconsistencies surrounding associated predictions, and it has been heavily criticized and deemed obsolete. We used a hierarchical Bayesian meta-analysis model to test whether defenses from apparent and unapparent plants differ in their effects on herbivores. We collected a total of 225 effect sizes from 158 published papers in which the effects of plant chemistry on herbivore performance were reported. As predicted by the plant-apparency hypothesis, we found a prevalence of quantitative defenses in woody plants and qualitative defenses in herbaceous plants. However, the detrimental impacts of qualitative defenses were more effective against specialists than generalists, and the effects of chemical defenses did not significantly differ between specialists and generalists for woody or herbaceous plants. A striking pattern that emerged from our data was a pervasiveness of beneficial effects of secondary metabolites on herbivore performance, especially generalists. This pattern provides evidence that herbivores are evolving effective counteradaptations to putative plant defenses. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

Neuroimmune Basis of Methamphetamine Toxicity

PubMed Central

Loftis, Jennifer M.; Janowsky, Aaron

2015-01-01

Although it is not known which antigen-specific immune responses (or if antigen-specific immune responses) are relevant or required for methamphetamine's neurotoxic effects, it is apparent that methamphetamine exposure is associated with significant effects on adaptive and innate immunity. Alterations in lymphocyte activity and number, changes in cytokine signaling, impairments in phagocytic functions, and glial activation and gliosis have all been reported. These drug-induced changes in immune response, particularly within the CNS, are now thought to play a critical role in the addiction process for methamphetamine dependence as well as for other substance use disorders. In Section 2, methamphetamine's effects on glial cell (e.g., microglia and astrocytes) activity and inflammatory signaling cascades are summarized, including how alterations in immune cell function can induce the neurotoxic and addictive effects of methamphetamine. Section 2 also describes neurotransmitter involvement in the modulation of methamphetamine's inflammatory effects. Section 3 discusses the very recent use of pharmacological and genetic animal models which have helped elucidate the behavioral effects of methamphetamine's neurotoxic effects and the role of the immune system. Section 4 is focused on the effects of methamphetamine on blood–brain barrier integrity and associated immune consequences. Clinical considerations such as the combined effects of methamphetamine and HIV and/or HCV on brain structure and function are included in Section 4. Finally, in Section 5, immune-based treatment strategies are reviewed, with a focus on vaccine development, neuroimmune therapies, and other anti-inflammatory approaches. PMID:25175865

Effect of electromagnetic fields on some biomechanical and biochemical properties of rat’s blood

NASA Astrophysics Data System (ADS)

Mohaseb, M. A.; Shahin, F. A.; Ali, F. M.; Baieth, H. A.

2017-06-01

In order to study the effect of electromagnetic fields (0.3 mT, 50 Hz) on some biomechanical and biochemical properties of rats’ blood, healthy thirty male albino rats of 150 ± 10 g were divided into three equal groups namely A, B1, B2. Group A used as a control group, group B1 was continuously exposed to a magnetic field of (0.3 mT, 50 Hz) for a period of 21 days for direct effect studies. Group B2 was continuously exposed to the same magnetic field for the same period of time, then was housed away from the magnetic field for a period of 45 days for delayed effects studies. After examination, the results indicated that the apparent viscosity and the consistency index increased significantly and very high significantly for groub B1 and B2 compared to control at P<0.05. Red blood cell counts (RBCs) membrane elasticity had significantly and very high significantly decreased for groups B1 and B2. Moreover, delayed effects studies indicated that there is deterioration in the bone marrow functions. These results are supported by the blood film image, where irregularities and deformations in the RBCs membranes had been occurred. We conclude that the cell membrane properties are highly affected by the extremely low frequency (ELF) magnetic fields, which proved to be biologically toxic.

Effects of the antituberculous drug ethambutol on zinc balance, distribution, and turnover: short-term studies modeling chronic toxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

King, A.B.

1987-01-01

Alterations in Zn metabolism have been reported in both tuberculous patients and experimental animals receiving ethambutol (d-2-2'-ethylenediimino-di-1-butanol dihydrochloride) (EMB), and these changes have been associated with ocular side effects of EMB. EMB has chelating properties but is not likely to chelate Zn at physiologic pH. However, its acid metabolite is a stronger chelator. This research addressed whether EMB affects the absorption and disposition of dietary Zn, and whether effects of EMB on Zn are modified by (a) marginal Zn intake of (b) drugs that may induce metabolism of EMB. Weanling male Sprague-Dawley rats fed an AIN-76A diet received daily bymore » gavage either deionized water or EMB doses of 400-1600 mg/kg bw. in a preliminary, 15-day dose-response study and 400-600 mg/kg in three subsequent 15- to 30-day studies. Apparent absorption and biological turnover of Zn were measured by /sup 65/Zn balance and retention in rats fed adequate (49 ppm) or marginal (11 ppm) Zn. Effects of EMB were similar in both dietary groups. EMB treatment produced alopecia and reduced feed intake, feed efficiency, weight gain, and serum Zn, but showed no effect on hepatic, renal, or femoral Zn concentrations. Absorption, turnover, and urinary excretion of Zn were increased in rats fed EMB.« less

Evaluating endocrine endpoints relative to reproductive success in Japanese quail exposed to estrogenic chemicals [poster

USGS Publications Warehouse

Henry, P.F.P.; Russek-Cohen, E.; Casey, C.S.; Abdelnabi, M.A.; Ottinger, M.A.

2000-01-01

The standard US EPA guidelines for avian reproductive testing may not be sufficiently sensitive to detect effects of sublethal and chronic exposure to endocrine disrupting toxins. There is a need to evaluate endocrine endpoints as potential markers for contaminant effects, and to determine their effectiveness and sensitivity when applied to wildlife. To this end, a three generational test was conducted using the Japanese quail (Coturnix japonica) and a proven estrogenic PCB. Birds were exposed during embryonic development via maternal deposition and/or direct egg injection at day 4. Standard measures of reproductive success and productivity used in toxicological studies, as well as multiple measures of physiological and behavioral responses used in endocrine studies were collected. Long term effects on growth and apparent development were similar between treated and control offspring. Fertility of treated eggs decreased from 75%+ 4.4 (x + se) for P1, to 59% + 12.5 for F1 and 54% + 14.2 for F2. All paired control birds mated to produce viable eggs, whereas 27 % of the F1 and 41 % of the F2 treated pairs failed to produce at least 1 viable egg. Although some decreases in productivity can be related to direct toxic exposure, the response from one generation to the next was not linear with treatment, indicating a potential effect from behavioral or other endocrine alterations.

Striatal increase of neurotrophic factors as a mechanism of nicotine protection in experimental parkinsonism.

PubMed

Maggio, R; Riva, M; Vaglini, F; Fornai, F; Racagni, G; Corsini, G U

1997-01-01

The repeated finding of an apparent protective effect of cigarette smoking on the risk of Parkinson's disease is one of the few consistent results in the epidemiology of this disorder. Among the innumerous substances that originate from tobacco smoke, nicotine is by far the most widely studied, and the most likely candidate for a protective effect against neuronal degeneration in Parkinson's disease. Nicotine is a natural alkaloid that has considerable stimulatory effects on the central nervous system (CNS). Its effects on the CNS are mediated by the activation of neuronal heteromeric acetylcholine-gated ion channel receptors (nAChR, also termed nicotinic acetylcholine receptors). In the present study, we describe the neuroprotective effects of (-)nicotine in two animal models of parkinsonism: the diethyldithiocarbamate (DDC)-induced enhancement of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice, and the methamphetamine-induced neurotoxicity in rats and mice. In parallel experiments, we found that (-)nicotine induces the basic fibroblast growth factor (FGF-2) and the brain-derived neurotrophic factor (BDNF) in rat striatum. As FGF-2 and BDNF have been reported to be neuroprotective for dopaminergic cells, our data indicate that the increase in neurotrophic factors is a possible mechanism by which (-)nicotine protects from experimental parkinsonisms. Moreover, they suggest that nAChR agonists could be of potential benefit in the progression of Parkinson's disease.

Detection of Sessile Serrated Adenomas in the Proximal Colon Using Wide-Field Fluorescence Endoscopy.

PubMed

Joshi, Bishnu P; Dai, Zhenzhen; Gao, Zhenghong; Lee, Jeong Hoon; Ghimire, Navin; Chen, Jing; Prabhu, Anoop; Wamsteker, Erik J; Kwon, Richard S; Elta, Grace H; Stoffel, Elena M; Pant, Asha; Kaltenbach, Tonya; Soetikno, Roy M; Appelman, Henry D; Kuick, Rork; Turgeon, D Kim; Wang, Thomas D

2017-04-01

Many cancers in the proximal colon develop via from sessile serrated adenomas (SSAs), which have flat, subtle features that are difficult to detect with conventional white-light colonoscopy. Many SSA cells have the V600E mutation in BRAF. We investigated whether this feature could be used with imaging methods to detect SSAs in patients. We used phage display to identify a peptide that binds specifically to SSAs, using subtractive hybridization with HT29 colorectal cancer cells containing the V600E mutation in BRAF and Hs738.St/Int cells as a control. Binding of fluorescently labeled peptide to colorectal cancer cells was evaluated with confocal fluorescence microscopy. Rats received intra-colonic 0.0086 mg/kg, 0.026 mg/kg, or 0.86 mg/kg peptide or vehicle and morbidity, mortality, and injury were monitored twice daily to assess toxicity. In the clinical safety study, fluorescently labeled peptide was topically administered, using a spray catheter, to the proximal colon of 25 subjects undergoing routine outpatient colonoscopies (3 subjects were given 2.25 μmol/L and 22 patients were given 76.4 μmol/L). We performed blood cell count, chemistry, liver function, and urine analyses approximately 24 hours after peptide administration. In the clinical imaging study, 38 subjects undergoing routine outpatient colonoscopies, at high risk for colorectal cancer, or with a suspected unresected proximal colonic polyp, were first evaluated by white-light endoscopy to identify suspicious regions. The fluorescently labeled peptide (76.4 μmol/L) was administered topically to proximal colon, unbound peptide was washed away, and white-light, reflectance, and fluorescence videos were recorded digitally. Fluorescence intensities of SSAs were compared with those of normal colonic mucosa. Endoscopists resected identified lesions, which were analyzed histologically by gastrointestinal pathologists (reference standard). We also analyzed the ability of the peptide to identify SSAs vs adenomas, hyperplastic polyps, and normal colonic mucosa in specimens obtained from the tissue bank at the University of Michigan. We identified the peptide sequence KCCFPAQ and measured an apparent dissociation constant of K d  = 72 nM and an apparent association time constant of K = 0.174 min -1 (5.76 minutes). During fluorescence imaging of patients during endoscopy, regions of SSA had 2.43-fold higher mean fluorescence intensity than that for normal colonic mucosa. Fluorescence labeling distinguished SSAs from normal colonic mucosa with 89% sensitivity and 92% specificity. The peptide had no observed toxic effects in animals or patients. In the analysis of ex vivo specimens, peptide bound to SSAs had significantly higher mean fluorescence intensity than to hyperplastic polyps. We have identified a fluorescently labeled peptide that has no observed toxic effects in animals or humans and can be used for wide-field imaging of lesions in the proximal colon. It distinguishes SSAs from normal colonic mucosa with 89% sensitivity and 92% specificity. This targeted imaging method might be used in early detection of premalignant serrated lesions during routine colonoscopies. ClinicalTrials.gov ID: NCT02156557. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Detection of Sessile Serrated Adenomas in Proximal Colon Using Wide-field Fluorescence Endoscopy

PubMed Central

Joshi, Bishnu P.; Dai, Zhenzhen; Gao, Zhenghong; Lee, Jeong Hoon; Ghimire, Navin; Chen, Jing; Prabhu, Anoop; Wamsteker, Erik J.; Kwon, Richard S.; Elta, Grace H.; Stoffel, Elena M.; Pant, Asha; Kaltenbach, Tonya; Soetikno, Roy M.; Appelman, Henry D.; Kuick, Rork; Turgeon, D. Kim; Wang, Thomas D.

2018-01-01

Background & Aims Many cancers in the proximal colon develop via from sessile serrated adenomas (SSAs), which have flat, subtle features that are difficult to detect with conventional white-light colonoscopy. Many SSA cells have the V600E mutation in BRAF. We investigated whether this feature could be used with imaging methods to detect SSAs in patients. Methods We used phage display to identify a peptide that binds specifically to SSAs, using subtractive hybridization with HT29 colorectal cancer cells containing the V600E mutation in BRAF and Hs738.St/Int cells as a control. Binding of fluorescently labeled peptide to colorectal cancer cells was evaluated with confocal fluorescence microscopy. Rats received intra-colonic 0.0086 mg/kg, 0.026 mg/kg, or 0.86 mg/kg peptide or vehicle and morbidity, mortality, and injury were monitored twice daily to assess toxicity. In the clinical safety study, fluorescently labeled peptide was topically administered, using a spray catheter, to the proximal colon of 25 subjects undergoing routine outpatient colonoscopies (3 subjects were given 2.25 µmol/L and 22 patients were given 76.4 µmol/L). We performed blood cell count, chemistry, liver function, and urine analyses approximately 24 hrs after peptide administration. In the clinical imaging study, 38 subjects undergoing routine outpatient colonoscopies, at high risk for colorectal cancer, or with a suspected unresected proximal colonic polyp, were first evaluated by white-light endoscopy, to identify suspicious regions. The fluorescently labeled peptide (76.4 µmol/L) was administered topically to proximal colon, unbound peptide was washed away, and white-light, reflectance, and fluorescence videos were recorded digitally. Fluorescence intensities of SSAs were compared with those of normal colonic mucosa. Endoscopists resected identified lesions, which were analyzed histologically by gastrointestinal pathologists (reference standard). We also analyzed the ability of the peptide to identify SSAs vs adenomas, hyperplastic polyps, and normal colonic mucosa in specimens obtained from the tissue bank at the University of Michigan. Results We identified the peptide sequence KCCFPAQ, and measured an apparent dissociation constant of kd = 72 nM and an apparent association time constant of k = 0.174 min−1 (5.76 min). During fluorescence imaging of patients during endoscopy, regions of SSA had 2.43-fold higher mean fluorescence intensity than that for normal colonic mucosa. Fluorescence labeling distinguished SSAs from normal colonic mucosa with 89% sensitivity and 92% specificity. The peptide had no observed toxic effects in animals or patients. In the analysis of ex vivo specimens, peptide bound to SSAs had significantly higher mean fluorescence intensity than to hyperplastic polyps. Conclusions We have identified a fluorescently labeled peptide that has no observed toxic effects in animals or humans and can be used for wide-field imaging of lesions in the proximal colon. It distinguishes SSAs from normal colonic mucosa with 89% sensitivity and 92% specificity. This targeted imaging method might be used in early detection of pre-malignant serrated lesions during routine colonoscopies. ClinicalTrials.gov no: NCT02156557 PMID:28012848

Risk assessment of human health from exposure to the discharged ballast water after full-scale electrolysis treatment.

PubMed

Zhang, Nahui; Wang, Yidan; Xue, Junzeng; Yuan, Lin; Wang, Qiong; Liu, Liang; Wu, Huixian; Hu, Kefeng

2016-06-01

The presence of disinfection by-products (DBPs) releasing from ballast water management systems (BWMS) can cause a possible adverse effects on humans. The objectives of this study were to compute the Derived No Effect Levels (DNELs) for different exposure scenarios and to compare these levels with the exposure levels from the measured DBPs in treated ballast water. The risk assessment showed that when using animal toxicity data, all the DNELs values were approximately 10(3)-10(12) times higher than the exposure levels of occupational and general public exposure scenarios, indicating the level of risk was low (risk characterization ratios (RCRs) < 1). However, when using human data, the RCRs were higher than 1 for dichlorobromomethane and trichloromethane, indicating that the risk of adverse effects on human were significant. This implies that there are apparent discrepancies between risk characterization from animal and human data, which may affect the overall results. We therefore recommend that when appropriate, human data should be used in risk assessment as much as possible, although human data are very limited. Moreover, more appropriate assessment factors can be considered to be employed in estimating the DNELs for human when the animal data is selected as the dose descriptors. Copyright © 2016 Elsevier Inc. All rights reserved.

Environmental effects on nutrient and energy metabolism in ruminants.

PubMed

Tamminga, S; Schrama, J W

1998-01-01

Domesticated animals all over the world are subjected to a wide variety of environmental conditions and challenges. Any deviation from "normal" may result in adaptive behavior of which changes in feed intake or feed intake pattern is by far the most important. Adaptive behavior may further include influences on passage rate of feed residues through the digestive tract, resulting in changes in digestibility. Adaptive behavior may also result in changes in heat production, either to maintain body temperature constant, or as a result of an elevated body temperature. Important environmental challenges are infectious diseases. Mild (sub-clinical) infections usually result in reduced performance, without affecting feed intake or digestibility. Severe infections may disrupt the barriers between the internal metabolism and the respiratory and/or digestive tract, resulting in severe losses of energy and protein. This situation is notably apparent in severe infections with parasites of the gastrointestinal tract and may be associated with severe protein losses. Feeding high protein diets may partly alleviate the negative effects. Contamination of air, water and feed may occasionally cause problems in farm animals. Such contamination may include pathogenic microbes, toxic secondary fungal metabolites and heavy metals. Negative effects associated with such contamination often show an impaired reproductive efficiency, but their influence on the utilization of energy and nutrients is not well documented.

Uptake of all-trans retinoic acid–containing aerosol by inhalation to lungs in a guinea pig model system—A pilot study

PubMed Central

Schäffer, Michael W.; Roy, Somdutta Sinha; Mukherjee, Shyamali; Ong, David E.; Das, Salil K.

2010-01-01

Systemic therapies with retinoic acid (RA) can result in toxic side effects without yielding biologically effective levels in target tissues such as lung. The authors adapted a PARI LC Star nebulizer to create a tubular system for short-term inhalation treatment of guinea pigs using a water-miscible formulation of all-trans RA (ATRA) or vehicle. Based on the initial average weight, animals received an estimated average ATRA doses of either 0.32 mg·kg−1 (low dose, 1.4 mM), or 0.62 mg·kg−1 (medium dose, 2.8 mM), or 1.26 mg·kg−1 (high dose, 5.6 mM) 20 minutes per day for 6 consecutive days. This system led to a rise of ATRA levels in lung, but not liver or plasma. Cellular lung levels of retinol, retinyl palmitate, and retinyl stearate also appeared to be unaffected (245.6 ± 10.7, 47.4 ± 3.4, and 132.8 ± 7.7 ng·g−1 wet weight, respectively). The application of this aerosolized ATRA also induced a dose-dependent protein expression of the cellular retinol-binding protein 1 (CRBP-1) in lung, without apparent harmful side effects. PMID:21043991

Effects of Metal Micro and Nano-Particles on hASCs: An In Vitro Model.

PubMed

Palombella, Silvia; Pirrone, Cristina; Rossi, Federica; Armenia, Ilaria; Cherubino, Mario; Valdatta, Luigi; Raspanti, Mario; Bernardini, Giovanni; Gornati, Rosalba

2017-08-03

As the knowledge about the interferences of nanomaterials on human staminal cells are scarce and contradictory, we undertook a comparative multidisciplinary study based on the size effect of zero-valent iron, cobalt, and nickel microparticles (MPs) and nanoparticles (NPs) using human adipose stem cells (hASCs) as a model, and evaluating cytotoxicity, morphology, cellular uptake, and gene expression. Our results suggested that the medium did not influence the cell sensitivity but, surprisingly, the iron microparticles (FeMPs) resulted in being toxic. These data were supported by modifications in mRNA expression of some genes implicated in the inflammatory response. Microscopic analysis confirmed that NPs, mainly internalized by endocytosis, persist in the vesicles without any apparent cell damage. Conversely, MPs are not internalized, and the effects on hASCs have to be ascribed to the release of ions in the culture medium, or to the reduced oxygen and nutrient exchange efficiency due to the presence of MP agglomerating around the cells. Notwithstanding the results depicting a heterogeneous scene that does not allow drawing a general conclusion, this work reiterates the importance of comparative investigations on MPs, NPs, and corresponding ions, and the need to continue the thorough verification of NP and MP innocuousness to ensure unaffected stem cell physiology and differentiation.

Preventive effect of oral administration of 6-(methylsulfinyl)hexyl isothiocyanate derived from wasabi (Wasabia japonica Matsum) against pulmonary metastasis of B16-BL6 mouse melanoma cells.

PubMed

Fuke, Yoko; Shinoda, Shoko; Nagata, Ikuko; Sawaki, Saeko; Murata, Mituyoshi; Ryoyama, Kazuo; Koizumi, Keiichi; Saiki, Ikuo; Nomura, Takahiro

2006-01-01

Effect of oral administration of 6-(methylsulfinyl)hexyl isothiocyanate (6-MITC) or a 6-MITC-containing T-wasabi fraction from wasabi root (Wasabia japonica Matsum) to inhibit the macroscopic pulmonary metastasis was studied with a murine B16-BL6 melanoma model. Two administration routes, subcutaneous or intravenous, and two administration times, prior to or concomitant with tumor inoculation, of 6-MITC or T-wasabi against the metastatic foci formation in C57BL/6J mouse lungs were compared. The number of metastasized foci per lung in either subcutaneous or intravenous injection was significantly reduced by intake of 6-MITC or a T-wasabi fraction. The maximum reduction by a T-wasabi fraction reached to 82%. Fifty-six percent of foci formation was inhibited by a 2 week-prior administration of 6-MITC (200 microM), whereas only 27% inhibition was obtained by a concomitant administration with tumor inoculation. Neither 6-MITC nor T-wasabi at tested concentrations showed any toxic effects. Together with our previous results, a component of the Japanese pungent spice, wasabi appears to inhibit not only tumor cell growth but also tumor metastasis. Therefore, 6-MITC from wasabi is apparently a useful dietary candidate for controlling tumor progression.

Bioremediation techniques-classification based on site of application: principles, advantages, limitations and prospects.

PubMed

Azubuike, Christopher Chibueze; Chikere, Chioma Blaise; Okpokwasili, Gideon Chijioke

2016-11-01

Environmental pollution has been on the rise in the past few decades owing to increased human activities on energy reservoirs, unsafe agricultural practices and rapid industrialization. Amongst the pollutants that are of environmental and public health concerns due to their toxicities are: heavy metals, nuclear wastes, pesticides, green house gases, and hydrocarbons. Remediation of polluted sites using microbial process (bioremediation) has proven effective and reliable due to its eco-friendly features. Bioremediation can either be carried out ex situ or in situ, depending on several factors, which include but not limited to cost, site characteristics, type and concentration of pollutants. Generally, ex situ techniques apparently are more expensive compared to in situ techniques as a result of additional cost attributable to excavation. However, cost of on-site installation of equipment, and inability to effectively visualize and control the subsurface of polluted sites are of major concerns when carrying out in situ bioremediation. Therefore, choosing appropriate bioremediation technique, which will effectively reduce pollutant concentrations to an innocuous state, is crucial for a successful bioremediation project. Furthermore, the two major approaches to enhance bioremediation are biostimulation and bioaugmentation provided that environmental factors, which determine the success of bioremediation, are maintained at optimal range. This review provides more insight into the two major bioremediation techniques, their principles, advantages, limitations and prospects.

Correlation of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced apoptotic cell death in the embryonic vasculature with embryotoxicity

USGS Publications Warehouse

Cantrell, Susannah M.; Joy-Schlezinger, Jennifer; Stegeman, John J.; Tillitt, Donald E.; Hannington, Mark D.

1998-01-01

Vertebrate embryos are particularly sensitive to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Identification of tissues that are susceptible to the adverse effects of TCDD is requisite for understanding the embryo toxic effects of TCDD. The objective of the present study was to quantitate the temporal appearance of and dose dependence of apoptosis in TCDD-exposed medaka embryos (Oryzias latipes). A fluorescent-based DNA end-labeling assay provided a sensitive method for detection of TCDD-induced apoptosis in tissue sections of medaka embryos. Apoptotic cells were readily apparent in the medial yolk vein at all observed embryonic stages in TCDD-exposed embryos. Slope-comparison analysis indicated that TCDD-induced programmed cell death in the embryonic medial yolk vein was mechanistically linked to embryo mortality. These data are consistent with the hypothesis that vascular damage contributes to the acute embryo toxic effects of TCDD. However, as sublethal concentrations of dioxin-like compounds are more typical of environmental exposures, tissue damage was also assessed in medaka fry that were exposed to low doses of TCDD during embryonic development. Cell death was detected in gill and digestive tissues in visibly healthy medaka fry that had been exposed to low doses of TCDD during embryonic development. Increased expression of cytochrome P450 1A is a major biochemical consequence of TCDD exposure and is often used as a biomarker for exposure to dioxin-like compounds. Therefore, we compared the tissue distribution of TCDD-induced P450 1A expression and TCDD-induced programmed cell death. TCDD-induced programmed cell death co-localized with TCDD-induced P450 1A expression in both embryos and in visibly healthy post-hatch fry. Our results suggest that aberrant programmed cell death may be a suitable marker for exposure of feral organisms to dioxin-like compounds.

Toxicity of selenium and other elements in food organisms to razorback sucker larvae

USGS Publications Warehouse

Hamilton, Steven J.; Holley, Kathy M.; Buhl, Kevin J.; Bullard, Fern A.; Weston, L. Ken; McDonald, Susan F.

2002-01-01

Elevated selenium concentrations documented in water, sediment, and biota in irrigation drain water studies by U.S. Department of the Interior agencies and academia have raised concerns that selenium may be adversely affecting endangered fish in the upper Colorado River basin. The objective of the study was to determine the effects on endangered razorback sucker (Xyrauchen texanus) larvae from exposure to selenium and other trace elements in water and zooplankton collected from sites adjacent to the Colorado River near Grand Junction, CO. A 30-day study was initiated with 5-day-old larvae exposed in a 4×4 factor experiment with four food and four water treatments, and the biological endpoints measured were survival, growth, development, and whole-body residues of selenium. Mean selenium concentration in reference water (24-Road) was <0.7 μg/l, in reference food (brine shrimp) was 3.2 μg/g, at Horsethief was 1.6 μg/l in water and 6.0 μg/g in zooplankton, at Adobe Creek was 3.4 μg/l in water and 32 μg/g in zooplankton, and at Walter Walker was 13 μg/l in water and 52 μg/g in zooplankton. Although there were differences in concentrations of inorganic elements in water and biota among the three sites, selenium was apparently the only element elevated to concentrations of concern. Effects on survival were more prominent from dietary exposure compared to waterborne exposure. Selenium concentrations of ≥4.6 μg/g in food organisms adversely affected the survival of razorback sucker larvae. The onset of mortality in larvae exposed to food and water from Walter Walker seemed delayed compared to mortality in larvae exposed to food and water from Horsethief, which has been observed in two other studies. Elevated arsenic in one food source seemed to interact with selenium to reduce the toxic effects of selenium.

Influence of organophosphate poisoning on human dendritic cells.

PubMed

Schäfer, Marina; Koppe, Franziska; Stenger, Bernhard; Brochhausen, Christoph; Schmidt, Annette; Steinritz, Dirk; Thiermann, Horst; Kirkpatrick, Charles James; Pohl, Christine

2013-12-05

Organophosphourus compounds (OPC, including nerve agents and pesticides) exhibit acute toxicity by inhibition of acetylcholinesterase. Lung affections are frequent complications and a risk factor for death. In addition, epidemiological studies reported immunological alterations after OPC exposure. In our experiments we investigated the effects of organophosphourus pesticides dimethoate and chlorpyrifos on dendritic cells (DC) that are essential for the initial immune response, especially in the pulmonary system. DC, differentiated from the monocyte cell line THP-1 by using various cytokines (IL-4, GM-CSF, TNF-α, Ionomycin), were exposed to organophosphourus compounds at different concentrations for a 24h time period. DC were characterized by flow cytometry and immunofluorescence using typical dendritic cell markers (e.g., CD11c, CD209 and CD83). After OPC exposure we investigated cell death, the secretion profile of inflammatory mediators, changes of DC morphology, and the effect on protein kinase signalling pathways. Our results revealed a successful differentiation of THP-1 into DC. OPC exposure caused a significant concentration-dependent influence on DC: Dendrites of the DC were shortened and damaged, DC-specific cell surface markers (i.e., CD83and CD209) decreased dramatically after chlorpyrifos exposure. Interestingly, the effects caused by dimethoate were in general less pronounced. The organophosphourus compounds affected the release of inflammatory cytokines, such as IL-1ß and IL-8. The anti-inflammatory cytokine IL-10 was significantly down regulated. Protein kinases like the Akt family or ERK, which are essential for cell survival and proliferation, were inhibited by both OPC. These findings indicate that the tested organophosphourus compounds induced significant changes in cell morphology, inhibited anti-inflammatory cytokines and influenced important protein signalling pathways which are involved in regulation of apoptosis. Thus our results highlight novel aspects -apparently independent of AChE inhibition- of OPC poisoning with regard to lung toxicity. Our findings contribute to the basic understanding of pulmonary complications caused by OPC poisoning. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Toxicity of selenium and other elements in food organisms to razorback sucker larvae.

PubMed

Hamilton, Steven J; Holley, Kathy M; Buhl, Kevin J; Bullard, Fern A; Weston, L Ken; McDonald, Susan F

2002-09-24

Elevated selenium concentrations documented in water, sediment, and biota in irrigation drain water studies by U.S. Department of the Interior agencies and academia have raised concerns that selenium may be adversely affecting endangered fish in the upper Colorado River basin. The objective of the study was to determine the effects on endangered razorback sucker (Xyrauchen texanus) larvae from exposure to selenium and other trace elements in water and zooplankton collected from sites adjacent to the Colorado River near Grand Junction, CO. A 30-day study was initiated with 5-day-old larvae exposed in a 4 x 4 factor experiment with four food and four water treatments, and the biological endpoints measured were survival, growth, development, and whole-body residues of selenium. Mean selenium concentration in reference water (24-Road) was <0.7 microg/l, in reference food (brine shrimp) was 3.2 microg/g, at Horsethief was 1.6 microg/l in water and 6.0 microg/g in zooplankton, at Adobe Creek was 3.4 microg/l in water and 32 microg/g in zooplankton, and at Walter Walker was 13 microg/l in water and 52 microg/g in zooplankton. Although there were differences in concentrations of inorganic elements in water and biota among the three sites, selenium was apparently the only element elevated to concentrations of concern. Effects on survival were more prominent from dietary exposure compared to waterborne exposure. Selenium concentrations of >or=4.6 microg/g in food organisms adversely affected the survival of razorback sucker larvae. The onset of mortality in larvae exposed to food and water from Walter Walker seemed delayed compared to mortality in larvae exposed to food and water from Horsethief, which has been observed in two other studies. Elevated arsenic in one food source seemed to interact with selenium to reduce the toxic effects of selenium.

Novel non-trimethoxylphenyl piperlongumine derivatives selectively kill cancer cells.

PubMed

Zhang, Youjun; Ma, Hao; Wu, Yuelin; Wu, Zhongli; Yao, Zhengguang; Zhang, Wannian; Zhuang, Chunlin; Miao, Zhenyuan

2017-06-01

Piperlongumine (PL) is a natural alkaloid with broad biological activities. Twelve analogues have been designed and synthesized with non-substituted benzyl rings or heterocycles in this work. Most of the compounds showed better anticancer activities than the parent PL without apparent toxicity in normal cells. Elevation of cellular ROS levels was one of the main anticancer mechanisms of these compounds. Cell apoptosis and cell cycle arrest for the best compound ZM90 were evaluated and similar mechanism of action with PL was demonstrated. The SAR was also characterized, providing worthy directions for further optimization of PL compounds. Copyright © 2017 Elsevier Ltd. All rights reserved.

Moderator's view: High-volume plasma exchange: pro, con and consensus.

PubMed

Kaplan, Andre A

2017-09-01

I have been asked to comment on the pro and con opinions regarding high-volume plasma exchange. The authors of both positions have provided cogent arguments and a reasonable approach to choosing the exchange volume for any given therapeutic plasma exchange. The major issue of relevance in this discussion is the nature of the toxins targeted for removal. These parameters include molecular weight, the apparent volume of distribution, the degree of protein binding, the biologic and chemical half-life, and the severity and rapidity of its toxicity. © The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Specific toxic effect of dinoflagellate Heterocapsa circularisquama on the rotifer Brachionus plicatilis.

PubMed

Kim, D; Sato, Y; Oda, T; Muramatsu, T; Matsuyama, Y; Honjo, T

2000-12-01

Heterocapsa circularisquama (Dinophyceae), a noxious red tide dinoflagellate, is known to have a specifically lethal effect on shellfish, especially bivalves such as pearl oyster (Pinctada fucata), but no detrimental effects of this alga on fishes have not been observed so far. In this study, we found that H. circularisquama was toxic to a microzooplankton, a rotifer (Brachionus plicatilis) in a cell concentration-dependent manner, while the cultured supernatant or ultrasonic ruptured H. circularisquama had no significant toxic effect on the rotifer. Since no such toxic effects on the rotifer were observed in Chattonella marina, Heterosigma akashiwo, or Cochlodinium polykrikoides, other species of harmful red tide plankton, H. circularisquama may have a strictly specific toxic mechanism against the rotifer as well as bivalves.

Metabolite toxicity determines the pace of molecular evolution within microbial populations.

PubMed

Lilja, Elin E; Johnson, David R

2017-02-14

The production of toxic metabolites has shaped the spatial and temporal arrangement of metabolic processes within microbial cells. While diverse solutions to mitigate metabolite toxicity have evolved, less is known about how evolution itself is affected by metabolite toxicity. We hypothesized that the pace of molecular evolution should increase as metabolite toxicity increases. At least two mechanisms could cause this. First, metabolite toxicity could increase the mutation rate. Second, metabolite toxicity could increase the number of available mutations with large beneficial effects that selection could act upon (e.g., mutations that provide tolerance to toxicity), which consequently would increase the rate at which those mutations increase in frequency. We tested this hypothesis by experimentally evolving the bacterium Pseudomonas stutzeri under denitrifying conditions. The metabolite nitrite accumulates during denitrification and has pH-dependent toxic effects, which allowed us to evolve P. stutzeri at different magnitudes of nitrite toxicity. We demonstrate that increased nitrite toxicity results in an increased pace of molecular evolution. We further demonstrate that this increase is generally due to an increased number of available mutations with large beneficial effects and not to an increased mutation rate. Our results demonstrate that the production of toxic metabolites can have important impacts on the evolutionary processes of microbial cells. Given the ubiquity of toxic metabolites, they could also have implications for understanding the evolutionary histories of biological organisms.

Paralytic shellfish poisoning toxins accumulation in purple clam Hiatula rostrata and toxic effect on milkfish Chanos chanos larval fish.

PubMed

Chen, C Y

2001-11-01

In an attempt to feed purple clams (Hiatula rostrata) with dinoglagellate Alexandrium minutum, the maximal accumulation toxicity of paralytic shellfish poisoning (PSP) toxins reached 40.6 MU/g on day 5 of feeding. Subsequently, the toxicity increased no further, although purple clams ingested more toxic algae. Furthermore, when milkfish (Chanos chanos) larvae were treated with toxic, nontoxic A. minutum or PSP toxin-containing extract in the water medium, it was found that the mortality of fish increased with the increasing concentrations of toxic algae. PSP toxin-containing extract did not show any toxic effect on milkfish larvae.

Critique on the use of the standardized avian acute oral toxicity test for first generation anticoagulant rodenticides

USGS Publications Warehouse

Vyas, Nimish B.; Rattner, Barnett A.

2012-01-01

Avian risk assessments for rodenticides are often driven by the results of standardized acute oral toxicity tests without regards to a toxicant's mode of action and time course of adverse effects. First generation anticoagulant rodenticides (FGARs) generally require multiple feedings over several days to achieve a threshold concentration in tissue and cause adverse effects. This exposure regimen is much different than that used in the standardized acute oral toxicity test methodology. Median lethal dose values derived from standardized acute oral toxicity tests underestimate the environmental hazard and risk of FGARs. Caution is warranted when FGAR toxicity, physiological effects, and pharmacokinetics derived from standardized acute oral toxicity testing are used for forensic confirmation of the cause of death in avian mortality incidents and when characterizing FGARs' risks to free-ranging birds.

Blood transcriptomics: applications in toxicology

PubMed Central

Joseph, Pius; Umbright, Christina; Sellamuthu, Rajendran

2015-01-01

The number of new chemicals that are being synthesized each year has been steadily increasing. While chemicals are of immense benefit to mankind, many of them have a significant negative impact, primarily owing to their inherent chemistry and toxicity, on the environment as well as human health. In addition to chemical exposures, human exposures to numerous non-chemical toxic agents take place in the environment and workplace. Given that human exposure to toxic agents is often unavoidable and many of these agents are found to have detrimental human health effects, it is important to develop strategies to prevent the adverse health effects associated with toxic exposures. Early detection of adverse health effects as well as a clear understanding of the mechanisms, especially at the molecular level, underlying these effects are key elements in preventing the adverse health effects associated with human exposure to toxic agents. Recent developments in genomics, especially transcriptomics, have prompted investigations into this important area of toxicology. Previous studies conducted in our laboratory and elsewhere have demonstrated the potential application of blood gene expression profiling as a sensitive, mechanistically relevant and practical surrogate approach for the early detection of adverse health effects associated with exposure to toxic agents. The advantages of blood gene expression profiling as a surrogate approach to detect early target organ toxicity and the molecular mechanisms underlying the toxicity are illustrated and discussed using recent studies on hepatotoxicity and pulmonary toxicity. Furthermore, the important challenges this emerging field in toxicology faces are presented in this review article. PMID:23456664

An integrated multi-label classifier with chemical-chemical interactions for prediction of chemical toxicity effects.

PubMed

Liu, Tao; Chen, Lei; Pan, Xiaoyong

2018-05-31

Chemical toxicity effect is one of the major reasons for declining candidate drugs. Detecting the toxicity effects of all chemicals can accelerate the procedures of drug discovery. However, it is time-consuming and expensive to identify the toxicity effects of a given chemical through traditional experiments. Designing quick, reliable and non-animal-involved computational methods is an alternative way. In this study, a novel integrated multi-label classifier was proposed. First, based on five types of chemical-chemical interactions retrieved from STITCH, each of which is derived from one aspect of chemicals, five individual classifiers were built. Then, several integrated classifiers were built by integrating some or all individual classifiers. By testing the integrated classifiers on a dataset with chemicals and their toxicity effects in Accelrys Toxicity database and non-toxic chemicals with their performance evaluated by jackknife test, an optimal integrated classifier was selected as the proposed classifier, which provided quite high prediction accuracies and wide applications. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Effects of arsenic toxicity on morphological characters in blackgram (Vigna mungo L.) during early growth stage.

PubMed

Shamim, M Z; Pandey, A

2017-07-31

Blackgram is an important pulse crop of the tropic and sub-tropic area and has been identified as a potential crop in many countries. In the south-East Asia arsenic toxicity in soil and water is one of the most environmental problems. Crop productivity is highly affected by cultivation in arsenic polluted soil or irrigation through arsenic polluted water. The present study was conducted to evaluate the effect of arsenic (As) on fresh shoot length, fresh shoot weight, fresh root length, fresh shoot weight and total fresh biomass, The results indicate that root length is more affected than shoot length due to arsenic toxicity. The fresh shoot weight observed was more affected than fresh root weight. This study indicates that arsenic toxicity causes the deleterious effect on blackgram growth. The toxic effect of blackgram depends on the genotypic variability. Some blackgram genotypes show very less toxic effect of arsenic due to its genetic makeup. Experimental findings of study indicate that longer root length and more shoot weight in arsenic stress condition may be tolerant blackgram genotype to arsenic toxicity.

Characterizing toxicity of metal-contaminated sediments from mining areas

USGS Publications Warehouse

Besser, John M.; Brumbaugh, William G.; Ingersoll, Christopher G.

2015-01-01

This paper reviews methods for testing the toxicity of metals associated with freshwater sediments, linking toxic effects with metal exposure and bioavailability, and developing sediment quality guidelines. The most broadly applicable approach for characterizing metal toxicity is whole-sediment toxicity testing, which attempts to simulate natural exposure conditions in the laboratory. Standard methods for whole-sediment testing can be adapted to test a wide variety of taxa. Chronic sediment tests that characterize effects on multiple endpoints (e.g., survival, growth, and reproduction) can be highly sensitive indicators of adverse effects on resident invertebrate taxa. Methods for testing of aqueous phases (pore water, overlying water, or elutriates) are used less frequently. Analysis of sediment toxicity data focuses on statistical comparisons between responses in sediments from the study area and responses in one or more uncontaminated reference sediments. For large or complex study areas, a greater number of reference sediments is recommended to reliably define the normal range of responses in uncontaminated sediments – the ‘reference envelope’. Data on metal concentrations and effects on test organisms across a gradient of contamination may allow development of concentration-response models, which estimate metal concentrations associated with specified levels of toxic effects (e.g. 20% effect concentration or EC20). Comparisons of toxic effects in laboratory tests with measures of impacts on resident benthic invertebrate communities can help document causal relationships between metal contamination and biological effects. Total or total-recoverable metal concentrations in sediments are the most common measure of metal contamination in sediments, but metal concentrations in labile sediment fractions (e.g., determined as part of selective sediment extraction protocols) may better represent metal bioavailability. Metals released by the weak-acid extraction of acid-volatile sulfide (AVS), termed simultaneously-extracted metals (SEM), are widely used to estimate the ‘potentially-bioavailable’ fraction of metals that is not bound to sulfides (i.e., SEM-AVS). Metal concentrations in pore water are widely considered to be direct measures of metal bioavailability, and predictions of toxicity based on pore-water metal concentrations may be further improved by modeling interactions of metals with other pore-water constituents using Biotic Ligand Models. Data from sediment toxicity tests and metal analyses has provided the basis for development of sediment quality guidelines, which estimate thresholds for toxicity of metals in sediments. Empirical guidelines such as Probable Effects Concentrations or (PECs) are based on associations between sediment metal concentrations and occurrence of toxic effects in large datasets. PECs do not model bioavailable metals, but they can be used to estimate the toxicity of metal mixtures using by calculation of probable effect quotients (PEQ = sediment metal concentration/PEC). In contrast, mechanistic guidelines, such as Equilibrium Partitioning Sediment Benchmarks (ESBs) attempt to predict both bioavailability and mixture toxicity. Application of these simple bioavailability models requires more extensive chemical characterization of sediments or pore water, compared to empirical guidelines, but may provide more reliable estimates of metal toxicity across a wide range of sediment types.

Effect of heating rate on toxicity of pyrolysis gases from some synthetic polymers

NASA Technical Reports Server (NTRS)

Hilado, C. J.; Soriano, J. A.; Kosola, K. L.

1977-01-01

The effect of heating rate on the toxicity of the pyrolysis gases from some synthetic polymers was investigate, using a screening test method. The synthetic polymers were polyethylene, polystyrene, polymethyl methacrylate, polycarbonate, ABS, polyaryl sulfone, polyether sulfone, and polyphenylene sulfide. The toxicants from the sulfur-containing polymers appeared to act more rapidly than the toxicants from the other polymers. It is not known whether this effect is due primarily to differences in concentration or in the nature of the toxicants. The carbon monoxide concentrations found do not account for the observed results.

Occupational Snake Bites: a Prospective Case Series of Patients Reported to the ToxIC North American Snakebite Registry.

PubMed

Spyres, Meghan B; Ruha, Anne-Michelle; Seifert, Steven; Onisko, Nancy; Padilla-Jones, Angela; Smith, Eric Anthony

2016-12-01

In the developing world, occupation has been identified as a risk factor for snake bite. Such an association has not been described in the USA. The objective of this study was to describe the epidemiology and clinical manifestations of occupational snake bite in patients reported to the ToxIC North American Snakebite Registry (NASBR). This was a prospective case series of patients reported to the ToxIC NASBR between January 1, 2014 and November 5, 2015. Variables collected included snake species, patient demographics, date and location of exposure, occupation, bite location, clinical manifestations, and management. Of 180 adult snake bites reported, 25 (13.9 %; 95 % CI 9.2-19.8 %) were occupational in nature. Rattlesnake envenomations were common (80 %). Most snake bites (96 %) occurred in men. Occupations most associated with snake bite were landscaping (28 %) and working directly with snakes (24 %). Fifty-six percent of bites occurred in an outdoor work environment. Seventy-six percent of envenomations were to the upper extremities. Intentional interaction occurred in 40 % of cases, all of which sustained finger envenomations. No cases presented with apparent acute ethanol intoxication. The majority of occupational snake bites occurred in men working outdoors and were unintentional injuries. Bites involving the upper extremity tended to result from intentional interactions. Acute ethanol intoxication did not appear to be involved with occupational envenomations.

1H-Benzo[d]imidazoles and 3,4-dihydroquinazolin-4-ones: Design, synthesis and antitubercular activity.

PubMed

Macchi, Fernanda Souza; Pissinate, Kenia; Villela, Anne Drumond; Abbadi, Bruno Lopes; Rodrigues-Junior, Valnês; Nabinger, Débora Dreher; Altenhofen, Stefani; Sperotto, Nathalia; da Silva Dadda, Adílio; Subtil, Fernanda Teixeira; de Freitas, Talita Freitas; Erhart Rauber, Ana Paula; Borsoi, Ana Flávia; Bonan, Carla Denise; Bizarro, Cristiano Valim; Basso, Luiz Augusto; Santos, Diógenes Santiago; Machado, Pablo

2018-06-02

Using a classical hybridization approach, a series of 1H-benzo[d]imidazoles and 3,4-dihydroquinazolin-4-ones were synthesized (39 examples) and evaluated as inhibitors of Mycobacterium tuberculosis growth. Chemical modification studies yielded potent antitubercular agents with minimum inhibitory concentration (MIC) values as low as 0.24 μM against M. tuberculosis H37Rv strain. Further, the synthesized compounds were active against four drug-resistant strains containing different levels of resistance for the first line drugs. These molecules were devoid of apparent toxicity to HepG2, HaCat, and Vero cells with IC 50s  > 30 μM. Viability in mammalian cell cultures was evaluated using MTT and neutral red assays. In addition, some 3,4-dihydroquinazolin-4-ones showed low risk of cardiac toxicity, no signals of neurotoxicity or morphological alteration in zebrafish (Danio rerio) toxicity models. 3,4-Dihydroquinazolin-4-ones 9q and 9w were considered the lead compounds of these series of molecules with MIC values of 0.24 μM and 0.94 μM against M. tuberculosis H37Rv, respectively. Taken together, these data indicate that this class of compounds may furnish candidates for future development of novel anti-TB drugs. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Solubility of nano-zinc oxide in environmentally and biologically important matrices

PubMed Central

Reed, Robert B.; Ladner, David A.; Higgins, Christopher P.; Westerhoff, Paul; Ranville, James F.

2011-01-01

Increasing manufacture and use of engineered nanoparticles (NPs) is leading to a greater probability for release of ENPs into the environment and exposure to organisms. In particular, zinc oxide (ZnO) is toxic, although it is unclear whether this toxicity is due to the zinc oxide nanoparticles (ZnO), dissolution to Zn2+, or some combination thereof. The goal of this study was to determine the relative solubilites of both commercially available and in-house synthesized ZnO in matrices used for environmental fate and transport or biological toxicity studies. Dissolution of ZnO was observed in nanopure water (7.18– 7.40 mg/L dissolved Zn, as measured by filtration) and Roswell Park Memorial Institute medium (RPMI-1640) (~5 mg/L), but much more dissolution was observed in Dulbecco’s Modified Eagle’s Medium (DMEM), where the dissolved Zn concentration exceeded 34 mg/L. Moderately hard water exhibited low zinc solubility, likely due to precipitation of a zinc carbonate solid phase. Precipitation of a zinc-containing solid phase in RPMI also appeared to limit zinc solubility. Equilibrium conditions with respect to ZnO solubility were not apparent in these matrices, even after more than 1,000 h of dissolution. These results suggest that solution chemistry exerts a strong influence on ZnO dissolution and can result in limits on zinc solubility due to precipitation of less soluble solid phases. PMID:21994124

Analyzing cytotoxic effects of selected isothiazol-3-one biocides using the toxic ratio concept and structure-activity relationship considerations.

PubMed

Arning, Jürgen; Matzke, Marianne; Stolte, Stefan; Nehen, Frauke; Bottin-Weber, Ulrike; Böschen, Andrea; Abdulkarim, Salha; Jastorff, Bernd; Ranke, Johannes

2009-12-01

To demonstrate how baseline toxicity can be separated from other more specific modes of toxic action and to address possible pitfals when dealing with hydrophobic substances, the four isothiazol-3-one biocides N-methylisothiazol-3-one (MIT), 5-chloro-N-methylisothiazol-3-one (CIT), N-octylisothiazol-3-one (OIT), and 4,5-dichloro-N-octylisothiazol-3-one (DCOIT) as an example for reactive electrophilic xenobiotics were tested for their cytotoxic effects on the human hepatoblastoma cell line Hep G2, on the marine bacterium Vibrio fischeri, and on the limnic green alga Scenedesmus vacuolatus. In each of the three test systems, toxic effects were observed in a consistent pattern. The two chlorinated compounds and OIT were found to be significantly more toxic than MIT. As compared to baseline toxicants, the small and polar MIT and CIT exhibited pronounced excess toxicity in each of the three test systems that is presumably triggered by their intrinsic reactivity toward cellular thiols. In contrast, OIT and DCOIT showed mainly toxicities that could be explained by their hydrophobicity. Analyzing and comparing these results using the toxic ratio concept and with data that indicate a dramatic depletion of cellular glutathione levels after incubation with DCOIT reveals that for highly hydrophobic substances, baseline level toxicity in an assay for acute toxicity can lead to an oversight of other more specific modes of toxic action that may cause significant effects that might be less reversible than those caused by unreactive baseline toxicants. This possibility should be taken into account in the hazard assessment of chemicals that are both hydrophobic and reactive.

Silver nanoparticles: a novel radiation sensitizer for glioma?

NASA Astrophysics Data System (ADS)

Liu, Peidang; Huang, Zhihai; Chen, Zhongwen; Xu, Ruizhi; Wu, Hao; Zang, Fengchao; Wang, Cailian; Gu, Ning

2013-11-01

Malignant gliomas are the most common primary intracranial tumors with a dismal prognosis. Previous investigations by our group demonstrated the radiosensitizing effect of silver nanoparticles (AgNPs) on glioma cells in vitro. The goal of the present study was to evaluate the efficacy of intratumoral administration of AgNPs in combination with a single dose of ionizing radiation at clinically relevant MV energies for the treatment of C6 glioma-bearing rats. AgNPs (10 or 20 μg/10 μl) were stereotactically administered on day 8 after tumor implantation. One day after AgNP injection, rats bearing glioma received 10 Gy radiation. The mean survival times were 100.5 and 98 days, the corresponding percent increase in life spans was 513.2% and 497.7%, and the cure rates were 41.7 and 38.5% at 200 days for the 10 and 20 μg AgNPs and radiation combination groups, respectively. In contrast, the mean survival times for irradiated controls, 10 and 20 μg AgNPs alone, and untreated controls were 24.5, 16.1, 19.4, and 16.4 days, respectively. Furthermore, a cooperative antiproliferative and proapoptotic effect was obtained when gliomas were treated with AgNPs followed by radiotherapy. Our results showed the therapeutic efficacy of AgNPs in combination with radiotherapy without apparent systemic toxicity, suggesting the clinical potential of AgNPs in improving the outcome of malignant glioma radiotherapy.Malignant gliomas are the most common primary intracranial tumors with a dismal prognosis. Previous investigations by our group demonstrated the radiosensitizing effect of silver nanoparticles (AgNPs) on glioma cells in vitro. The goal of the present study was to evaluate the efficacy of intratumoral administration of AgNPs in combination with a single dose of ionizing radiation at clinically relevant MV energies for the treatment of C6 glioma-bearing rats. AgNPs (10 or 20 μg/10 μl) were stereotactically administered on day 8 after tumor implantation. One day after AgNP injection, rats bearing glioma received 10 Gy radiation. The mean survival times were 100.5 and 98 days, the corresponding percent increase in life spans was 513.2% and 497.7%, and the cure rates were 41.7 and 38.5% at 200 days for the 10 and 20 μg AgNPs and radiation combination groups, respectively. In contrast, the mean survival times for irradiated controls, 10 and 20 μg AgNPs alone, and untreated controls were 24.5, 16.1, 19.4, and 16.4 days, respectively. Furthermore, a cooperative antiproliferative and proapoptotic effect was obtained when gliomas were treated with AgNPs followed by radiotherapy. Our results showed the therapeutic efficacy of AgNPs in combination with radiotherapy without apparent systemic toxicity, suggesting the clinical potential of AgNPs in improving the outcome of malignant glioma radiotherapy. Electronic supplementary information (ESI) available. See DOI: 10.1039/c3nr01351k

Maternally Mediated Developmental Toxicity

EPA Science Inventory

The current practice for the assessment of an agent’s potential effects on the developing embryo/fetus includes administration of high, maternally toxic doses to pregnant laboratory animals. For most agents evaluated, developmental effects occur concomitant with maternal toxicity...

Palbociclib in Combination With Fulvestrant in Women With Hormone Receptor-Positive/HER2-Negative Advanced Metastatic Breast Cancer: Detailed Safety Analysis From a Multicenter, Randomized, Placebo-Controlled, Phase III Study (PALOMA-3)

PubMed Central

Bartlett, Cynthia Huang; Schnell, Patrick; DeMichele, Angela M.; Loi, Sherene; Ro, Jungsil; Colleoni, Marco; Iwata, Hiroji; Harbeck, Nadia; Cristofanilli, Massimo; Zhang, Ke; Thiele, Alexandra; Turner, Nicholas C.; Rugo, Hope S.

2016-01-01

Background. Palbociclib enhances endocrine therapy and improves clinical outcomes in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Because this is a new target, it is clinically important to understand palbociclib’s safety profile to effectively manage toxicity and optimize clinical benefit. Materials and Methods. Patients with endocrine-resistant, HR-positive/HER2-negative MBC (n = 521) were randomly assigned 2:1 to receive fulvestrant (500 mg intramuscular injection) with or without goserelin with oral palbociclib (125 mg daily; 3 weeks on/1 week off) or placebo. Safety assessments at baseline and day 1 of each cycle included blood counts on day 15 for the first 2 cycles. Hematologic toxicity was assessed by using laboratory data. Results. A total of 517 patients were treated (palbociclib, n = 345; placebo, n = 172); median follow-up was 8.9 months. With palbociclib, neutropenia was the most common grade 3 (55%) and 4 (10%) adverse event; median times to onset and duration of grade ≥3 episodes were 16 and 7 days, respectively. Asian ethnicity and below-median neutrophil counts at baseline were significantly associated with an increased chance of developing grade 3–4 neutropenia with palbociclib. Dose modifications for grade 3–4 neutropenia had no adverse effect on progression-free survival. In the palbociclib arm, febrile neutropenia occurred in 3 (<1%) patients. The percentage of grade 1–2 infections was higher than in the placebo arm. Grade 1 stomatitis occurred in 8% of patients. Conclusion. Palbociclib plus fulvestrant treatment was well-tolerated, and the primary toxicity of asymptomatic neutropenia was effectively managed by dose modification without apparent loss of efficacy. This study appears at ClinicalTrials.gov, NCT01942135. Implications for Practice: Treatment with palbociclib in combination with fulvestrant was generally safe and well-tolerated in patients with hormone receptor (HR)-positive metastatic breast cancer. Consistent with the drug's proposed mechanism of action, palbociclib-related neutropenia differs in its clinical time course, patterns, and consequences from those seen with chemotherapy. Neutropenia can be effectively managed by a dose reduction, interruption, or cycle delay without compromising efficacy. A significant efficacy gain and a favorable safety profile support the consideration of incorporating palbociclib into the routine management of HR-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. PMID:27368881

Palbociclib in Combination With Fulvestrant in Women With Hormone Receptor-Positive/HER2-Negative Advanced Metastatic Breast Cancer: Detailed Safety Analysis From a Multicenter, Randomized, Placebo-Controlled, Phase III Study (PALOMA-3).

PubMed

Verma, Sunil; Bartlett, Cynthia Huang; Schnell, Patrick; DeMichele, Angela M; Loi, Sherene; Ro, Jungsil; Colleoni, Marco; Iwata, Hiroji; Harbeck, Nadia; Cristofanilli, Massimo; Zhang, Ke; Thiele, Alexandra; Turner, Nicholas C; Rugo, Hope S

2016-10-01

Palbociclib enhances endocrine therapy and improves clinical outcomes in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Because this is a new target, it is clinically important to understand palbociclib's safety profile to effectively manage toxicity and optimize clinical benefit. Patients with endocrine-resistant, HR-positive/HER2-negative MBC (n = 521) were randomly assigned 2:1 to receive fulvestrant (500 mg intramuscular injection) with or without goserelin with oral palbociclib (125 mg daily; 3 weeks on/1 week off) or placebo. Safety assessments at baseline and day 1 of each cycle included blood counts on day 15 for the first 2 cycles. Hematologic toxicity was assessed by using laboratory data. A total of 517 patients were treated (palbociclib, n = 345; placebo, n = 172); median follow-up was 8.9 months. With palbociclib, neutropenia was the most common grade 3 (55%) and 4 (10%) adverse event; median times to onset and duration of grade ≥3 episodes were 16 and 7 days, respectively. Asian ethnicity and below-median neutrophil counts at baseline were significantly associated with an increased chance of developing grade 3-4 neutropenia with palbociclib. Dose modifications for grade 3-4 neutropenia had no adverse effect on progression-free survival. In the palbociclib arm, febrile neutropenia occurred in 3 (<1%) patients. The percentage of grade 1-2 infections was higher than in the placebo arm. Grade 1 stomatitis occurred in 8% of patients. Palbociclib plus fulvestrant treatment was well-tolerated, and the primary toxicity of asymptomatic neutropenia was effectively managed by dose modification without apparent loss of efficacy. This study appears at ClinicalTrials.gov, NCT01942135. Treatment with palbociclib in combination with fulvestrant was generally safe and well-tolerated in patients with hormone receptor (HR)-positive metastatic breast cancer. Consistent with the drug's proposed mechanism of action, palbociclib-related neutropenia differs in its clinical time course, patterns, and consequences from those seen with chemotherapy. Neutropenia can be effectively managed by a dose reduction, interruption, or cycle delay without compromising efficacy. A significant efficacy gain and a favorable safety profile support the consideration of incorporating palbociclib into the routine management of HR-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. ©AlphaMed Press.

Development of a topical niosomal preparation of acetazolamide: preparation and evaluation.

PubMed

Aggarwal, Deepika; Garg, Alka; Kaur, Indu P

2004-12-01

Orally administered acetazolamide has a limited use in glaucoma due to the systemic side effects associated with its use. No topical formulation of acetazolamide is available, mainly because of it having a limited aqueous solubility and poor corneal permeation. To enhance the bioavailability of acetazolamide by the topical route and to improve the corneal permeability of the drug, niosomes of acetazolamide were prepared (employing span 60 and cholesterol) by different methods. Transmission electron microscopy (TEM) of the selected formulation was carried out to study the morphology. Niosomes were also prepared in the presence of dicetyl phosphate and stearylamine to obtain negatively and positively charged vesicles, respectively. It was found that the reverse-phase evaporation method (REV) gave the maximum drug entrapment efficiency (43.75%) as compared with ether injection (39.62%) and film hydration (31.43%) techniques. Drug entrapment efficiency varied with the charge and the percent entrapment efficiency for the REV method was 43.75, 51.23 and 36.26% for neutral, positively charged and negatively charged niosomes, respectively. Corneal permeability studies, however, showed that the percent permeation and the apparent permeability coefficient for the charged niosomes were less than for the neutral ones. A bioadhesive niosomal formulation of acetazolamide was also prepared and compared with the positively charged formulation, considering that both of them would have a prolonged stay in the cul-de-sac because of their expected interactions with mucin. The formulations were also compared based on their intraocular pressure (IOP)-lowering capacity. The positively charged niosomes (REV2), although showing good corneal permeability and pharmacodynamics, were however found to be inappropriate in terms of the corneal cell toxicity. The bioadhesive coated formulation (REV1bio) compared well with REV2 and also showed a much lesser toxicity. Further, the IOP-lowering effect of the developed formulations was compared with that of a marketed formulation of dorzolamide 2%, a topical carbonic anhydrase inhibitor. The developed niosomal formulations of acetazolamide showed a comparable physiological effect (33% reduction of IOP in REV1bio and 37% reduction in dorzolamide) with a duration of up to 6 h (the duration being 3 h for dorzolamide). Results of the study indicate that it is possible to develop a safe (as indicated by corneal toxicity studies) and physiologically active topical niosomal formulation of acetazolamide relative in efficiency to the newer local carbonic anhydrase inhibitor, dorzolamide. The developed formulations can form a cost effective treatment plan, which is especially important in the treatment of glaucoma, a chronic ailment affecting middle-aged to old patients.

Causes of highway road dust toxicity to an estuarine amphipod: Evaluating the effects of nicotine.

PubMed

Hiki, Kyoshiro; Nakajima, Fumiyuki; Tobino, Tomohiro

2017-02-01

Urban road dust can potentially have adverse effects on ecosystems if it is discharged into receiving waters. This study investigated the causes of highway road dust toxicity by performing sediment toxicity identification evaluation (TIE) tests with an estuarine amphipod, Grandidierella japonica. In addition to metals and polycyclic aromatic hydrocarbons, which are traditionally considered to be the major toxicants in road runoff, we focused on dissolved nicotine as a causative toxicant. The sediment TIE results suggested that organic contaminants contributed to the majority of toxicity, and that the contribution of unionized nicotine to the toxicity was the highest among the chemicals considered. However, additional mortality tests with 48-h pulsed nicotine exposure demonstrated that exposure to nicotine at the same concentration as the baseline level in TIE tests did not cause significant 10-day amphipod mortality. Thus, the road dust toxicity could not be explained only by unionized nicotine, thereby suggesting contributions from joint effects of the measured toxicants and the presence of other unmeasured factors. Copyright © 2016 Elsevier Ltd. All rights reserved.

Toxicities of triclosan, phenol, and copper sulfate in activated sludge.

PubMed

Neumegen, Rosalind A; Fernández-Alba, Amadeo R; Chisti, Yusuf

2005-04-01

The effect of toxicants on the BOD degradation rate constant was used to quantitatively establish the toxicity of triclosan, phenol, and copper (II) against activated sludge microorganisms. Toxicities were tested over the following ranges of concentrations: 0-450 mg/L for phenol, 0-2 mg/L for triclosan, and 0-35 mg/L for copper sulfate (pentahydrate). According to the EC(50) values, triclosan was the most toxic compound tested (EC(50) = 1.82 +/- 0.1 mg/L), copper (II) had intermediate toxicity (EC(50) = 18.3 +/- 0.37 mg/L), and phenol was the least toxic (EC(50) = 270 +/- 0.26 mg/L). The presence of 0.2% DMSO had no toxic effect on the activated sludge. The toxicity evaluation method used was simple, reproducible, and directly relevant to activated sludge wastewater treatment processes.