Exploiting translational coupling for the selection of cells producing toxic recombinant proteins from expression vectors.

PubMed

Tagliavia, Marcello; Cuttitta, Angela

2016-01-01

High rates of plasmid instability are associated with the use of some expression vectors in Escherichia coli, resulting in the loss of recombinant protein expression. This is due to sequence alterations in vector promoter elements caused by the background expression of the cloned gene, which leads to the selection of fast-growing, plasmid-containing cells that do not express the target protein. This phenomenon, which is worsened when expressing toxic proteins, results in preparations containing very little or no recombinant protein, or even in clone loss; however, no methods to prevent loss of recombinant protein expression are currently available. We have exploited the phenomenon of translational coupling, a mechanism of prokaryotic gene expression regulation, in order to select cells containing plasmids still able to express recombinant proteins. Here we designed an expression vector in which the cloned gene and selection marker are co-expressed. Our approach allowed for the selection of the recombinant protein-expressing cells and proved effective even for clones encoding toxic proteins.

Status and Assessment of Chesapeake Bay Wildlife Contamination

USGS Publications Warehouse

Heinz, G.H.; Wiemeyer, Stanley N.; Clark, D.R.; Albers, P.H.; Henry, P.; Batiuk, R.A.

1992-01-01

As an integral component of its priority setting process, the Chesapeake Bay Program`s Toxics Subcommittee has sought the expertise of Chesapeake Bay researchers and managers in developing a series of Chesapeake Bay toxics status and assessment papers. In the report, evidence for historical and current contaminant effects on key bird species, mammals, reptiles and amphibians which inhabit the Chesapeake Bay basin is examined. For each group of wildlife species, a general overview of effects caused by specific toxic substances is followed by detailed accounts of contaminant effects on selected species. Sponsored by Environmental Protection Agency, Annapolis, MD. Chesapeake Bay Program.

Stormwater filtration of toxic heavy metal ions using lignocellulosic materials selection process, fiberization, chemical modification, and mat formation

Treesearch

James S. Han

1999-01-01

Lignocellulosic materials were evaluated for their effectiveness in filtering toxic heavy metals from stormwater. Kenaf, alfalfa, juniper, and aspen fibers were used as models to evaluate the effectiveness and limitations of chemical modification and the extent of fiber degradation. Individual and mixed aqueous solutions of nickel, copper, zinc, and cadmium in various...

Lactobacillus plantarum CCFM8661 alleviates lead toxicity in mice.

PubMed

Tian, Fengwei; Zhai, Qixiao; Zhao, Jianxin; Liu, Xiaoming; Wang, Gang; Zhang, Hao; Zhang, Heping; Chen, Wei

2012-12-01

Lead causes a broad range of adverse effects in humans and animals. The objective was to evaluate the potency of lactobacilli to bind lead in vitro and the protective effects of a selected Lactobacillus plantarum CCFM8661 against lead-induced toxicity in mice. Nine strains of bacteria were used to investigate their binding abilities of lead in vitro, and L. plantarum CCFM8661 was selected for animal experiments because of its excellent lead binding capacity. Both living and dead L. plantarum CCFM8661 were used to treat 90 male Kunming mice during or after the exposure to 1 g/L lead acetate in drinking water. The results showed oral administration of both living and dead L. plantarum CCFM8661 offered a significant protective effect against lead toxicity by recovering blood δ-aminolevulinic acid dehydratase activity, decreasing the lead levels in blood and tissues, and preventing alterations in the levels of glutathione, glutathione peroxidase, malondialdehyde, superoxide dismutase, and reactive oxygen species caused by lead exposure. Moreover, L. plantarum CCFM8661 was more effective when administered consistently during the entire lead exposure, not after the exposure. Our results suggest that L. plantarum CCFM8661 has the potency to provide a dietary strategy against lead toxicity.

In Vitro and In Vivo Toxicity Profiling of Ammonium-Based Deep Eutectic Solvents

PubMed Central

Hayyan, Maan; Looi, Chung Yeng; Hayyan, Adeeb; Wong, Won Fen; Hashim, Mohd Ali

2015-01-01

The cytotoxic potential of ammonium-based deep eutectic solvents (DESs) with four hydrogen bond donors, namely glycerine (Gl), ethylene glycol (EG), triethylene glycol (TEG) and urea (U) were investigated. The toxicity of DESs was examined using In Vitro cell lines and In Vivo animal model. IC50 and selectivity index were determined for the DESs, their individual components and their combinations as aqueous solutions for comparison purposes. The cytotoxicity effect of DESs varied depending on cell lines. The IC50 for the GlDES, EGDES, UDES and TEGDES followed the sequence of TEGDES< GlDES< EGDES< UDES for OKF6, MCF-7, A375, HT29 and H413, respectively. GlDES was selective against MCF-7 and A375, EGDES was selective against MCF-7, PC3, HepG2 and HT29, UDES was selective against MCF-7, PC3, HepG2 and HT29, and TEGDES was selective against MCF-7 and A375. However, acute toxicity studies using ICR mice showed that these DESs were relatively toxic in comparison to their individual components. DES did not cause DNA damage, but it could enhance ROS production and induce apoptosis in treated cancer cells as evidenced by marked LDH release. Furthermore, the examined DESs showed less cytotoxicity compared with ionic liquids. To the best of our knowledge, this is the first time that combined In Vitro and In Vivo toxicity profiles of DESs were being demonstrated, raising the toxicity issue of these neoteric mixtures and their potential applicability to be used for therapeutic purposes. PMID:25679975

Silymarin-Loaded Eudragit Nanoparticles: Formulation, Characterization, and Hepatoprotective and Toxicity Evaluation.

PubMed

El-Nahas, Amira E; Allam, Ahmed N; Abdelmonsif, Doaa A; El-Kamel, Amal H

2017-11-01

The objectives of this study were to formulate, characterize silymarin-loaded Eudragit nanoparticles (SNPs) and evaluate their hepatoprotective and cytotoxic effects after oral administration. SNPs were prepared by nanoprecipitation technique and were evaluated for particle size, entrapment efficiency, TEM, solid-state characterization, and in vitro drug release. The hepatoprotective activity was evaluated after oral administration of selected SNPs in carbon tetrachloride-intoxicated rats. Potential in vivo acute cytotoxicity study was also assessed. The selected SNPs contained 50 mg silymarin and 50 mg Eudragit polymers (1:1 w/w Eudragit RS 100 & Eudragit LS 100). Morphology of the selected SNPs (particle size of 84.70 nm and entrapment efficiency of 83.45% with 100% drug release after 12 h) revealed spherical and uniformly distributed nanoparticles. DSC and FT-IR studies suggested the presence of silymarin in an amorphous state and absence of chemical interaction. The hepatoprotective evaluation of the selected SNPs in CCl 4 -intoxicated rats revealed significant improvement in the activities of different biochemical parameters (P ≤ 0.01) compared to the marketed product. The histopathological studies suggested that the selected SNPs produced better hepatoprotective effect in CCl 4 -intoxicated rats compared with the commercially marketed product. Toxicity study revealed no evident toxic effect for blank or silymarin-loaded nanoparticles at the dose level of 50 mg/kg body weight. The obtained results suggested that the selected SNPs were safe and potentially offered enhancement in the pharmacological hepatoprotective properties of silymarin.

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.

Lead-free solders: issues of toxicity, availability and impacts of extraction

NASA Technical Reports Server (NTRS)

Ku, A.; Shapiro, A. A.; Kua, A.; Ogunseitan, O.; Saphores, J. D.; Schoenung, J. M.

2003-01-01

This project set out to evaluate the critical issues of toxicity and public health effects, material availability, and the environmental impacts of raw material extraction and metal finishing, with the goal of using environmental impact as a factor in selecting feasible lead-free alloys.

40 CFR 798.5200 - Mouse visible specific locus test.

Code of Federal Regulations, 2010 CFR

2010-07-01

... control groups. (4) Control groups—(i) Concurrent controls. The use of positive or spontaneous controls is... control groups. (ii) Test chemical vehicle, doses used and rationale for dose selection, toxicity data... SUBSTANCES CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Genetic Toxicity § 798.5200 Mouse...

40 CFR 798.5200 - Mouse visible specific locus test.

Code of Federal Regulations, 2013 CFR

2013-07-01

... control groups. (4) Control groups—(i) Concurrent controls. The use of positive or spontaneous controls is... control groups. (ii) Test chemical vehicle, doses used and rationale for dose selection, toxicity data... SUBSTANCES CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Genetic Toxicity § 798.5200 Mouse...

40 CFR 798.5200 - Mouse visible specific locus test.

Code of Federal Regulations, 2012 CFR

2012-07-01

... control groups. (4) Control groups—(i) Concurrent controls. The use of positive or spontaneous controls is... control groups. (ii) Test chemical vehicle, doses used and rationale for dose selection, toxicity data... SUBSTANCES CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Genetic Toxicity § 798.5200 Mouse...

40 CFR 798.5200 - Mouse visible specific locus test.

Code of Federal Regulations, 2014 CFR

2014-07-01

... control groups. (4) Control groups—(i) Concurrent controls. The use of positive or spontaneous controls is... control groups. (ii) Test chemical vehicle, doses used and rationale for dose selection, toxicity data... SUBSTANCES CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Genetic Toxicity § 798.5200 Mouse...

40 CFR 798.5200 - Mouse visible specific locus test.

Code of Federal Regulations, 2011 CFR

2011-07-01

... control groups. (4) Control groups—(i) Concurrent controls. The use of positive or spontaneous controls is... control groups. (ii) Test chemical vehicle, doses used and rationale for dose selection, toxicity data... SUBSTANCES CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Genetic Toxicity § 798.5200 Mouse...

Chemical and toxicological evaluation of underground coal gasification (UCG) effluents. The coal rank effect.

PubMed

Kapusta, Krzysztof; Stańczyk, Krzysztof

2015-02-01

The effect of coal rank on the composition and toxicity of water effluents resulting from two underground coal gasification experiments with distinct coal samples (lignite and hard coal) was investigated. A broad range of organic and inorganic parameters was determined in the sampled condensates. The physicochemical tests were supplemented by toxicity bioassays based on the luminescent bacteria Vibrio fischeri as the test organism. The principal component analysis and Pearson correlation analysis were adopted to assist in the interpretation of the raw experimental data, and the multiple regression statistical method was subsequently employed to enable predictions of the toxicity based on the values of the selected parameters. Significant differences in the qualitative and quantitative description of the contamination profiles were identified for both types of coal under study. Independent of the coal rank, the most characteristic organic components of the studied condensates were phenols, naphthalene and benzene. In the inorganic array, ammonia, sulphates and selected heavy metals and metalloids were identified as the dominant constituents. Except for benzene with its alkyl homologues (BTEX), selected polycyclic aromatic hydrocarbons (PAHs), zinc and selenium, the values of the remaining parameters were considerably greater for the hard coal condensates. The studies revealed that all of the tested UCG condensates were extremely toxic to V. fischeri; however, the average toxicity level for the hard coal condensates was approximately 56% higher than that obtained for the lignite. The statistical analysis provided results supporting that the toxicity of the condensates was most positively correlated with the concentrations of free ammonia, phenols and certain heavy metals. Copyright © 2014 Elsevier Inc. All rights reserved.

Effects of selected food phytochemicals in reducing the toxic actions of TCDD and p,p′-DDT in U937 macrophages

PubMed Central

Sciullo, Eric M.; Vogel, Christoph F.; Wu, Dalei; Murakami, Akira; Ohigashi, Hajime

2010-01-01

To assess the effectiveness of selected food phytochemicals in reducing the toxic effects of the environmental toxicants, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and p,p′-DDT (DDT), we tested the potencies of auraptene, nobiletin, zerumbone, and (±)-13-hydroxy-10-oxo-trans-11-octadecenoic acid (13-HOA) in reversing the inflammatory action of these toxicants in U937 human macrophages. Using quantitative RT–PCR as the initial screening assay, we identified antagonistic actions of zerumbone and auraptene against the action of TCDD and DDT in up-regulating the mRNA expressions of COX-2 and VEGF. The functional significance of the inhibitory action of zerumbone on COX-2 expression was confirmed by demonstrating its suppression of TCDD-induced activation of COX-2 gene expression in mouse MMDD1 cells. We tested auraptene on DDT-induced reactive oxygen species (ROS) formation in U937 macrophages and found that auraptene is a powerful agent antagonizing this action of DDT. To confirm the significance of these actions of zerumbone and auraptene at the cellular level, we assessed their influence on TCDD-induced apoptosis resistance in intact U937 macrophages and found that they are capable of reversing this action of TCDD. In conclusion, zerumbone and auraptene were identified to be the most effective agents in protecting U937 macrophages from developing these cell toxic effects of TCDD and DDT. PMID:20865247

When dinner is dangerous: toxic frogs elicit species-specific responses from a generalist snake predator.

PubMed

Phillips, Ben; Shine, Richard

2007-12-01

In arms races between predators and prey, some evolved tactics are unbeatable by the other player. For example, many types of prey are inedible because they have evolved chemical defenses. In this case, prey death removes any selective advantage of toxicity to the prey but not the selective advantage to a predator of being able to consume the prey. In the absence of effective selection for postmortem persistence of the toxicity then, some chemical defenses probably break down rapidly after prey death. If so, predators can overcome the toxic defense simply by waiting for that breakdown before consuming the prey. Floodplain death adders (Acanthophis praelongus) are highly venomous frog-eating elapid snakes native to northern Australia. Some of the frogs they eat are nontoxic (Litoria nasuta), others produce gluelike mucus when seized by a predator (Limnodynastes convexiusculus), and one species (Litoria dahlii) is dangerously toxic to snakes. Both the glue and the toxin degrade within about 20 min of prey death. Adders deal with these prey types in different and highly stereotyped ways: they consume nontoxic frogs directly but envenomate and release the other taxa, waiting until the chemical defense loses its potency before consuming the prey.

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.

The role of genetic background in susceptibility to chemical warfare nerve agents across rodent and non-human primate models.

PubMed

Matson, Liana M; McCarren, Hilary S; Cadieux, C Linn; Cerasoli, Douglas M; McDonough, John H

2018-01-15

Genetics likely play a role in various responses to nerve agent exposure, as genetic background plays an important role in behavioral, neurological, and physiological responses to environmental stimuli. Mouse strains or selected lines can be used to identify susceptibility based on background genetic features to nerve agent exposure. Additional genetic techniques can then be used to identify mechanisms underlying resistance and sensitivity, with the ultimate goal of developing more effective and targeted therapies. Here, we discuss the available literature on strain and selected line differences in cholinesterase activity levels and response to nerve agent-induced toxicity and seizures. We also discuss the available cholinesterase and toxicity literature across different non-human primate species. The available data suggest that robust genetic differences exist in cholinesterase activity, nerve agent-induced toxicity, and chemical-induced seizures. Available cholinesterase data suggest that acetylcholinesterase activity differs across strains, but are limited by the paucity of carboxylesterase data in strains and selected lines. Toxicity and seizures, two outcomes of nerve agent exposure, have not been fully evaluated for genetic differences, and thus further studies are required to understand baseline strain and selected line differences. Published by Elsevier B.V.

Baseline ecological risk assessment of the Calcasieu Estuary, Louisiana: 2. An evaluation of the predictive ability of effects-based sediment quality guidelines

USGS Publications Warehouse

MacDonald, Donald D.; Ingersoll, Christopher G.; Smorong, Dawn E.; Sinclair, Jesse A.; Lindskoog, Rebekka; Wang, Ning; Severn, Corrine; Gouguet, Ron; Meyer, John; Field, Jay

2011-01-01

Three sets of effects-based sediment-quality guidelines (SQGs) were evaluated to support the selection of sediment-quality benchmarks for assessing risks to benthic invertebrates in the Calcasieu Estuary, Louisiana. These SQGs included probable effect concentrations (PECs), effects range median values (ERMs), and logistic regression model (LRMs)-based T50 values. The results of this investigation indicate that all three sets of SQGs tend to underestimate sediment toxicity in the Calcasieu Estuary (i.e., relative to the national data sets), as evaluated using the results of 10-day toxicity tests with the amphipod, Hyalella azteca, or Ampelisca abdita, and 28-day whole-sediment toxicity tests with the H. azteca. These results emphasize the importance of deriving site-specific toxicity thresholds for assessing risks to benthic invertebrates.

Bio-functionalized silver nanoparticles for selective colorimetric sensing of toxic metal ions and antimicrobial studies

NASA Astrophysics Data System (ADS)

Vinod Kumar, V.; Anbarasan, S.; Christena, Lawrence Rene; SaiSubramanian, Nagarajan; Philip Anthony, Savarimuthu

2014-08-01

Hibiscus Sabdariffa (Gongura) plant extracts (leaves (HL) and stem (HS) were used for the first time in the green synthesis of bio-functionalized silver nanoparticles (AgNPs). The bio-functionality of AgNPs has been successfully utilized for selective colorimetric sensing of potentially health and environmentally hazardous Hg2+, Cd2+ and Pb2+ metal ions at ppm level in aqueous solution. Importantly, clearly distinguishable colour for all three metal ions was observed. The influence of extract preparation condition and pH were also explored on the formation of AgNPs. Both selectivity and sensitivity differed for AgNPs synthesized from different parts of the plant. Direct correlation between the stability of green synthesized AgNPs at different pH and its antibacterial effects has been established. The selective colorimetric sensing of toxic metal ions and antimicrobial effect of green synthesized AgNPs demonstrated the multifunctional applications of green nanotechnology.

Evaluation of cytotoxic and antitumoral properties of Tessaria absinthioides (Hook & Arn) DC, "pájaro bobo", aqueous extract.

PubMed

Persia, Fabio A; Rinaldini, Estefanía; Carrión, Adriana; Hapon, María Belén; Gamarra-Luques, Carlos

2017-01-01

Higher plants have provided various natural derived drugs used currently in western medicine. Tessaria absinthioides (Hook. & Arn.) DC, Asteraceae, is a native plant from South-America with reported ethnopharmacological and culinary uses. Despite recent scientific reports about plants properties, there is not a well conducted research about its anticancer and potential toxic effects. The current work demonstrates the plant aqueous extract composition; the in vitro induced cytotoxicity, and explores, in vivo, its oral toxicity and antitumoral effects. Composition of aqueous extract was determined by phytochemical reactions. Cytotoxicity was tested in tumoral (Hela, Gli-37, HCT-116 and MCF-7) and non-tumoral (HBL-100) cells, using MTT assay. Oral toxicity and the antitumor activity against colorectal carcinoma were studied in rodents. The chemical analysis revealed the presence of flavonoids, carbohydrates, sterols, terpenes and tannins. Cytotoxicity towards tumoral cells was observed (CV50: 3.0 to 14.8 υg/ml); while in non-tumoral cells, extracts evidenced a selective reduced toxicity (CV50: 29.5 υg/ml). Oral administration of the extract does not induce acute nor dose-repeated toxicity at doses up to 2000 mg/kg and 1000 mg/kg/day, respectively. The antitumoral effect was confirmed by a significant increase in a median survival from 24 weeks (non-treated) to 30 weeks (T. absinthioides treated). The present data indicate that T. absinthioides extract exhibits cytotoxicity against cancer cell lines, with no-toxic effects and significant antitumoral effects in colorectal cancer when is orally administrated. In conclusion, T. absinthioides possesses selective cytotoxicity and antitumoral activities, making its plant derivatives products promising for cancer research and treatment.

Lethal and sublethal effects of selected insecticides and an insect growth regulator on the boll weevil (Coleoptera: Curculionidae) ectoparasitoid Catolaccus grandis (Hymenoptera: Pteromalidae).

PubMed

Elzen, G W; Maldonado, S N; Rojas, M G

2000-04-01

A laboratory culture of Catolaccus grandis (Burks), an ectoparasitoid of the boll weevil, Anthonomus grandis grandis Boheman, was exposed to lethal and sublethal doses of insecticides and an insect growth regulator using a spray chamber bioassay. Materials tested were azinphos-methyl, endosulfan, fipronil, malathion, cyfluthrin, dimethoate, spinosad, methyl parathion, acephate, oxamyl, and tebufenozide. At full rates, spinosad was significantly less toxic to female C. grandis than other treatments except endosulfan. Fipronil and malathion were significantly more toxic to females than other treatments. Most of the chemicals tested were highly toxic to male C. grandis; spinosad was least toxic. At reduced rates, most of 4 selected chemicals tested were low in toxicity to C. grandis; however, a reduced rate of malathion was significantly more toxic to females than other treatments. No C. grandis pupae developed from parasitism during a 24-h treatment period with malathion or spinosad. The sex ratio of progeny from sprayed adults appeared to be unaffected by the treatments.

Cationic lipid-conjugated hydrocortisone as selective antitumor agent.

PubMed

Rathore, Bhowmira; Chandra Sekhar Jaggarapu, Madhan Mohan; Ganguly, Anirban; Reddy Rachamalla, Hari Krishna; Banerjee, Rajkumar

2016-01-27

Hydrocortisone, the endogenously expressed steroidal, hormonal ligand for glucocorticoid receptor (GR), is body's natural anti-inflammatory and xenobiotic metabolizing agent. It has both palliative as well as adverse effects in different cancer patients. Herein, we show that conjugation product of C16-carbon chain-associated cationic lipid and hydrocortisone (namely, HYC16) induces selective toxicity in cancer (e.g. melanoma, breast cancer and lung adenocarcinoma) cells with least toxicity in normal cells, through induction of apoptosis and cell cycle arrest at G2/M phase. Further, significant tumor growth inhibition was observed in syngeneic melanoma tumor model with considerable induction of apoptosis in tumor-associated cells. In contrast to hydrocortisone, significantly higher anti-angiogenic behavior of HYC16 helped in effective tumor shrinkage. This is the first demonstration to convert natural hormone hydrocortisone into a selective bioactive entity possessing anti-tumor effect. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Framework for Optimizing Selection of Interspecies Correlation Estimation Models to Address Species Diversity and Toxicity Gaps in an Aquatic Database

EPA Science Inventory

The Chemical Aquatic Fate and Effects (CAFE) database is a tool that facilitates assessments of accidental chemical releases into aquatic environments. CAFE contains aquatic toxicity data used in the development of species sensitivity distributions (SSDs) and the estimation of ha...

Developmental Toxicity Evaluations of Whole Mixtures of Disinfection By-products using Concentrated Drinking Water in Rats: Gestational and Lactational Effects of Sulfate and Sodium

EPA Science Inventory

A developmental toxicity bioassay was used in three experiments to evaluate drinking water concentrates for suitability in multigenerational studies. First, chlorinated water was concentrated 135 fold by reverse osmosis; select lost disinfection by-products were spiked back. Co...

Developmental Toxicity Evaluations of Whole Mixtures of Disinfection By-products using Concentrated Drinking Water in Rats: Gestational and Lactational Effects of Sulfate and Sodium*

EPA Science Inventory

A developmental toxicity bioassay was used in three experiments to evaluate drinking water concentrates for suitability in multigenerational studies. First, chlorinated water was concentrated 135 fold by reverse osmosis; select lost disinfection by-products were spiked back. Conc...

Measures of fish behavior as indicators of sublethal toxicosis during standard toxicity tests

USGS Publications Warehouse

Little, E.E.; DeLonay, A.J.

1996-01-01

Behavioral functions essential for growth and survival can be dramatically altered by sublethal exposure to toxicants. Measures of these behavioral responses are effective in detecting adverse effects of sublethal contaminant exposure. Behavioral responses of fishes can be qualitatively and quantitatively evaluated during routine toxicity tests. At selected intervals of exposure, qualitative evaluations are accomplished through direct observations, whereas video recordings are used for quantitative evaluations. Standardized procedures for behavioral evaluation are readily applicable to different fish species and provide rapid, sensitive, and ecologically relevant assessments of sublethal exposure. The methods are readily applied to standardized test protocols.

Insights on the criteria of selection of vegetable and mineral dielectric fluids used in power transformers on the basis of their biodegradability and toxicity assessments.

PubMed

Módenes, Aparecido Nivaldo; Sanderson, Karina; Trigueros, Daniela Estelita Goes; Schuelter, Adilson Ricken; Espinoza-Quiñones, Fernando Rodolfo; Neves, Camila Vargas; Zanão Junior, Luiz Antônio; Kroumov, Alexander Dimitrov

2018-05-01

Leakage of transformer dielectric fluids is a concern because it may pose a risk of environmental contamination. In this study, the deleterious effects of vegetable and mineral dielectric fluids in water bodies were investigated using biodegradability and acute toxicity tests with Danio rerio and Artemia salina. Regarding biodegradability, all four tested vegetable oils (soy, canola, sunflower and crambe) were considered as easily biodegradable, presenting degradation rates significantly higher than the Lubrax-type mineral fluid. Acute toxicity tests were performed in two separate experiments without solution renewal. In the first experiment, the organisms were exposed in direct contact to different concentrations of vegetable (soy) and mineral (Lubrax) oils. Total soy-type vegetable oil has a higher toxic effect than Lubrax-type mineral oil. In the second experiment, the organisms were exposed to increasing percentages of the water-soluble fraction (WSF) of both types of tested oils. The LC 50 values for the water-soluble fraction of the Lubrax-type mineral oil were about 5 and 8% for the Danio rerio and Artemia salina bioindicators, respectively, whereas the vegetable oil did not present toxic effect, regardless of its WSF. These results have shown that a strict selection of dielectric fluids and monitoring the leakage from power transformers is a serious duty of environmental protection agencies. Copyright © 2018 Elsevier Ltd. All rights reserved.

Toxicity evaluation of selected ammonium-based ionic liquid forms with MCPP and dicamba moieties on Pseudomonas putida.

PubMed

Piotrowska, Aleksandra; Syguda, Anna; Wyrwas, Bogdan; Chrzanowski, Łukasz; Heipieper, Hermann J

2017-01-01

Combination of the hydrophilic herbicidal anion with hydrophobic, antimicrobial ammonium cation allows to obtain compounds in ionic liquid form with better properties then conventional herbicides. Both cation and anion can be modified by selection of herbicide and the length of alkyl chains in cation structure. However the knowledge of their potential toxic effects are still limited. Furthermore, the relation between hydrophobicity associated with the length of alkyl chains and toxicity for ionic liquids has not been thoroughly studied. Therefore we investigated toxic effects of herbicidal ionic liquid forms on growth inhibition, given as EC 50, of the common soil bacterium Pseudomonas putida. We thereby concentrated on quaternary ammonium salts. Analyzed compounds were composed of dicamba or MCPP moieties and cation with various alkyl chain lengths (n = 6,8,10) We compared them with commercial herbicides, and ammonium-based ionic liquids with neutral anion (Br - ). In addition, cis-trans isomerisation of unsaturated membrane fatty acids in Pseudomonas putida was applied as the proxy for toxicity and membrane activity. We showed that toxicity increased with the length of alkyl chains. However, this correlation is only valid for six and eight carbon atom in alkyl chains, where for n = 10 the EC 50 values rise by one order of magnitude. In our studies, the herbicidal ionic liquids [C 10 ,C 10 ,C 1 ,C 1 N][MCPP] and [C 10 ,C 10 ,C 1 ,C 1 N][dicamba] showed the lowest toxicity among analyzed quaternary ammonium salts and comparable toxicity with corresponding herbicides. No clear increase in toxicity could be followed by changing the anion moieties for ammonium-based ionic liquid forms. Copyright © 2016 Elsevier Ltd. All rights reserved.

A Predictive Model for Toxicity Effects Assessment of Biotransformed Hepatic Drugs Using Iterative Sampling Method.

PubMed

Tharwat, Alaa; Moemen, Yasmine S; Hassanien, Aboul Ella

2016-12-09

Measuring toxicity is one of the main steps in drug development. Hence, there is a high demand for computational models to predict the toxicity effects of the potential drugs. In this study, we used a dataset, which consists of four toxicity effects:mutagenic, tumorigenic, irritant and reproductive effects. The proposed model consists of three phases. In the first phase, rough set-based methods are used to select the most discriminative features for reducing the classification time and improving the classification performance. Due to the imbalanced class distribution, in the second phase, different sampling methods such as Random Under-Sampling, Random Over-Sampling and Synthetic Minority Oversampling Technique are used to solve the problem of imbalanced datasets. ITerative Sampling (ITS) method is proposed to avoid the limitations of those methods. ITS method has two steps. The first step (sampling step) iteratively modifies the prior distribution of the minority and majority classes. In the second step, a data cleaning method is used to remove the overlapping that is produced from the first step. In the third phase, Bagging classifier is used to classify an unknown drug into toxic or non-toxic. The experimental results proved that the proposed model performed well in classifying the unknown samples according to all toxic effects in the imbalanced datasets.

COMPILATION OF AVAILABLE DATA ON BUILDING DECONTAMINATION ALTERNATIVES

EPA Science Inventory

The report presents an analysis of selected technologies that have been tested for their potential effectiveness in decontaminating a building that has been attacked using biological or chemical warfare agents, or using toxic industrial compounds. The technologies selected to be ...

Comparative toxicity of bentazon and molinate on growth, photosynthetic pigments, photosynthesis, and respiration of the Portuguese ricefield cyanobacterium Nostoc muscorum.

PubMed

Galhano, Victor; Peixoto, Francisco; Gomes-Laranjo, José; Fernández-Valiente, Eduardo

2010-04-01

Bentazon and molinate are selective herbicides recommended for integrated weed management in rice. Their toxicity on growth and some biochemical and physiological parameters of Nostoc muscorum, an abundant cyanobacterium in Portuguese rice fields, was evaluated under laboratory conditions during time- and concentration-dependent exposure for 72 h. Results showed that toxic concentrations (0.75-2 mM) of both herbicides have pleiotropic effects on the cyanobacterium. Molinate was more toxic than bentazon to growth, respiration, chlorophyll-a, carotenoids, and phycobiliproteins contents. Protein content was increased by both herbicides although the effect was particularly evident with higher concentrations of molinate (1.5-2 mM). The herbicides had contrasting effects on carbohydrates content: molinate increased this organic fraction whereas bentazon decreased it. Photosynthesis and respiration were inhibited by both herbicides.

Fumigant toxicity of basil oil compounds and related compounds to Thrips palmi and Orius strigicollis.

PubMed

Kim, Kwang-Ho; Yi, Chang-Geun; Ahn, Young-Joon; Kim, Soon Il; Lee, Sang-Guei; Kim, Jun-Ran

2015-09-01

This study was aimed at assessing the fumigant toxicity to adult Thrips palmi (a serious insect pest) and Orius strigicollis (a beneficial predator insect) of basil (Ocimum basilicum) essential oil compounds and structurally related compounds using vapour-phase toxicity bioassays. Against adult T. palmi, linalool (LD50 0.0055 mg cm(-3) ) was the most toxic fumigant and was 15.2-fold more effective than dichlorvos (0.0837 mg cm(-3) ). Strong fumigant toxicity was also observed in pulegone (0.0095 mg cm(-3) ), (±)-camphor (0.0097 mg cm(-3) ) and 1,8-cineole (0.0167 mg cm(-3) ). Moderate toxicity was produced by camphene, 3-carene, (-)-menthone, (+)-α-pinene, (+)-β-pinene, α-terpineol and (-)-α-thujone (0.0215-0.0388 mg cm(-3) ). Against adult O. strigicollis, dichlorvos (LD50 9.0 × 10(-10) mg cm(-3) ) was the most toxic fumigant, whereas the LD50 values of these compounds ranged from 0.0127 to >0.23 mg cm(-3) . Based upon the selective toxicity ratio, the compounds described are more selective than dichlorvos. The basil oil compounds described merit further study as potential insecticides for control of T. palmi in greenhouses because of their generally lower toxicity to O. strigicollis and their greater activity as a fumigant than dichlorvos. © 2014 Society of Chemical Industry.

[Use of dinoflagellates as a metal toxicity assessment tool in aquatic system].

PubMed

Yuan, Li-juan; He, Meng-chang

2009-10-15

Although dinoflagellates have been used to assess biological toxicity of contaminants, this method still lacks of corresponding toxicity assessment standard. This study appraised the toxicity of selected heavy metals to dinoflagellates based on the dinoflagellates bioluminescence with QwikLite developed by the United States Navy. The results show that single heavy metal biological toxicity is in the order: Hg2+ > Cu2+ > Cd2+ > As5+ > Pb2+ > Cr6+; Two, three and four heavy metal mixture experiments show synergism primarily, antagonism is in minority. pH has not remarkable effect on dinoflagellates, they can be applied directly in natural water, but pH influence Hg2+ and Cu2+ toxicity greatly, eliminating the influence of pH is essential when doing these two kind of ions measurements. The nutrients has little influence on dinoflagellates, change in COD has obvious effect on the response relationships between dinoflagellates and Hg2+ or CU2+. Metal toxicity assessment using dinoflagellates shows great sensitivity, narrow response scope and high stability. Dinoflagellates are good species for heavy metal biological toxicity test in aquatic system.

Selective toxin effects on faster and slower growing individuals in the formation of hormesis at the population level - A case study with Lactuca sativa and PCIB.

PubMed

Belz, Regina G; Sinkkonen, Aki

2016-10-01

Natural plant populations have large phenotypic plasticity that enhances acclimation to local stress factors such as toxin exposures. While consequences of high toxin exposures are well addressed, effects of low-dose toxin exposures on plant populations are seldom investigated. In particular, the importance of 'selective low-dose toxicity' and hormesis, i.e. stimulatory effects, has not been studied simultaneously. Since selective toxicity can change the size distribution of populations, we assumed that hormesis alters the size distribution at the population level, and investigated whether and how these two low-dose phenomena coexist. The study was conducted with Lactuca sativa L. exposed to the auxin-inhibitor 2-(p-chlorophenoxy)-2-methylpropionic acid (PCIB) in vitro. In two separate experiments, L. sativa was exposed to 12 PCIB doses in 24 replicates (50 plants/replicate). Shoot/root growth responses at the population level were compared to the fast-growing (≥90% percentile) and the slow-growing subpopulations (≤10% percentile) by Mann-Whitney U testing and dose-response modelling. In the formation of pronounced PCIB hormesis at the population level, low-dose effects proved selective, but widely stimulatory which seems to counteract low-dose selective toxicity. The selectivity of hormesis was dose- and growth rate-dependent. Stimulation occurred at lower concentrations and stimulation percentage was higher among slow-growing individuals, but partly or entirely masked at the population level by moderate or negligible stimulation among the faster growing individuals. We conclude that the hormetic effect up to the maximum stimulation may be primarily facilitated by an increase in size of the most slow-growing individuals, while thereafter it seems that mainly the fast-growing individuals contributed to the observed hormesis at the population level. As size distribution within a population is related to survival, our study hints that selective effects on slow- and fast-growing individuals may change population dynamics, providing that similar effects can be repeated under field conditions. Copyright © 2016 Elsevier B.V. All rights reserved.

DOCUMENTATION FOR THE GRIDDED HOURLY ATRAZINE EMISSIONS DATA SET FOR THE LAKE MICHIGAN MASS BALANCE STUDY: A FINAL CONTRACT REPORT

EPA Science Inventory

In order to develop effective strategies for toxics management, the Great Lakes National Program Office (GLNPO) of the United States Environmental Protection Agency (U.S. EPA), in 1994, launched an ambitious five year program to conduct a mass balance study of selected toxics p...

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.

Effects of cadmium and zinc toxicity on orientation behaviour of Echinoparyphium recurvatum (Digenea: Echinostomatidae) cercariae.

PubMed

Morley, N J; Crane, M; Lewis, J W

2003-08-15

The effects of cadmium and zinc toxicity on orientation behaviour (photo- and geo-taxis) of Echinoparyphium recurvatum cercariae was investigated at concentrations ranging from 10 to 1000 microg l(-1). Exposure to the toxicants at all metal concentrations caused a change in orientation to negative phototaxis and positive geotaxis during the submaximal dispersal phase (0.5 h cercarial age). Autometallography staining of cercariae exposed to 1000 microg l(-1) cadmium or zinc showed selective binding of heavy metals to tegumental surface sites associated with sensory receptors. The significance to parasite transmission of changes in cercarial orientation behaviour in metal polluted environments is discussed.

Acute aquatic toxicity of biodiesel fuels

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

Wright, B.; Haws, R.; Little, D.

1995-12-31

This study develops data on the acute aquatic toxicity of selected biodiesel fuels which may become subject to environmental effects test regulations under the US Toxic Substances Control Act (TSCA). The test substances are Rape Methyl Ester (RME), Rape Ethyl Ester (REE), Methyl Soyate (MS), a biodiesel mixture of 20% REE and 80% Diesel, a biodiesel mixture of 50% REE and diesel, and a reference substance of Phillips D-2 Reference Diesel. The test procedure follows the Daphnid Acute Toxicity Test outlined in 40 CFR {section} 797.1300 of the TSCA regulations. Daphnia Magna are exposed to the test substance in amore » flow-through system consisting of a mixing chamber, a proportional diluter, and duplicate test chambers. Novel system modifications are described that accommodate the testing of oil-based test substances with Daphnia. The acute aquatic toxicity is estimated by an EC50, an effective concentration producing immobility in 50% of the test specimen.« less

Noncardiac Vascular Toxicities of Vascular Endothelial Growth Factor Inhibitors in Advanced Cancer: A Review

PubMed Central

Bowen, Joanne; Gibson, Rachel; Tan, Thean; Okera, Meena; Stringer, Andrea

2011-01-01

Summary. The introduction of molecularly targeted anticancer therapies has brought the promise of longer survival times for select patients with cancers previously considered untreatable. However, it has also brought new toxicities that require understanding and management, sometimes for long periods of time. Vascular endothelial growth factor inhibitors are associated with a broad range of adverse effects, with vascular toxicity being particularly serious. This review focuses on the current understanding of the pathophysiology and mechanisms of macrovascular toxicities (hypertension, hemorrhage, and thromboembolism), their incidence and severity, the current clinical management, and implications in the advanced cancer setting. Movement of these agents into the early disease setting will alter the impact of these toxicities. Search Strategy and Selection Criteria. Information for this review was collected by searching PubMed/Medline and American Society of Clinical Oncology abstract databases. The medical subject heading terms used included toxicity, hypertension, thromboembolism, hemorrhage, intestinal perforation, risk factors, pharmacokinetics, and metabolism, combined with free text search terms including, but not limited to, VEGF inhibitor*, bevacizumab, sunitinib, and sorafenib. Articles published in English before March 2010 were included, in addition to information from case reports and pharmaceutical agent package inserts. PMID:21441297

Building-related symptoms are linked to the in vitro toxicity of indoor dust and airborne microbial propagules in schools: A cross-sectional study.

PubMed

Salin, J T; Salkinoja-Salonen, M; Salin, P J; Nelo, K; Holma, T; Ohtonen, P; Syrjälä, H

2017-04-01

Indoor microbial toxicity is suspected to cause some building-related symptoms, but supporting epidemiological data are lacking. We examined whether the in vitro toxicity of indoor samples from school buildings was associated with work-related health symptoms (building-related symptoms, BRS). Administrators of the Helsinki City Real Estate Department selected 15 schools for the study, and a questionnaire on symptoms connected to work was sent to the teachers in the selected schools for voluntary completion. The cellular toxicity of classroom samples was determined by testing substances extracted from wiped indoor dust and by testing microbial biomass that was cultured on fallout plates. Boar sperm cells were used as indicator cells, and motility loss was the indicator for toxic effects. The effects were expressed as the half maximal effective concentration (EC 50 ) at which >50% of the exposed boar sperm cells were immobile compared to vehicle control. Completed symptom questionnaires were received from 232 teachers [median age, 43 years; 190 (82.3%) women] with a median time of 6 years working at their school. Samples from their classrooms were available and were assessed for cellular toxicity. The Poisson regression model showed that the impact of extracts of surface-wiped school classroom dust on teacher work-related BRS was 2.8-fold (95% CI: 1.6-4.9) higher in classrooms with a toxic threshold EC 50 of 6µgml -1 versus classrooms with insignificant EC 50 values (EC 50 >50µgml -1 ); P<0.001. The number of symptoms that were alleviated during vacation was higher in school classrooms with high sperm toxicity compared to less toxic sites; the RR was 1.9 (95% CI: 1.1-3.3, P=0.03) for wiped dust extracts. Teachers working in classrooms where the samples showed high sperm toxicity had more BRS. The boar sperm cell motility inhibition assay appears promising as a tool for demonstrating the presence of indoor substances associated with BRS. Copyright © 2017 Elsevier Inc. All rights reserved.

Relative toxicity and residual activity of insecticides used in blueberry pest management: mortality of natural enemies.

PubMed

Roubos, Craig R; Rodriguez-Saona, Cesar; Holdcraft, Robert; Mason, Keith S; Isaacs, Rufus

2014-02-01

A series of bioassays were conducted to determine the relative toxicities and residual activities of insecticides labeled for use in blueberry (Vaccinium corymbosum L.) on natural enemies, to identify products with low toxicity or short duration effects on biological control agents. In total, 14 insecticides were evaluated using treated petri dishes and four commercially available natural enemies (Aphidius colemani Viereck, Orius insidiosus [Say], Chrysoperla rufilabris [Burmeister], and Hippodamia convergens [Guérin-Menéville]). Dishes were aged under greenhouse conditions for 0, 3, 7, or 14 d before introducing insects to test residual activity. Acute effects (combined mortality and knockdown) varied by insecticide, residue age, and natural enemy species. Broad-spectrum insecticides caused high mortality to all biocontrol agents, whereas products approved for use in organic agriculture had little effect. The reduced-risk insecticide acetamiprid consistently caused significant acute effects, even after aging for 14 d. Methoxyfenozide, novaluron, and chlorantraniliprole, which also are classified as reduced-risk insecticides, had low toxicity, and along with the organic products could be compatible with biological control. This study provides information to guide blueberry growers in their selection of insecticides. Further research will be needed to determine whether adoption of a pest management program based on the use of more selective insecticides will result in higher levels of biological control in blueberry.

Classification of Chemicals Based On Structured Toxicity ...

EPA Pesticide Factsheets

Thirty years and millions of dollars worth of pesticide registration toxicity studies, historically stored as hardcopy and scanned documents, have been digitized into highly standardized and structured toxicity data within the Toxicity Reference Database (ToxRefDB). Toxicity-based classifications of chemicals were performed as a model application of ToxRefDB. These endpoints will ultimately provide the anchoring toxicity information for the development of predictive models and biological signatures utilizing in vitro assay data. Utilizing query and structured data mining approaches, toxicity profiles were uniformly generated for greater than 300 chemicals. Based on observation rate, species concordance and regulatory relevance, individual and aggregated effects have been selected to classify the chemicals providing a set of predictable endpoints. ToxRefDB exhibits the utility of transforming unstructured toxicity data into structured data and, furthermore, into computable outputs, and serves as a model for applying such data to address modern toxicological problems.

Selecting surrogate endpoints for estimating pesticide effects on avian reproductive success.

PubMed

Bennett, Richard S; Etterson, Matthew A

2013-10-01

A Markov chain nest productivity model (MCnest) has been developed for projecting the effects of a specific pesticide-use scenario on the annual reproductive success of avian species of concern. A critical element in MCnest is the use of surrogate endpoints, defined as measured endpoints from avian toxicity tests that represent specific types of effects possible in field populations at specific phases of a nesting attempt. In this article, we discuss the attributes of surrogate endpoints and provide guidance for selecting surrogates from existing avian laboratory tests as well as other possible sources. We also discuss some of the assumptions and uncertainties related to using surrogate endpoints to represent field effects. The process of explicitly considering how toxicity test results can be used to assess effects in the field helps identify uncertainties and data gaps that could be targeted in higher-tier risk assessments. © 2013 SETAC.

Overexpression of the essential Sis1 chaperone reduces TDP-43 effects on toxicity and proteolysis

PubMed Central

Park, Sei-Kyoung; Hong, Joo Y.; Arslan, Fatih; Tietsort, Alex; Tank, Elizabeth M. H.; Li, Xingli

2017-01-01

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by selective loss of motor neurons with inclusions frequently containing the RNA/DNA binding protein TDP-43. Using a yeast model of ALS exhibiting TDP-43 dependent toxicity, we now show that TDP-43 overexpression dramatically alters cell shape and reduces ubiquitin dependent proteolysis of a reporter construct. Furthermore, we show that an excess of the Hsp40 chaperone, Sis1, reduced TDP-43’s effect on toxicity, cell shape and proteolysis. The strength of these effects was influenced by the presence of the endogenous yeast prion, [PIN+]. Although overexpression of Sis1 altered the TDP-43 aggregation pattern, we did not detect physical association of Sis1 with TDP-43, suggesting the possibility of indirect effects on TDP-43 aggregation. Furthermore, overexpression of the mammalian Sis1 homologue, DNAJB1, relieves TDP-43 mediated toxicity in primary rodent cortical neurons, suggesting that Sis1 and its homologues may have neuroprotective effects in ALS. PMID:28531192

[Non-selective and selective non-steroidal anti-inflammatory drugs, administration in pregnancy and breast feeding].

PubMed

Fardet, Laurence; Nizard, Jacky; Généreau, Thierry

2002-09-28

THE FACTS: Non steroidal anti-inflammatory drugs (NSAI), except aspirin, are classically contraindicated during pregnancy. Nevertheless, they are widely used, in particular by the obstetricians. During pregnancy, the potential toxicity of these drugs is double, maternal and fetal. The maternal toxicity is comparable to that, already known in adults, with however, some particularities at the time of labor and delivery. The fetal toxicity is mainly renal and cardiovascular, with the NSAI responsible for oligoamniosis and premature closure of the arterial canal of the fetus. On the other hand, the use of these molecules during breast-feeding does not seem source of adverse events, notably in the newborn. THE VARIOUS MOLECULES: Among the family of non-selective non-steroidal anti-inflammatories, indications and adverse events of the various molecules differ considerably. Moreover, whereas the majority of these molecules are non-selective, i.e. inhibiting the two isoforms of cyclooxygenase, new therapeutics, specifically inhibiting cyclooxygenase-2, are now available. Few studies have been published concerning their prescription during pregnancy and breast-feeding and their maternal and fetal side effects remain ignored by most of the practitioners.

Lethal and sub-lethal effects of select macrocyclic lactones insecticides on forager worker honey bees under laboratory experimental conditions.

PubMed

Abdu-Allah, Gamal A M; Pittendrigh, Barry R

2018-01-01

Selective insecticide application is one important strategy for more precisely targeting harmful insects while avoiding or mitigating collateral damage to beneficial insects like honey bees. Recently, macrocyclic lactone-class insecticides have been introduced into the market place as selective bio-insecticides for controlling many arthropod pests, but how to target this selectivity only to harmful insects has yet to be achieved. In this study, the authors investigated the acute toxicity of fourmacrocyclic lactone insecticides (commercialized as abamectin, emamectin benzoate, spinetoram, and spinosad) both topically and through feeding studies with adult forager honey bees. Results indicated emamectin benzoate as topically 133.3, 750.0, and 38.3-fold and orally 3.3, 7.6, and 31.7-fold more toxic, respectively than abamectin, spinetoram and spinosad. Using Hazard Quotients for estimates of field toxicity, abamectin was measured as the safest insecticide both topically and orally for honey bees. Moreover, a significant reduction of sugar solution consumption by treatment group honey bees for orally applied emamectin benzoate and spinetoram suggests that these insecticides may have repellent properties.

Bio-functionalized silver nanoparticles for selective colorimetric sensing of toxic metal ions and antimicrobial studies.

PubMed

Vinod Kumar, V; Anbarasan, S; Christena, Lawrence Rene; SaiSubramanian, Nagarajan; Philip Anthony, Savarimuthu

2014-08-14

Hibiscus Sabdariffa (Gongura) plant extracts (leaves (HL) and stem (HS)) were used for the first time in the green synthesis of bio-functionalized silver nanoparticles (AgNPs). The bio-functionality of AgNPs has been successfully utilized for selective colorimetric sensing of potentially health and environmentally hazardous Hg(2+), Cd(2+) and Pb(2+) metal ions at ppm level in aqueous solution. Importantly, clearly distinguishable colour for all three metal ions was observed. The influence of extract preparation condition and pH were also explored on the formation of AgNPs. Both selectivity and sensitivity differed for AgNPs synthesized from different parts of the plant. Direct correlation between the stability of green synthesized AgNPs at different pH and its antibacterial effects has been established. The selective colorimetric sensing of toxic metal ions and antimicrobial effect of green synthesized AgNPs demonstrated the multifunctional applications of green nanotechnology. Copyright © 2014 Elsevier B.V. All rights reserved.

Mechanistic insights into selective killing of OXPHOS-dependent cancer cells by arctigenin.

PubMed

Brecht, Karin; Riebel, Virginie; Couttet, Philippe; Paech, Franziska; Wolf, Armin; Chibout, Salah-Dine; Pognan, Francois; Krähenbühl, Stephan; Uteng, Marianne

2017-04-01

Arctigenin has previously been identified as a potential anti-tumor treatment for advanced pancreatic cancer. However, the mechanism of how arctigenin kills cancer cells is not fully understood. In the present work we studied the mechanism of toxicity by arctigenin in the human pancreatic cell line, Panc-1, with special emphasis on the mitochondria. A comparison of Panc-1 cells cultured in glucose versus galactose medium was applied, allowing assessments of effects in glycolytic versus oxidative phosphorylation (OXPHOS)-dependent Panc-1 cells. For control purposes, the mitochondrial toxic response to treatment with arctigenin was compared to the anti-cancer drug, sorafenib, which is a tyrosine kinase inhibitor known for mitochondrial toxic off-target effects (Will et al., 2008). In both Panc-1 OXPHOS-dependent and glycolytic cells, arctigenin dissipated the mitochondrial membrane potential, which was demonstrated to be due to inhibition of the mitochondrial complexes II and IV. However, arctigenin selectively killed only the OXPHOS-dependent Panc-1 cells. This selective killing of OXPHOS-dependent Panc-1 cells was accompanied by generation of ER stress, mitochondrial membrane permeabilization and caspase activation leading to apoptosis and aponecrosis. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

Oikari, A.O.J.

Relevance of the choice of a test organism intended to be representative for a given environment seems to be under continual debate in aquatic ecotoxicology. For instance, it is commonly argue that acute toxicity tests with rainbow trout, the species most often recommended as a standard cold water teleost, were not representative for Nordic countries because the species is an alien in local faunas. A comparative study with several freshwater species was therefore initiated to clarify the validity of this assumption. As a first approximation, standard LC 50 assays were conducted. The species used were chosen only on the basismore » of their local availability, i.e, they randomly represented the fish fauna of Nordic inland waters. Furthermore, inter-species variation of toxicity response was compared with certain other, quantitatively more important, intra-species sources of variability affecting the toxicity of chemicals. Use of reference toxicants has been recommended as a means of standardizing bioassays. Compounds, characteristic of effluents from the pulp and paper industry, were selected for the present study. The toxicity of organic acids such a phenols and resin acids, as well as that of pupmill effluents, strongly depends on water pH. Because of the possibility that species differences could exist in this respect, effects of water acidity on toxicity of these types of substances to a randomly selected local species was investigated. Finally, as an example of the biological source of assay variability, the effect of yolk absorption was studied with a subsequent crisis period due to moderate starvation under laboratory conditions.« less

Annotated Bibliography of Bioassays Related to Sediment Toxicity Testing in Washington State

DTIC Science & Technology

1990-10-01

effects of sediments contaminated with heavy metals, petroleum hydrocarbons , synthetic organic compounds and radionuclides. It also provides an... molluscs (adults only), echinoderm larvae and fish), and bioassay procedures with selected toxicants (metals, petrochemicals, pesticides, contaminated...reference sediment + 15 mm test sediment. Bioaccumulation tests (with same organisms) are a’so discussed. EPA/COE (U.S. Environmental Protection Agency

Analysis and prediction of structure-reactive toxicity relationships of substituted aromatic compounds

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

Liu, Z.T.; Wang, L.S.; Chen, S.P.

1996-12-31

The fundamental differentiation of toxicity is between reactive and nonreactive toxicity. Reactive toxicity is associated with a specific mechanism for the reaction with an enzyme or inhibition of a metabolic pathway, and nonreactive toxicity is related directly to the quantity of toxicant acting upon the cell. The quantitative structure-activity relationships (QSARs) have been successfully used in the nonreactive toxicity, such as prediction of the toxicity of nonreactive compounds based on their solubility in the lipids of organisms. The elements of molecular structure that are most closely related to nonreactive toxicity are those that describe the partitioning of the toxicant intomore » the organism, while QSARs for the reactive toxicity are less common in the environmental toxicology literature. With the recent increase in the use of synthetic substituted benzenes as industrial chemicals, the accurate analysis of the effect of reactive toxic chemicals has become recognized with QSAR. For this purpose, we selected the fish (Carassias auratus) as the test organism, measured the acute toxicity of 50% lethal concentration (LC{sub 50}) of the chemicals and the adenosine triphosphate (ATP) content of the liver cells for the organism. These determined the relationships of the acute toxicity of some substituted benzenes with their physicochemical structural parameters. The effects on the ATP content was also compared to predict biological reactivities of the chemicals, so as to find some clues to explain the mode of mechanism of the toxicity. 17 refs., 1 tab.« less

Inhibition of Human Immunodeficiency Virus Replication by Antisense Oligodeoxynucleotides

NASA Astrophysics Data System (ADS)

Goodchild, John; Agrawal, Sudhir; Civeira, Maria P.; Sarin, Prem S.; Sun, Daisy; Zamecnik, Paul C.

1988-08-01

Twenty different target sites within human immunodeficiency virus (HIV) RNA were selected for studies of inhibition of HIV replication by antisense oligonucleotides. Target sites were selected based on their potential capacity to block recognition functions during viral replication. Antisense oligomers complementary to sites within or near the sequence repeated at the ends of retrovirus RNA (R region) and to certain splice sites were most effective. The effect of antisense oligomer length on inhibiting virus replication was also investigated, and preliminary toxicity studies in mice show that these compounds are toxic only at high levels. The results indicate potential usefulness for these oligomers in the treatment of patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex either alone or in combination with other drugs.

Microbiological and toxicological effects of Perla black bean (Phaseolus vulgaris L.) extracts: in vitro and in vivo studies.

PubMed

Lara-Díaz, Víctor Javier; Gaytán-Ramos, Angel A; Dávalos-Balderas, Alfredo José; Santos-Guzmán, Jesús; Mata-Cárdenas, Benito David; Vargas-Villarreal, Javier; Barbosa-Quintana, Alvaro; Sanson, Misu; López-Reyes, Alberto Gabriel; Moreno-Cuevas, Jorge E

2009-02-01

We investigated the microbiological and toxicological effects of three Perla black bean extracts on the growth and culture of selected pathogenic microorganisms, the toxicity over Vero cell lines and an in vivo rat model. Three different solvents were used to obtain Perla black bean extracts. All three Perla black bean extracts were tested for antibacterial and antiparasitic activity and further analysed for intrinsic cytotoxicity (IC(50)). Methanol Perla black bean extract was used for acute toxicity test in rats, with the up-and-down doping method. All Perla black bean extracts inhibited bacterial growth. Pseudomonas aeruginosa, Proteus vulgaris, Klebsiella oxytoca, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus epidermidis and Listeria monocytogenes showed inhibition, while Escherichia coli and Enterobacter aerogenes did not. Acidified water and acetic acid Perla black bean extract were tested in parasites. The best IC(50) was observed for Giardia lamblia, while higher concentrations were active against Entamoeba histolytica and Trichomonas vaginalis. The Vero cells toxicity levels (IC(50)) for methanol, acidified water and acetic acid Perla black bean extract were [mean +/- S.D. (95% CI)]: 275 +/- 6.2 (267.9-282.0), 390 +/- 4.6 (384.8-395.2) and 209 +/- 3.39 (205.6-212.4) microg/ml, respectively. In vivo acute toxicity assays did not show changes in absolute organ weights, gross and histological examinations of selected tissues or functional tests. The acetic acid and methanol Perla black bean extract proved to exhibit strong antibacterial activity and the acidified water Perla black bean extract exerted parasiticidal effects against Giardia lamblia, Entamoeba hystolitica and Trichomonas vaginalis. The three Perla black bean extracts assayed over Vero cells showed very low toxicity and the methanol Perla black bean extract in vivo did not cause toxicity.

Improved synthesis of N-benzylaminoferrocene-based prodrugs and evaluation of their toxicity and antileukemic activity.

PubMed

Daum, Steffen; Chekhun, Vasiliy F; Todor, Igor N; Lukianova, Natalia Yu; Shvets, Yulia V; Sellner, Leopold; Putzker, Kerstin; Lewis, Joe; Zenz, Thorsten; de Graaf, Inge A M; Groothuis, Geny M M; Casini, Angela; Zozulia, Oleksii; Hampel, Frank; Mokhir, Andriy

2015-02-26

We report on an improved method of synthesis of N-benzylaminoferrocene-based prodrugs and demonstrate its applicability by preparing nine new aminoferrocenes. Their effect on the viability of selected cancer cells having different p53 status was studied. The obtained data are in agreement with the hypothesis that the toxicity of aminoferrocenes is not dependent upon p53 status. Subsequently the toxicity of a selected prodrug (4) was investigated ex vivo using rat precision cut liver slices and in vivo on hybrid male mice BDF1. In both experiments no toxicity was observed: ex vivo, up to 10 μM; in vivo, up to 6 mg/kg. Finally, prodrug 4 was shown to extend the survival of BDF1 mice carrying L1210 leukemia from 13.7 ± 0.6 days to 17.5 ± 0.7 days when injected daily 6 times at a dose of 26 μg/kg starting from the second day after injection of L1210 cells.

Effects of Central Kalimantan plant extracts on intraerythrocytic Babesia gibsoni in culture.

PubMed

Subeki; Matsuura, Hideyuki; Yamasaki, Masahiro; Yamato, Osamu; Maede, Yoshimitsu; Katakura, Ken; Suzuki, Mamoru; Trimurningsih; Chairul; Yoshihara, Teruhiko

2004-07-01

The inhibitory effects of 45 plant extracts selected from Central Kalimantan, Indonesia on Babesia gibsoni in vitro and their acute toxicity to mice were evaluated. Of these plant extracts studied, Arcangelisia flava, Curcuma zedoaria, Garcinia benthamiana, Lansium domesticum and Peronema canescens were found to have appreciable antibabesial activity with IC50 values from 5.3 to 49.3 microg/ml without acute toxicity in mice at the intraperitoneal dose of 0.7 g/kg of body weight.

Mechanisms of Cellular Membrane Effects of TCDD, Selected Perfluorinated Acids and Polyhalogenated Aromatic Hydrocarbons

DTIC Science & Technology

1985-02-01

toxic response of both cell lines after treatment with the perfluorinated acids ( perfluoro -n-octanoic acid, 9-H hexadecafluoro-n-nonanoic acid, and...throughout the experiments to eliminate the effect of serum on toxicity. The results for perfluoro -n-octanoic acid ( PFOA ) in both cell lines are presented in...the TK+/+ cells but not in the TK+/- cells. The results for the perfluoro -n-decanoic acid ( PFDA ) are presented in Table 3. A dose-response reldtionship

[Problems of cardiovascular toxicity of coxibs and non-selective NSA].

PubMed

Forejtová, S

2006-01-01

Non-steroidal antirheumatics (NSA) belong to the most often prescribed drugs. Certain observation studies indicate that they are used by 20 to 30% of population of developed countries. The most common NSA's adverse effects are gastrointestinal complications. Coxibs have been developed as an alternative to conventional non-selective NSA; with similar efficacy, they should reduce the risk of development of gastrointestinal complications. In the few last years, possible toxicity of coxibs and other non-steroidal antirheumatics has been widely discussed. The VIGOR study, which was performed 6 years ago, showed five times higher incidence of nonfatal myocardial infarction in patients with rofecoxib therapy as compared with naproxen. Afterwards, there was much debate about rofecoxib, and coxibs in general, whose cardiotoxicity was supported and confuted at the same time. Possible cardioprotective effect of naproxen was discussed too. Later on, results of the APPROVE study (Adenoma Polyp Prevention on Vioxx) made Merck & Co., Inc. withdraw rofecoxib from all markets voluntarily. In the end of 2004, three controversial studies on celecoxib were published. Although the first study (Adenoma Prevention with Celecoxib study, APC) showed higher cardiovascular risk of celecoxib, the second study (Prevention of Adenomatosus Polyps, PreSAP) did not verify these results. Surprisingly, the third study (Alzheimer Disease and Prevention Trial, ADAPT) proved 50% increase of the risk of cardiovascular (CV) toxicity of naproxen. In the last year, researchers have tried to decide whether CV toxicity is a class effect of coxib group or a class effect of all NSA. Many observation studies proved higher CV risk both of coxibs (particularly rofecoxib) and non-selective NSA including naproxen. These new findings moved the American FDA (Food and Drug Administration) to publish guidance concerning higher CV risk of all coxibs and NSA. For the time being, the EMEA (European Agency for Evaluation of Medicinal Products) does not change its attitude to NSA; coxibs are contraindicated in patients with ischemic heart disease, cerebrovascular disease and peripheral artery disease; they should be used with caution in high-risk patients. Final assessment of the problems of CV toxicity of NSA and coxibs will be a case of a long-term randomized study focused on the incidence of cardiovascular adverse effects.

Characterization of the Apoptotic Response Induced by the Cyanine Dye D112: A Potentially Selective Anti-Cancer Compound

PubMed Central

Yang, Ning; Gilman, Paul; Mirzayans, Razmik; Sun, Xuejun; Touret, Nicolas; Weinfeld, Michael; Goping, Ing Swie

2015-01-01

Chemotherapeutic drugs that are used in anti-cancer treatments often cause the death of both cancerous and noncancerous cells. This non-selective toxicity is the root cause of untoward side effects that limits the effectiveness of therapy. In order to improve chemotherapeutic options for cancer patients, there is a need to identify novel compounds with higher discrimination for cancer cells. In the past, methine dyes that increase the sensitivity of photographic emulsions have been investigated for anti-cancer properties. In the 1970's, Kodak Laboratories initiated a screen of approximately 7000 dye structural variants for selective toxicity. Among these, D112 was identified as a promising compound with elevated toxicity against a colon cancer cell line in comparison to a non-transformed cell line. Despite these results changing industry priorities led to a halt in further studies on D112. We decided to revive investigations on D112 and have further characterized D112-induced cellular toxicity. We identified that in response to D112 treatment, the T-cell leukemia cell line Jurkat showed caspase activation, mitochondrial depolarization, and phosphatidylserine externalization, all of which are hallmarks of apoptosis. Chemical inhibition of caspase enzymatic activity and blockade of the mitochondrial pathway through Bcl-2 expression inhibited D112-induced apoptosis. At lower concentrations, D112 induced growth arrest. To gain insight into the molecular mechanism of D112 induced mitochondrial dysfunction, we analyzed the intracellular localization of D112, and found that D112 associated with mitochondria. Interestingly, in the cell lines that we tested, D112 showed increased toxicity toward transformed versus non-transformed cells. Results from this work identify D112 as a potentially interesting molecule warranting further investigation. PMID:25927702

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) Is Selectively Toxic to Primary Dopaminergic Neurons In Vitro

PubMed Central

Griggs, Amy M.; Agim, Zeynep S.; Mishra, Vartika R.; Tambe, Mitali A.; Director-Myska, Alison E.; Turteltaub, Kenneth W.; McCabe, George P.; Rochet, Jean-Christophe; Cannon, Jason R.

2014-01-01

Parkinson's disease (PD) is the second most common neurodegenerative disease. Much data has linked the etiology of PD to a variety of environmental factors. The majority of cases are thought to arise from a combination of genetic susceptibility and environmental factors. Chronic exposures to dietary factors, including meat, have been identified as potential risk factors. Although heterocyclic amines that are produced during high-temperature meat cooking are known to be carcinogenic, their effect on the nervous system has yet to be studied in depth. In this study, we investigated neurotoxic effects of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a highly abundant heterocyclic amine in cooked meat, in vitro. We tested toxicity of PhIP and the two major phase I metabolites, N-OH-PhIP and 4′-OH-PhIP, using primary mesencephalic cultures from rat embryos. This culture system contains both dopaminergic and nondopaminergic neurons, which allows specificity of neurotoxicity to be readily examined. We find that exposure to PhIP or N-OH-PhIP is selectively toxic to dopaminergic neurons in primary cultures, resulting in a decreased percentage of dopaminergic neurons. Neurite length is decreased in surviving dopaminergic neurons. Exposure to 4′-OH-PhIP did not produce significant neurotoxicity. PhIP treatment also increased formation of oxidative damage markers, 4-hydroxy-2-nonenal (HNE) and 3-nitrotyrosine in dopaminergic neurons. Pretreatment with N-acetylcysteine was protective. Finally, treatment with blueberry extract, a dietary factor with known antioxidant and other protective mechanisms, prevented PhIP-induced toxicity. Collectively, our study suggests, for the first time, that PhIP is selectively toxic to dopaminergic neurons likely through inducing oxidative stress. PMID:24718704

Persistence of toxic and unethical leadership: how does the US Army improve leader development and selection

DTIC Science & Technology

2015-05-21

Source Assessment and Feedback OER Officer Evaluation Report PME Professional Military Education TRADOC Training and Doctrine Command...Toxic leadership is a combination of self-centered attitudes, motivations , and behaviors that have adverse effects on subordinates, the...process of influencing people by providing purpose, direction and motivation to accomplish the mission and improve the organization.”28 The ideal

Machine learning for toxicity characterization of organic chemical emissions using USEtox database: Learning the structure of the input space.

PubMed

Marvuglia, Antonino; Kanevski, Mikhail; Benetto, Enrico

2015-10-01

Toxicity characterization of chemical emissions in Life Cycle Assessment (LCA) is a complex task which usually proceeds via multimedia (fate, exposure and effect) models attached to models of dose-response relationships to assess the effects on target. Different models and approaches do exist, but all require a vast amount of data on the properties of the chemical compounds being assessed, which are hard to collect or hardly publicly available (especially for thousands of less common or newly developed chemicals), therefore hampering in practice the assessment in LCA. An example is USEtox, a consensual model for the characterization of human toxicity and freshwater ecotoxicity. This paper places itself in a line of research aiming at providing a methodology to reduce the number of input parameters necessary to run multimedia fate models, focusing in particular to the application of the USEtox toxicity model. By focusing on USEtox, in this paper two main goals are pursued: 1) performing an extensive exploratory analysis (using dimensionality reduction techniques) of the input space constituted by the substance-specific properties at the aim of detecting particular patterns in the data manifold and estimating the dimension of the subspace in which the data manifold actually lies; and 2) exploring the application of a set of linear models, based on partial least squares (PLS) regression, as well as a nonlinear model (general regression neural network--GRNN) in the seek for an automatic selection strategy of the most informative variables according to the modelled output (USEtox factor). After extensive analysis, the intrinsic dimension of the input manifold has been identified between three and four. The variables selected as most informative may vary according to the output modelled and the model used, but for the toxicity factors modelled in this paper the input variables selected as most informative are coherent with prior expectations based on scientific knowledge of toxicity factors modelling. Thus the outcomes of the analysis are promising for the future application of the approach to other portions of the model, affected by important data gaps, e.g., to the calculation of human health effect factors. Copyright © 2015. Published by Elsevier Ltd.

THE TOXICITY OF RUBBERS AND PLASTICS USED IN TRANSFUSION-GIVING SETS

PubMed Central

Cruickshank, C. N. D.; Hooper, Caroline; Lewis, H. B. M.; MacDougall, J. D. B.

1960-01-01

The toxicity of different rubbers and plastics used in transfusion-giving sets has been investigated by examining their effects on (a) cultures of chick embryo tissues, (b) the oxygen uptake of guinea-pig skin tissue cultures, and (c) the growth of Str. pyogenes. The results of the laboratory tests have been compared with the incidence of thrombophlebitis after prolonged transfusions through the various materials. It was found that where the materials inhibited the growth of Str. pyogenes they were also toxic to tissue cultures, but that some materials which were toxic to tissue cultures did not inhibit bacterial growth. The assessments of the relative toxicity of the materials tested by the two tissue culture methods were in agreement. The skin respiration studies, however, gave more information on the early effects of the toxic materials. The relative toxicity of the materials as revealed by these tests could be correlated with the differences in the incidence of thrombophlebitis following intravenous infusions administered through giving-sets assembled with the materials tested. It is suggested therefore that the toxicity revealed by these tests is of clinical importance, and that tissue culture toxicity tests will prove to be of value in selecting rubbers and plastics for clinical purposes. Images PMID:13813084

Oxygen toxicity.

PubMed

Stogner, S W; Payne, D K

1992-12-01

The objective of this article is to provide an overview of the biochemistry of oxygen metabolism, including the formation of free radicals and the role of endogenous antioxidants. Pathophysiologic correlates underlying the clinical manifestations of oxygen toxicity are reviewed and management strategies are outlined. References from basic science and clinical journals were selected from the authors' files and from a search of a computerized database of the biomedical literature. Articles selected for review included both historical and current literature concerning the biochemistry and pathophysiology of oxygen toxicity in animals and humans. The benefits of oxygen therapy have been known for many years; however, its potential toxicity has not been recognized until the last two decades. The lungs, the eyes, and, under certain conditions, the central nervous system are the organs most affected by prolonged exposure to hyperoxic environments. Free radical formation during cellular metabolism under hyperoxic conditions is recognized as the biochemical basis of oxygen injury to cells and organs. Endogenous antioxidants are a primary means of detoxifying reactive oxygen species and preventing hyperoxia-induced cellular damage. When this defense fails or is overwhelmed by the excessive production of hyperoxia-induced free-radical species, distinctive morphologic changes occur at the cellular level. The amount of hyperoxia required to cause cellular damage and the time course of these changes vary from species to species and from individual to individual within the same species. Age, nutritional status, presence of underlying diseases, and certain drugs may influence the development of oxygen toxicity. There is currently no reliably effective drug for preventing or delaying the development of oxygen toxicity in humans. Use of the lowest effective oxygen concentration, the avoidance of certain drugs, and attention to nutritional and metabolic factors remain the best means currently available to avoid or minimize oxygen toxicity. Research is continuing into more effective ways to prevent, diagnose, and treat this disorder.

Nail toxicity induced by cancer chemotherapy.

PubMed

Gilbar, Peter; Hain, Alice; Peereboom, Veta-Marie

2009-09-01

To provide a comprehensive literature review of chemotherapy-induced nail toxicity, including clinical presentation, implicated drugs and approaches for prevention and management. A search of MEDLINE and EMBASE (1966-2008) databases was conducted using the terms (and variations of the terms) antineoplastic agents, nails, nail toxicity, onycholysis, and paronychia. Bibliographies from selected articles were reviewed for appropriate references. The retrieved literature was reviewed to include all articles relevant to the clinical presentation, diagnosis, incidence, prevention, and treatment of chemotherapy-induced nail toxicity. Nail toxicity is a relatively uncommon adverse effect linked to a number of chemotherapeutic agents. Clinical presentation varies, depending on which nail structure is affected and the severity of the insult. Nail changes may involve all or some nails. Toxicity may be asymptomatic and limited to cosmetic concerns, however, more severe effects, involving pain and discomfort can occur. Taxanes and anthracyclines are the antineoplastic drug groups most commonly implicated. It is suggested that the administration schedule may influence the incidence of nail abnormalities, for example reported cases linked to the weekly administration of paclitaxel.Before instituting chemotherapy, patients should be educated regarding potential nail toxicities and strategies for prevention implemented. Management includes appropriate nail cutting, avoiding potential irritants, topical, or oral antimicrobials, and possibly cessation or dose reduction of the offending agent. Cryotherapy, through the application of frozen gloves or socks, has been beneficial in reducing docetaxel-induced nail toxicity and may be effective for other drugs.

Cardiovascular Mitochondrial Dysfunction Induced by Cocaine: Biomarkers and Possible Beneficial Effects of Modulators of Oxidative Stress.

PubMed

Graziani, Manuela; Sarti, Paolo; Arese, Marzia; Magnifico, Maria Chiara; Badiani, Aldo; Saso, Luciano

2017-01-01

Cocaine abuse has long been known to cause morbidity and mortality due to its cardiovascular toxic effects. The pathogenesis of the cardiovascular toxicity of cocaine use has been largely reviewed, and the most recent data indicate a fundamental role of oxidative stress in cocaine-induced cardiovascular toxicity, indicating that mitochondrial dysfunction is involved in the mechanisms of oxidative stress. The comprehension of the mechanisms involving mitochondrial dysfunction could help in selecting the most appropriate mitochondria injury biological marker, such as superoxide dismutase-2 activity and glutathionylated hemoglobin. The potential use of modulators of oxidative stress (mitoubiquinone, the short-chain quinone idebenone, and allopurinol) in the treatment of cocaine cardiotoxic effects is also suggested to promote further investigations on these potential mitochondria-targeted antioxidant strategies.

Characterization of selected bed-sediment-bound organic and inorganic contaminants and toxicity, Barnegat Bay and major tributaries, New Jersey, 2012

USGS Publications Warehouse

Romanok, Kristin M.; Reilly, Timothy J.; Lopez, Anthony R.; Trainor, John J.; Hladik, Michelle; Stanley, Jacob K.; Farrar, Daniel

2014-01-01

A study of bed-sediment toxicity and organic and inorganic contaminants was conducted by the U.S. Geological Survey (USGS) in cooperation with the New Jersey Department of Environmental Protection (NJDEP). Bed-sediment samples were collected once from 22 sites in Barnegat Bay and selected major tributaries during August–September 2012 and analyzed for toxicity and a suite of organic and inorganic contaminants by the USGS and the U.S. Army Corps of Engineers. Sampling sites were selected to coincide with an existing water-quality monitoring network used by the NJDEP and others in order to evaluate water-quality conditions in Barnegat Bay and the surrounding watershed. Two of the 22 sites are reference sites and are within or adjacent to the study area; bed-sediment samples from reference sites allow for comparisons of results for the Barnegat Bay watershed to results from less affected settings within the region. Toxicity testing was conducted by exposing the estuarine amphipod Leptocheirus plumulosus and the freshwater amphipod Hyalella azteca to sediments for 28 days, and the percent survival, difference in biomass, and individual dry weights were measured. Reproductive effects also were evaluated for estuarine samples. Bed-sediment samples from four sites within Barnegat Bay were subjected to a toxicity identification evaluation to determine probable causes of toxicity. Samples were analyzed for a suite of 94 currently-used pesticides, 21 legacy pesticides, 24 trace elements, 40 polycyclic aromatic hydrocarbons, 7 polychlorinated biphenyls (PCBs) as Arochlor mixtures, and 145 individual PCB congeners. Concentrations of detected compounds were compared to sediment-quality guidelines, where appropriate.

Toxicological aspects of photocatalytic degradation of selected xenobiotics with nano-sized Mn-doped TiO2.

PubMed

Ozmen, Murat; Güngördü, Abbas; Erdemoglu, Sema; Ozmen, Nesrin; Asilturk, Meltem

2015-08-01

The toxic effects of two selected xenobiotics, bisphenol A (BPA) and atrazine (ATZ), were evaluated after photocatalytic degradation using nano-sized, Mn-doped TiO2. Undoped and Mn-doped TiO2 nanoparticles were synthesized. The samples were characterized by X-ray diffractometry (XRD), scanning electron microscopy (SEM), UV-vis-diffuse reflectance spectra (DRS), X-ray fluorescence spectroscopy (XRF), and BET surface area. The photocatalytic efficiency of the undoped and Mn-doped TiO2 was evaluated for BPA and ATZ. The toxicity of the synthesized photocatalysts and photocatalytic by-products of BPA and ATZ was determined using frog embryos and tadpoles, zebrafish embryos, and bioluminescent bacteria. Possible toxic effects were also evaluated using selected enzyme biomarkers. The results showed that Mn-doped TiO2 nanoparticles did not cause significant lethality in Xenopus laevis embryos and tadpoles, but nonfiltered samples caused lethality in zebrafish. Furthermore, Mn-doping of TiO2 increased the photocatalytic degradation capability of nanoparticles, and it successfully degraded BPA and AZT, but degradation of AZT caused an increase of the lethal effects on both tadpoles and fish embryos. Degradation of BPA caused a significant reduction of lethal effects, especially after 2-4h of degradation. However, biochemical assays showed that both Mn-doped TiO2 and the degradation by-products caused a significant change of selected biomarkers on X. laevis tadpoles; thus, the ecological risks of Mn-doped TiO2 should be considered due to nanomaterial applications and for spilled nanoparticles in an aquatic ecosystem. Also, the risk of nanoparticles should be considered using indicator reference biochemical markers to verify the environmental health impacts. Copyright © 2015 Elsevier B.V. All rights reserved.

Cardiac Amyloidosis

MedlinePlus

... adding salt to food, and avoiding eating in restaurants. Daily weighing can be helpful: a weight gain ... effective but toxic therapy, and very careful patient selection is needed. View this table: View inline View ...

Classification of toxicity effects of biotransformed hepatic drugs using whale optimized support vector machines.

PubMed

Tharwat, Alaa; Moemen, Yasmine S; Hassanien, Aboul Ella

2017-04-01

Measuring toxicity is an important step in drug development. Nevertheless, the current experimental methods used to estimate the drug toxicity are expensive and time-consuming, indicating that they are not suitable for large-scale evaluation of drug toxicity in the early stage of drug development. Hence, there is a high demand to develop computational models that can predict the drug toxicity risks. In this study, we used a dataset that consists of 553 drugs that biotransformed in liver. The toxic effects were calculated for the current data, namely, mutagenic, tumorigenic, irritant and reproductive effect. Each drug is represented by 31 chemical descriptors (features). The proposed model consists of three phases. In the first phase, the most discriminative subset of features is selected using rough set-based methods to reduce the classification time while improving the classification performance. In the second phase, different sampling methods such as Random Under-Sampling, Random Over-Sampling and Synthetic Minority Oversampling Technique (SMOTE), BorderLine SMOTE and Safe Level SMOTE are used to solve the problem of imbalanced dataset. In the third phase, the Support Vector Machines (SVM) classifier is used to classify an unknown drug into toxic or non-toxic. SVM parameters such as the penalty parameter and kernel parameter have a great impact on the classification accuracy of the model. In this paper, Whale Optimization Algorithm (WOA) has been proposed to optimize the parameters of SVM, so that the classification error can be reduced. The experimental results proved that the proposed model achieved high sensitivity to all toxic effects. Overall, the high sensitivity of the WOA+SVM model indicates that it could be used for the prediction of drug toxicity in the early stage of drug development. Copyright © 2017 Elsevier Inc. All rights reserved.

Acute photo-induced toxicity and toxicokinetics of single compounds and mixtures of polycyclic aromatic hydrocarbons in zebrafish.

PubMed

Willis, Alison M; Oris, James T

2014-09-01

The present study examined photo-induced toxicity and toxicokinetics for acute exposure to selected polycyclic aromatic hydrocarbons (PAHs) in zebrafish. Photo-enhanced toxicity from co-exposure to ultraviolet (UV) radiation and PAHs enhanced the toxicity and exhibited toxic effects at PAH concentrations orders of magnitude below effects observed in the absence of UV. Because environmental exposure to PAHs is usually in the form of complex mixtures, the present study examined the photo-induced toxicity of both single compounds and mixtures of PAHs. In a sensitive larval life stage of zebrafish, acute photo-induced median lethal concentrations (LC50s) were derived for 4 PAHs (anthracene, pyrene, carbazole, and phenanthrene) to examine the hypothesis that phototoxic (anthracene and pyrene) and nonphototoxic (carbazole and phenanthrene) pathways of mixtures could be predicted from single exposures. Anthracene and pyrene were phototoxic as predicted; however, carbazole exhibited moderate photo-induced toxicity and phenanthrene exhibited weak photo-induced toxicity. The toxicity of each chemical alone was used to compare the toxicity of mixtures in binary, tertiary, and quaternary combinations of these PAHs, and a predictive model for environmental mixtures was generated. The results indicated that the acute toxicity of PAH mixtures was additive in phototoxic scenarios, regardless of the magnitude of photo-enhancement. Based on PAH concentrations found in water and circumstances of high UV dose to aquatic systems, there exists potential risk of photo-induced toxicity to aquatic organisms. © 2014 SETAC.

Effect of zeolite on toxicity of ammonia in freshwater sediments: Implications for toxicity identification evaluation procedures

USGS Publications Warehouse

Besser, J.M.; Ingersoll, C.G.; Leonard, E.N.; Mount, D.R.

1998-01-01

Techniques for reducing ammonia toxicity in freshwater sediments were investigated as part of a project to develop toxicity identification and evaluation (TIE) procedures for whole sediments. Although ammonia is a natural constituent of freshwater sediments, pollution can lead to ammonia concentrations that are toxic to benthic invertebrates, and ammonia can also contribute to the toxicity of sediments that contain more persistent contaminants. We investigated the use of amendments of a natural zeolite mineral, clinoptilolite, to reduce concentrations of ammonia in sediment pore water. Zeolites have been widely used for removal of ammonia in water treatment and in aqueous TIE procedures. The addition of granulated zeolite to ammonia-spiked sediments reduced pore-water ammonia concentrations and reduced ammonia toxicity to invertebrates. Amendments of 20% zeolite (v/v) reduced ammonia concentrations in pore water by ???70% in spiked sediments with ammonia concentrations typical of contaminated freshwater sediments. Zeolite amendments reduced toxicity of ammonia-spiked sediments to three taxa of benthic invertebrates (Hyalella azteca, Lumbriculus variegatus, and Chironomus tentans), despite their widely differing sensitivity to ammonia toxicity. In contrast, zeolite amendments did not reduce acute toxicity of sediments containing high concentrations of cadmium or copper or reduce concentrations of these metals in pore waters. These studies suggest that zeolite amendments, used in conjunction with toxicity tests with sensitive taxa such as H. azteca, may be an effective technique for selective reduction of ammonia toxicity in freshwater sediments.

Boron Toxicity Causes Multiple Effects on Malus domestica Pollen Tube Growth.

PubMed

Fang, Kefeng; Zhang, Weiwei; Xing, Yu; Zhang, Qing; Yang, Liu; Cao, Qingqin; Qin, Ling

2016-01-01

Boron is an important micronutrient for plants. However, boron is also toxic to cells at high concentrations, although the mechanism of this toxicity is not known. This study aimed to evaluate the effect of boron toxicity on Malus domestica pollen tube growth and its possible regulatory pathway. Our results showed that a high concentration of boron inhibited pollen germination and tube growth and led to the morphological abnormality of pollen tubes. Fluorescent labeling coupled with a scanning ion-selective electrode technique detected that boron toxicity could decrease [Ca(2+)]c and induce the disappearance of the [Ca(2+)]c gradient, which are critical for pollen tube polar growth. Actin filaments were therefore altered by boron toxicity. Immuno-localization and fluorescence labeling, together with fourier-transform infrared analysis, suggested that boron toxicity influenced the accumulation and distribution of callose, de-esterified pectins, esterified pectins, and arabinogalactan proteins in pollen tubes. All of the above results provide new insights into the regulatory role of boron in pollen tube development. In summary, boron likely plays a structural and regulatory role in relation to [Ca(2+)]c, actin cytoskeleton and cell wall components and thus regulates Malus domestica pollen germination and tube polar growth.

Boron Toxicity Causes Multiple Effects on Malus domestica Pollen Tube Growth

PubMed Central

Fang, Kefeng; Zhang, Weiwei; Xing, Yu; Zhang, Qing; Yang, Liu; Cao, Qingqin; Qin, Ling

2016-01-01

Boron is an important micronutrient for plants. However, boron is also toxic to cells at high concentrations, although the mechanism of this toxicity is not known. This study aimed to evaluate the effect of boron toxicity on Malus domestica pollen tube growth and its possible regulatory pathway. Our results showed that a high concentration of boron inhibited pollen germination and tube growth and led to the morphological abnormality of pollen tubes. Fluorescent labeling coupled with a scanning ion-selective electrode technique detected that boron toxicity could decrease [Ca2+]c and induce the disappearance of the [Ca2+]c gradient, which are critical for pollen tube polar growth. Actin filaments were therefore altered by boron toxicity. Immuno-localization and fluorescence labeling, together with fourier-transform infrared analysis, suggested that boron toxicity influenced the accumulation and distribution of callose, de-esterified pectins, esterified pectins, and arabinogalactan proteins in pollen tubes. All of the above results provide new insights into the regulatory role of boron in pollen tube development. In summary, boron likely plays a structural and regulatory role in relation to [Ca2+]c, actin cytoskeleton and cell wall components and thus regulates Malus domestica pollen germination and tube polar growth. PMID:26955377

Determination of toxic metals in drinking water sources in the Chief Albert Luthuli Local Municipality in Mpumalanga, South Africa

NASA Astrophysics Data System (ADS)

Nthunya, Lebea N.; Masheane, Monaheng L.; Malinga, Soraya P.; Nxumalo, Edward N.; Mamba, Bhekie B.; Mhlanga, Sabelo D.

2017-08-01

This study was conducted to determine the presence and levels of toxic metals on selected water sources in a rural community in Lochiel, South Africa. Collection of water samples from identified drinking water sources (open wells, community tanks, water treatment works and boreholes) was done in all seasons of the year (winter, spring, summer and autumn) between 2014 and 2015. The concentrations of identified toxic metals (cobalt, chromium, copper, lead, zinc, manganese and iron) were measured using ICP-OES. Some water sources were found to contain concentrations of toxic metals at levels slightly higher than USEPA, WHO and SANS241 set limits (e.g. manganese and cobalt), while others were found to be within the acceptable limits. This suggested that the residents residing in locations that have water sources containing toxic metals at the concentrations above the set limits are at risk and susceptible to suffer diseases caused by these toxic metals. The side effects of the metals may not be acute; however prolonged exposure to the toxic metals may result in detrimental effects since they are known to bioaccumulate in the body.

Selective Toxicity of Apigenin on Cancerous Hepatocytes by Directly Targeting their Mitochondria.

PubMed

Seydi, Enayatollah; Rasekh, Hamid R; Salimi, Ahmad; Mohsenifar, Zhaleh; Pourahmad, Jalal

2016-01-01

hepatocellular carcinoma (HCC) is the third cause of mortality due to cancer throughout the world. The main goal of the current research was to evaluate the selective toxicity of apigenin (APG) on hepatocytes and mitochondria obtained from the liver of HCC rats). In this research, HCC induced by a single dose of diethylnitrosamine (DEN); 200 mg/kg, i.p, and 2-acetylaminofluorene (2-AAF) (0.02%, through dietary) for 14 days. For confirmation of HCC, histopathological evaluations and determination of serum concentrations of liver toxicity enzymes and specific liver cancer marker; alpha-fetoprotein (AFP) were performed. Then, cancerous and non- cancerous hepatocytes were isolated by using the collagen perfusion method. Eventually, mitochondria isolated from HCC and normal hepatocytes were tested for every eventual toxic effects of APG. After confirmation of HCC, the results of this research showed that APG (10, 20 and 40 μM) increased mitochondrial parameters such as, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) level, mitochondrial swelling and cytochrome c expulsion only in cancerous hepatocytes. Apoptotic effect of APG on HCC cells was confirmed by caspase-3 activation and Annexin V-FITC and PI double staining analysis. These results propose the eligibility of the flavonoid APG as a complementary therapeutic agent for patients with hepatocellular carcinoma.

Toxicity and residual effects of insecticides on Ascia monuste and predator Solenopsis saevissima.

PubMed

Araújo, Tamíris A de; Picanço, Marcelo C; Ferreira, Dalton de O; Campos, Júlia Nd; Arcanjo, Lucas de P; Silva, Gerson A

2017-11-01

Investigating the impact of pesticides on non-target organisms is essential for sustainable integrated pest management programs. We therefore assessed the toxicity of ten insecticides to the brassica caterpillar Ascia monuste and its ant predator Solenopsis saevissima and examined the effect that the insecticide synergists had on toxicity to the predator. We also assessed the residual period of control and impact of the insecticides during the brassica growing cycle. All insecticides except flubendiamide exhibited mortality above the threshold required by Brazilian legislation (80%). Chlorantraniliprole, cyantraniliprole, indoxacarb and spinosad exhibited lower toxicity to the ant predator than they did to the brassica caterpillar. The results obtained for synergized insecticides suggest that selectivity to the predator was due the involvement of cytochrome P450-dependent monooxygenases. Chlorfenapyr and cyantraniliprole exhibited the highest residual periods of control to the brassica caterpillar, whereas malathion had the greatest impact on the predator. Most of the insecticides efficiently controlled the brassica caterpillar, but not all exhibited selectivity to the predator. Therefore, due to the distinctive responses of organisms with respect to residual periods of control and the impact of the insecticides, spraying frequency must be strongly considered in integrated pest management programs. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

Biochemical alterations in duckweed and algae induced by carrier solvents: Selection of an appropriate solvent in toxicity testing.

PubMed

Hu, Li-Xin; Tian, Fei; Martin, Francis L; Ying, Guang-Guo

2017-10-01

Carrier solvents are often used in aquatic toxicity testing for test chemicals with hydrophobic properties. However, the knowledge of solvent effects on test organisms remains limited. The present study aimed to determine the biochemical effects of the 4 common solvents methanol, ethanol, acetone, and dimethyl sulfoxide (DMSO) on 2 test species, Lemna minor and Raphidocelis subcapitata, by applying Fourier transform infrared spectroscopy (FTIR) coupled with multivariate analysis to select appropriate solvents for toxicity testing. The results showed biochemical variations associated with solvent treatments at different doses on test species. From the infrared spectra obtained, the structures of lipid membrane and protein phosphorylation in the test species were found to be sensitive to the solvents. Methanol and ethanol mainly affected the protein secondary structure, whereas acetone and DMSO primarily induced alterations in carbohydrates and proteins in the test species. The FTIR results demonstrated that methanol and ethanol showed higher biochemical alterations in the test species than acetone and DMSO, especially at the high doses (0.1 and 1% v/v). Based on the growth inhibition displayed and FTIR spectroscopy, acetone, and DMSO can be used as carrier solvents in toxicity testing when their doses are lower than 0.1% v/v. Environ Toxicol Chem 2017;36:2631-2639. © 2017 SETAC. © 2017 SETAC.

Ecological effects and environmental fate of solid rocket exhaust

NASA Technical Reports Server (NTRS)

Nimmo, B.; Stout, I. J.; Mickus, J.; Vickers, D.; Madsen, B.

1974-01-01

Specific target processes were classified as to the chemical, chemical-physical, and biological reactions and toxic effects of solid rocket emissions within selected ecosystems at Kennedy Space Center. Exposure of Citris seedlings, English peas, and bush beans to SRM exhaust under laboratory conditions demonstrated reduced growth rates, but at very high concentrations. Field studies of natural plant populations in three diverse ecosystems failed to reveal any structural damage at the concentration levels tested. Background information on elemental composition of selected woody plants from two terrestrial ecosystems is reported. LD sub 50 for a native mouse (peromysous gossypinus) exposed to SRM exhaust was determined to be 50 ppm/g body weight. Results strongly indicate that other components of the SRM exhaust act synergically to enhance the toxic effects of HCl gas when inhaled. A brief summary is given regarding the work on SRM exhaust and its possible impact on hatchability of incubating bird eggs.

Evaluation of the Susceptibility of the Pea Aphid, Acyrthosiphon pisum, to a Selection of Novel Biorational Insecticides using an Artificial Diet

PubMed Central

Sadeghi, Amin; Van Damme, Els J.M.; Smagghe, Guy

2009-01-01

An improved technique was developed to assay the toxicity of insecticides against aphids using an artificial diet. The susceptibility of the pea aphid Acyrthosiphon pisum (Harris) (Hemiptera: Aphidoidea) was determined for a selection of novel biorational insecticides, each representing a novel mode of action. Flonicamid, a novel systemic insecticide with selective activity as feeding blocker against sucking insects, showed high toxicity against first-instar A. pisum nymphs with an LC50 of 20.4 μg/ml after 24 h, and of 0.24 µg/ml after 72 h. The toxicity was compared with another feeding blocker, pymetrozine, and the neonicotinoid, imidacloprid. In addition, four insect growth regulators were tested. The chitin synthesis inhibitor flufenoxuron, the juvenile hormone analogue pyriproxyfen, and the azadirachtin compound Neem Azal-T/S showed strong effects and reduced the aphid population by 50% after 3 days of treatment at a concentration of 7–9 µg/ml. The ecdysone agonist tested, halofenozide, was less potent. In conclusion, the improved aphid feeding apparatus can be useful as a miniature screening device for insecticides against different aphid pests. The present study demonstrated rapid and strong toxicity of flonicamid, and other biorational insecticides towards A. pisum. PMID:20053120

Alterations of mitochondrial DNA in CEM cells selected for resistance toward ddC toxicity.

PubMed

Bjerke, M; Franco, M; Johansson, M; Balzarini, J; Karlsson, A

2006-01-01

2 ',3 '-dideoxycytidine (ddC) is a nucleoside analog that has been shown to produce a delayed toxicity which may be due to the depletion of mitochondrial DNA (mtDNA). In order to gain further understanding of the events involved in mitochondrial toxicity, two different CEM cell lines were selected for resistance to the delayed ddC toxicity.

Aquatic Toxicity Information Retrieval Data Base (ACQUIRE). Data file

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

Not Available

The purpose of Acquire is to provide scientists and managers quick access to a comprehensive, systematic, computerized compilation of aquatic toxicity data. Scientific papers published both nationally and internationally on the toxicity of chemicals to aquatic organisms and plants are collected and reviewed for ACQUIRE. Independently compiled data files that meet ACQUIRE parameter and quality assurance criteria are also included. Selected toxicity test results and related testing information for any individual chemical from laboratory and field aquatic toxicity effects are included for tests with freshwater and marine organisms. The total number of data records in ACQUIRE is now over 105,300.more » This includes data from 6000 references, for 5200 chemicals and 2400 test species. A major data file, Acute Toxicity of Organic Chemicals (ATOC), has been incorporated into ACQUIRE. The ATOC file contains laboratory acute test data on 525 organic chemicals using juvenile fathead minnows.« less

Identification of a Potent Phosphoinositide 3‐Kinase Pan Inhibitor Displaying a Strategic Carboxylic Acid Group and Development of Its Prodrugs

PubMed Central

Pirali, Tracey; Ciraolo, Elisa; Aprile, Silvio; Massarotti, Alberto; Berndt, Alex; Griglio, Alessia; Serafini, Marta; Mercalli, Valentina; Landoni, Clarissa; Campa, Carlo Cosimo; Margaria, Jean Piero; Silva, Rangel L.; Grosa, Giorgio; Sorba, Giovanni; Williams, Roger

2017-01-01

Abstract Activation of the phosphoinositide 3‐kinase (PI3K) pathway is a key signaling event in cancer, inflammation, and other proliferative diseases. PI3K inhibitors are already approved for some specific clinical indications, but their systemic on‐target toxicity limits their larger use. In particular, whereas toxicity is tolerable in acute treatment of life‐threatening diseases, this is less acceptable in chronic conditions. In the past, the strategy to overcome this drawback was to block selected isoforms mainly expressed in leukocytes, but redundancy within the PI3K family members challenges the effectiveness of this approach. On the other hand, decreasing exposure to selected target cells represents a so‐far unexplored alternative to circumvent systemic toxicity. In this manuscript, we describe the generation of a library of triazolylquinolones and the development of the first prodrug pan‐PI3K inhibitor. PMID:28857471

High-Content Analysis Provides Mechanistic Insights into the Testicular Toxicity of Bisphenol A and Selected Analogues in Mouse Spermatogonial Cells.

PubMed

Liang, Shenxuan; Yin, Lei; Shengyang Yu, Kevin; Hofmann, Marie-Claude; Yu, Xiaozhong

2017-01-01

Bisphenol A (BPA), an endocrine-disrupting compound, was found to be a testicular toxicant in animal models. Bisphenol S (BPS), bisphenol AF (BPAF), and tetrabromobisphenol A (TBBPA) were recently introduced to the market as alternatives to BPA. However, toxicological data of these compounds in the male reproductive system are still limited so far. This study developed and validated an automated multi-parametric high-content analysis (HCA) using the C18-4 spermatogonial cell line as a model. We applied these validated HCA, including nuclear morphology, DNA content, cell cycle progression, DNA synthesis, cytoskeleton integrity, and DNA damage responses, to characterize and compare the testicular toxicities of BPA and 3 selected commercial available BPA analogues, BPS, BPAF, and TBBPA. HCA revealed BPAF and TBBPA exhibited higher spermatogonial toxicities as compared with BPA and BPS, including dose- and time-dependent alterations in nuclear morphology, cell cycle, DNA damage responses, and perturbation of the cytoskeleton. Our results demonstrated that this specific culture model together with HCA can be utilized for quantitative screening and discriminating of chemical-specific testicular toxicity in spermatogonial cells. It also provides a fast and cost-effective approach for the identification of environmental chemicals that could have detrimental effects on reproduction. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Acrylamide: inhibition of formation in processed food and mitigation of toxicity in cells, animals, and humans.

PubMed

Friedman, Mendel

2015-06-01

Potentially toxic acrylamide is largely derived from the heat-inducing reactions between the amino group of the amino acid asparagine and carbonyl groups of glucose and fructose in plant-derived foods including cereals, coffees, almonds, olives, potatoes, and sweet potatoes. This review surveys and consolidates the following dietary aspects of acrylamide: distribution in food, exposure and consumption by diverse populations, reduction of the content in different food categories, and mitigation of adverse in vivo effects. Methods to reduce acrylamide levels include selecting commercial food with a low acrylamide content, selecting cereal and potato varieties with low levels of asparagine and reducing sugars, selecting processing conditions that minimize acrylamide formation, adding food-compatible compounds and plant extracts to food formulations before processing that inhibit acrylamide formation during processing of cereal products, coffees, teas, olives, almonds, and potato products, and reducing multiorgan toxicity (antifertility, carcinogenicity, neurotoxicity, teratogenicity). The herein described observations and recommendations are of scientific interest for food chemistry, pharmacology, and toxicology, but also have the potential to benefit nutrition, food safety, and human health.

Selective control of common crap: ineffectiveness of 2-(digeranylamino)-ethanol (GD-174) in pond trials

USGS Publications Warehouse

Gilderhus, P.A.; Burress, R.M.

1983-01-01

The candidate piscicide, 2-(digeranylamino)-ethanol, (commonly known as GD-174) was subjected to efficacy trials in ponds under a wide variety of conditions. Results of the trials were disappointing considering that laboratory tests had shown the compound to be selectively toxic to common carp (Cyprinus carpio). Results of pretreatment, on-site toxicity tests were misleading and indicated concentrations that failed to kill all of the carp in 19 of 23 ponds. In a few instances, the chemical killed the carp with little or no effect on nontarget fishes. No fish were killed in some trials and large numbers of nontarget fishes were killed in others. Twenty of 25 pond trials were judged to be unsuccessful. Success or failure of pond treatments could not be correlated with any particular combination of physical, chemical, and biological factors. Because the activity of GD-174 against mixed populations of fish cannot be predicted, further development of this compound as a selective toxicant for carp has been discontinued at the National Fishery Research Laboratory.

Complementary effect of natural and sexual selection against immigrants maintains differentiation between locally adapted fish

NASA Astrophysics Data System (ADS)

Plath, Martin; Riesch, Rüdiger; Oranth, Alexandra; Dzienko, Justina; Karau, Nora; Schießl, Angela; Stadler, Stefan; Wigh, Adriana; Zimmer, Claudia; Arias-Rodriguez, Lenin; Schlupp, Ingo; Tobler, Michael

2010-08-01

Adaptation to ecologically heterogeneous environments can drive speciation. But what mechanisms maintain reproductive isolation among locally adapted populations? Using poeciliid fishes in a system with naturally occurring toxic hydrogen sulfide, we show that (a) fish from non-sulfidic sites ( Poecilia mexicana) show high mortality (95 %) after 24 h when exposed to the toxicant, while locally adapted fish from sulfidic sites ( Poecilia sulphuraria) experience low mortality (13 %) when transferred to non-sulfidic water. (b) Mate choice tests revealed that P. mexicana females exhibit a preference for conspecific males in non-sulfidic water, but not in sulfidic water, whereas P. sulphuraria females never showed a preference. Increased costs of mate choice in sulfidic, hypoxic water, and the lack of selection for reinforcement due to the low survival of P. mexicana may explain the absence of a preference in P. sulphuraria females. Taken together, our study may be the first to demonstrate independent—but complementary—effects of natural and sexual selection against immigrants maintaining differentiation between locally adapted fish populations.

Complementary effect of natural and sexual selection against immigrants maintains differentiation between locally adapted fish.

PubMed

Plath, Martin; Riesch, Rüdiger; Oranth, Alexandra; Dzienko, Justina; Karau, Nora; Schiessl, Angela; Stadler, Stefan; Wigh, Adriana; Zimmer, Claudia; Arias-Rodriguez, Lenin; Schlupp, Ingo; Tobler, Michael

2010-08-01

Adaptation to ecologically heterogeneous environments can drive speciation. But what mechanisms maintain reproductive isolation among locally adapted populations? Using poeciliid fishes in a system with naturally occurring toxic hydrogen sulfide, we show that (a) fish from non-sulfidic sites (Poecilia mexicana) show high mortality (95 %) after 24 h when exposed to the toxicant, while locally adapted fish from sulfidic sites (Poecilia sulphuraria) experience low mortality (13 %) when transferred to non-sulfidic water. (b) Mate choice tests revealed that P. mexicana females exhibit a preference for conspecific males in non-sulfidic water, but not in sulfidic water, whereas P. sulphuraria females never showed a preference. Increased costs of mate choice in sulfidic, hypoxic water, and the lack of selection for reinforcement due to the low survival of P. mexicana may explain the absence of a preference in P. sulphuraria females. Taken together, our study may be the first to demonstrate independent-but complementary-effects of natural and sexual selection against immigrants maintaining differentiation between locally adapted fish populations.

Toxicity of Cold Lake Blend and Western Canadian Select dilbits to standard aquatic test species

EPA Science Inventory

Dilbits are blends of bitumen and natural gas condensates or crude oils with only limited toxicity data. Two dilbits, Cold Lake Blend and Western Canadian Select, were tested as either unweathered or weathered oils for acute and chronic toxicity to standard freshwater and estuari...

Probing the structural and molecular basis of nucleotide selectivity by human mitochondrial DNA polymerase γ

PubMed Central

Sohl, Christal D.; Szymanski, Michal R.; Mislak, Andrea C.; Shumate, Christie K.; Amiralaei, Sheida; Schinazi, Raymond F.; Anderson, Karen S.; Yin, Y. Whitney

2015-01-01

Nucleoside analog reverse transcriptase inhibitors (NRTIs) are the essential components of highly active antiretroviral (HAART) therapy targeting HIV reverse transcriptase (RT). NRTI triphosphates (NRTI-TP), the biologically active forms, act as chain terminators of viral DNA synthesis. Unfortunately, NRTIs also inhibit human mitochondrial DNA polymerase (Pol γ), causing unwanted mitochondrial toxicity. Understanding the structural and mechanistic differences between Pol γ and RT in response to NRTIs will provide invaluable insight to aid in designing more effective drugs with lower toxicity. The NRTIs emtricitabine [(-)-2,3′-dideoxy-5-fluoro-3′-thiacytidine, (-)-FTC] and lamivudine, [(-)-2,3′-dideoxy-3′-thiacytidine, (-)-3TC] are both potent RT inhibitors, but Pol γ discriminates against (-)-FTC-TP by two orders of magnitude better than (-)-3TC-TP. Furthermore, although (-)-FTC-TP is only slightly more potent against HIV RT than its enantiomer (+)-FTC-TP, it is discriminated by human Pol γ four orders of magnitude more efficiently than (+)-FTC-TP. As a result, (-)-FTC is a much less toxic NRTI. Here, we present the structural and kinetic basis for this striking difference by identifying the discriminator residues of drug selectivity in both viral and human enzymes responsible for substrate selection and inhibitor specificity. For the first time, to our knowledge, this work illuminates the mechanism of (-)-FTC-TP differential selectivity and provides a structural scaffold for development of novel NRTIs with lower toxicity. PMID:26124101

Safety assessment of boron by application of new uncertainty factors and their subdivision.

PubMed

Hasegawa, Ryuichi; Hirata-Koizumi, Mutsuko; Dourson, Michael L; Parker, Ann; Ono, Atsushi; Hirose, Akihiko

2013-02-01

The available toxicity information for boron was reevaluated and four appropriate toxicity studies were selected in order to derive a tolerable daily intake (TDI) using newly proposed uncertainty factors (UFs) presented in Hasegawa et al. (2010). No observed adverse effect levels (NOAELs) of 17.5 and 8.8 mgB/kg/day for the critical effect of testicular toxicity were found in 2-year rat and dog feeding studies. Also, the 95% lower confidence limit of the benchmark doses for 5% reduction of fetal body weight (BMDL(05)) was calculated as 44.9 and 10.3 mgB/kg/day in mouse and rat developmental toxicity studies, respectively. Measured values available for differences in boron clearance between rats and humans and variability in the glomerular filtration rate (GFR) in pregnant women were used to derive chemical specific UFs. For the remaining uncertainty, newly proposed default UFs, which were derived from the latest applicable information with a probabilistic approach, and their subdivided factors for toxicokinetic and toxicodynamic variability were applied. Finally, overall UFs were calculated as 68 for rat testicular toxicity, 40 for dog testicular toxicity, 247 for mouse developmental toxicity and 78 for rat developmental toxicity. It is concluded that 0.13 mgB/kg/day is the most appropriate TDI for boron, based on rat developmental toxicity. Copyright © 2012 Elsevier Inc. All rights reserved.

Comparative assessment of three in vitro exposure methods for combustion toxicity.

PubMed

Lestari, Fatma; Markovic, Boban; Green, Anthony R; Chattopadhyay, Gautam; Hayes, Amanda J

2006-01-01

A comparative assessment of three approaches for the use of human cells in vitro to investigate combustion toxicity was conducted. These included one indirect and two direct (passive and dynamic) exposure methods. The indirect method used an impinger system in which culture medium was used to trap the toxicants, whilst the direct exposure involved the use of a Horizontal Harvard Navicyte Chamber at the air/liquid interface. The cytotoxic effects of thermal decomposition products were assessed using the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay (Promega) on a selection of human cells including: HepG2, A549 and skin fibroblasts. A small scale laboratory fire test using a vertical tube furnace was designed for the generation of combustion products. Polymethyl methacrylate (PMMA) was selected as a model polymer to study the cytotoxic effects of combustion products. NOAEC (no observable adverse effect concentration), IC10 (10% inhibitory concentration), IC50 (50% inhibitory concentration) and TLC (total lethal concentration) values were determined from dose response curves. Assessment using the NRU (neutral red uptake) and ATP (adenosine triphosphate) assays on human lung derived cells (A549) was also undertaken. Comparison between in vitro cytotoxicity results against published toxicity data for PMMA combustion and predicted LC50 (50% lethal concentration) values calculated from identified compounds using GCMS (gas chromatography mass spectrometry) was determined. The results suggested that the indirect exposure method did not appear to simulate closely exposure via inhalation, whilst exposure at the air/liquid interface by using the dynamic method proved to be a more representative method of human inhalation. This exposure method may be a potential system for in vitro cytotoxicity testing in combustion toxicity. Copyright 2005 John Wiley & Sons, Ltd.

Tier 3 Toxicity Value White Paper

EPA Pesticide Factsheets

The purpose of this white paper is to articulate the issues pertaining to Tier 3 toxicity values and provide recommendations on processes that will improve the transparency and consistency of identifying, evaluating, selecting, and documenting Tier 3 toxicity values for use in the Superfund and Resource Conservation and Recovery Act (RCRA) programs. This white paper will be used to assist regional risk assessors in selecting Tier 3 toxicity values as well as provide the foundation for future regional and national efforts to improve guidance and policy on Tier 3 toxicity values.

Wastewater toxicity of tannin- versus chromium-based leather tanneries in Marrakesh, Morocco.

PubMed

De Nicola, E; Meriç, S; Della Rocca, C; Gallo, M; Iaccarino, M; Manini, P; Petruzzelli, D; Belgiorno, V; Cheggour, M; Di Gennaro, A; Moukrim, A; Tünay, O; Pagano, G

2007-10-01

The toxicity of leather tanning wastewater from a traditional tannery (TT), which is based on vegetable tannin (VT), was compared with wastewater from a tannery combining the use of chromium-based tanning (CT) with VT-based tanning operations. Wastewater samples from a TT and a CT plant as well as from five sewer sampling points were collected in Marrakesh, Morocco, and the concentrations of VT and some selected inorganics were measured. A set of bioassays were used to test wastewater toxicity in sea urchin (Paracentrotus lividus) embryos and sperm, in Daphnia magna, and in marine microalgae (Dunaliella tertiolecta). Toxicity end points included: (1) developmental defects, embryonic mortality, sperm fertilization success, and offspring damage in sea urchins; (2) D. magna immobilization; and (3) algal growth rate inhibition. Toxicity tests on TT and CT effluents (TTE and CTE) were run at dilutions ranging from 0.1% to 2% (sea urchins and algae) or up to 12% in D. magna. Parallel bioassays were run on VT extract (VTE) at nominal tannin concentrations ranging from 0.1 to 10 mg l(-1). The results showed higher toxicity of CTE compared with TTE. CTE toxicity in sea urchins and algae showed concentration-related trends, whereas TTE exerted hormetic effects at levels of 0.1% to 0.2% and toxic effects at levels >or=1%. The same trends were observed for VTE, suggesting a prevailing role of tannin in TTE-associated effects. The moderate wastewater toxicity of VT-based tanneries might prompt interest in the VT tanning process.

Environmental interactions with the toxicity of plant essential oils to the poultry red mite Dermanyssus gallinae.

PubMed

George, D R; Sparagano, O A E; Port, G; Okello, E; Shiel, R S; Guy, J H

2010-03-01

The toxicity of a range of plant essential oils to the poultry red mite, Dermanyssus gallinae (De Geer) (Acari: Dermanyssidae), a serious ectoparasitic pest of laying hens throughout Europe and elsewhere, was assessed in the laboratory. Dermanyssus gallinae may cause losses in egg production, anaemia and, in extreme cases, death of hens. With changes in legislation and consumer demand, alternatives to synthetic acaricides are needed to manage this pest. Fifty plant essential oils were selected for their toxicity to arthropods reported in the literature. Twenty-four of these essential oils were found to kill > 75% of adult D. gallinae in contact toxicity tests over a 24-h period at a rate of 0.21 mg/cm(2). Subsequent testing at lower rates showed that the essential oils of cade, manuka and thyme were especially toxic to adult D. gallinae. The toxicity of the seven most acaricidal essential oils was found to be stable at different temperatures likely to be encountered in commercial poultry housing (15 degrees C, 22 degrees C and 29 degrees C), although results suggest that humidity and dust might influence the toxicity of some of the oils tested. The toxicity of clove bud essential oil to D. gallinae, for example, was increased at high humidity and dust levels compared with ambient levels. The results suggest that certain essential oils may make effective botanical pesticides for use against D. gallinae, although it is likely that issues relating to the consistency of the toxic effect of some oils will determine which oils will be most effective in practice.

Linking Inflammation and Parkinson Disease: Hypochlorous Acid Generates Parkinsonian Poisons

PubMed Central

Jeitner, Thomas M.; Kalogiannis, Mike; Krasnikov, Boris F.; Gomlin, Irving; Peltier, Morgan R.; Moran, Graham R.

2016-01-01

Inflammation is a common feature of Parkinson Disease and other neurodegenerative disorders. Hypochlorous acid (HOCl) is a reactive oxygen species formed by neutrophils and other myeloperoxidase-containing cells during inflammation. HOCl chlorinates the amine and catechol moieties of dopamine to produce chlorinated derivatives collectively termed chlorodopamine. Here, we report that chlorodopamine is toxic to dopaminergic neurons both in vivo and in vitro. Intrastriatal administration of 90 nmol chlorodopamine to mice resulted in loss of dopaminergic neurons from the substantia nigra and decreased ambulation-results that were comparable to those produced by the same dose of the parkinsonian poison, 1-methyl-4-phenylpyridinium (MPP+). Chlorodopamine was also more toxic to differentiated SH SY5Y cells than HOCl. The basis of this selective toxicity is likely mediated by chlorodopamine uptake through the dopamine transporter, as expression of this transporter in COS-7 cells conferred sensitivity to chlorodopamine toxicity. Pharmacological blockade of the dopamine transporter also mitigated the deleterious effects of chlorodopamine in vivo. The cellular actions of chlorodopamine included inactivation of the α-ketoglutarate dehydrogenase complex, as well as inhibition of mitochondrial respiration. The latter effect is consistent with inhibition of cytochrome c oxidase. Illumination at 670 nm, which stimulates cytochrome c oxidase, reversed the effects of chlorodopamine. The observed changes in mitochondrial biochemistry were also accompanied by the swelling of these organelles. Overall, our findings suggest that chlorination of dopamine by HOCl generates toxins that selectively kill dopaminergic neurons in the substantia nigra in a manner comparable to MPP+. PMID:27026709

Toxicity Assessment of Wild Mushrooms from the Western Ghats, India: An in Vitro and Sub-Acute in Vivo Study

PubMed Central

Sai Latha, S.; Naveen, S.; Pradeep, C. K.; Sivaraj, C.; Dinesh, M. G.; Anilakumar, K. R.

2018-01-01

Background: Poisoning by different kinds of toxic mushrooms is unfortunately becoming an increasingly important medical problem, evident from the growing number of reports worldwide since the 1950s. Mycetism being a health concern, deserves scientific attention. In this perspective, the present study aims to assess the potential effects of ingesting the selected wild mushrooms from regions of the Western Ghats, India. Methods: The preliminary cytotoxicity of the selected mushrooms was studied in vitro on the intestinal NCM460 and the Chang's liver cell lines on the basis of cell viability. Further, the hepatotoxicity was assessed by measuring biologically relevant endpoints such as membrane integrity, mitochondrial stress and oxidative status. A 28 day sub-acute toxicity study was carried out by orally administering the mushroom extracts to mice at 250 and 500 mg/kg body weight. The hematological and serum analysis as well as histological examinations were carried out to evaluate their in vivo toxicity. GC-MS analysis of the mushrooms facilitated the identification of their volatile chemical profile. Result: The in vitro intestinal cytotoxicity exhibited by these wild mushrooms in comparison to the edible mushroom indicated their potential gastrointestinal toxicity. The pathological findings in small intestine on exposure to Chlorophyllum molybdites and Agaricus endoxanthus also validates the speculations about their intestinal toxicity. The toxic insult to the hepatocytes due to Amanita angustilamellata, Entoloma crassum, and Clarkeinda trachodes was predictive of the observed in vivo hepatotoxicity which was also accompanied by renal toxicity at the higher dose of 500 mg/kg bwt. Conclusion: The potential toxicity exhibited by these representative mushrooms from the wild warrants caution about their consumption. The present work could also have broader implications for global mycetism. PMID:29487528

Modulatory effects of Zn2+ ions on the toxicity of citrate- and PVP-capped gold nanoparticles towards freshwater algae, Scenedesmus obliquus.

PubMed

Iswarya, V; Johnson, J B; Parashar, Abhinav; Pulimi, Mrudula; Chandrasekaran, N; Mukherjee, Amitava

2017-02-01

Gold nanoparticles (GNPs) are widely used for medical purposes, both in diagnostics as well as drug delivery, and hence are prone to release and distribution in the environment. Thus, we have explored the effects of GNPs with two distinct surface capping (citrate and PVP), and three different sizes (16, 27, and 37 nm) at 0.01-, 0.1-, and 1-mg L -1 concentrations on a predominant freshwater alga Scenedesmus obliquus in the sterile freshwater matrix. We have also investigated how an abundant metal ion from freshwater, i.e., Zn 2+ ions may modulate the effects of the selected GNPs (40 nm, citrate, and PVP capped). Preliminary toxicity results revealed that gold nanoparticles were highly toxic in comparison to zinc ions alone. A significant modulation in the toxicity of Zn ions was not noticed in the presence of GNPs. In contrast, zinc ions minimized the toxicity produced by GNPs (both CIT-37 and PVP-37), despite its individual toxicity. Approximately, about 42, 33, and 25% toxicity reduction was noted at 0.05-, 0.5-, and 5-mg L -1 Zn ions, respectively, for CIT-37 GNPs, while 31% (0.05 mg L -1 ), 24% (0.5 mg L -1 ), and 9% (5 mg L -1 ) of toxicity reduction were noted for PVP-37 GNPs. Maximum toxicity reduction was seen at 0.05 mg L -1 of Zn ions. Abbott modeling substantiated antagonistic effects offered by Zn 2+ ions on GNPs. Stability and sedimentation data revealed that the addition of zinc ions gradually induced the aggregation of NPs and in turn significantly reduced the toxicity of GNPs. Thus, the naturally existing ions like Zn 2+ have an ability to modulate the toxicity of GNPs in a real-world environment scenario.

Evaluation of Cytotoxic Responses Caused by Selected Organophosphorus Esters in Chick Sympathetic Ganglia Cultures

PubMed Central

Obersteiner, E. J.; Sharma, R. P.

1978-01-01

Ten day old chick sympathetic ganglia cultured in a microslide assembly were treated with a selected group of organophosphate pesticides to evaluate their cytotoxicity ranges, and the usefulness of such a model for screening pesticides. Examination by phase contrast and light microscopy for chemically-induced morphological alteration of nerve fibers, glial cells and neurons provided the criteria for quantitation and assessment of the toxic effects. Concentrations that produced half-maximal effects ranged from 1 × 10-6M (severely toxic) for methylparathian, diazinon, paraoxon, mevinphos, diisopropylfluorophosphate, tri-o-tolyl phosphate and its mixed isomers to a 1 × 10-3M (intermediate) for malathion, leptophos, coumaphos, mono- and dicrotophos. Some or no effects were evident at 1 × 102-M for O'ethyl-O-p-nitrophenyl phenyl phosphonothioate, tri-m-tolylphosphate, chlorpyriphos and triphenyl phosphate. In all instances, nerve fibers were more sensitive than neurons or glial cells to insecticides. All cellular growth was inhibited at 1 × 10-2M (except triphenyl phosphate). Below 1 x 10-7M, no inhibitory effects were evident. The secondary abnormalities included decreased cellular migration, diffuse cellular growth pattern, increased vacuolization, nerve fiber swelling and cellular degeneration. The cytotoxic effects of these chemicals do not appear to be related to in vivo toxicity or cholinesterase inhibition potential. ImagesFig. 1.Fig. 2.Fig. 3.Fig. 4.Fig. 5.Fig. 6. PMID:565668

Mixture toxicity of six sulfonamides and their two transformation products to green algae Scenedesmus vacuolatus and duckweed Lemna minor.

PubMed

Białk-Bielińska, Anna; Caban, Magda; Pieczyńska, Aleksandra; Stepnowski, Piotr; Stolte, Stefan

2017-04-01

Since humans and ecosystems are continually exposed to a very complex and permanently changing mixture of chemicals, there is increasing concern in the general public about the potential adverse effects they may cause. Among all "emerging pollutants", pharmaceuticals in particular have raised great environmental concern. For these reasons the aim of our study was to evaluate the mixture toxicity of six antimicrobial sulfonamides (SAs) and their two most commonly identified degradation products - sulfanilic acid (SNA) and sulfanilamide (SN) - to limnic green algae Scenedesmus vacuolatus and duckweed Lemna minor. The ecotoxicological data for the single toxicity of SNA and SN towards selected organisms are presented. The concept of Concentration Addition (CA) was applied to estimate the effects, and less than additive effects were observed. In general terms, it seems sufficiently precautionary for the aquatic environment to consider the toxicity of a sulfonamide mixture as additive. The Concentration Addition model proves to be a reasonable worst-case estimation. Such a comparative study on the mixture toxicity of sulfonamides and their transformation products has been presented for the first time. Copyright © 2017 Elsevier Ltd. All rights reserved.

The repellent and persistent toxic effects of essential oils against the poultry red mite, Dermanyssus gallinae.

PubMed

Nechita, I S; Poirel, M T; Cozma, V; Zenner, L

2015-12-15

The economic impact of the poultry red mite, Dermanyssus gallinae, the lack of new acaricides, the occurrence of resistance and tighter legislation have all led to the need to find new ways to control this pest. One promising alternative method of control focuses on employing repellent and/or toxic effects of selected plant essential oils against D. gallinae. Ten essential oils (basil, thyme, coriander, eucalyptus, lavender, lemon, fir tree, oregano, mint, and juniper) were tested for the persistence of toxic and repellent effects. In filter-paper toxicity bioassays against D. gallinae, the best results were observed for lavender (more than 97% mortality after 48 and 72 h) and thyme (84% at 72 h) at a dose of 0.12 mg/cm(2). In addition, two oils showed significant persistent toxic effects 15 and 30 days post application to filter papers. Thyme was the most effective (100% mortality at 72 h), followed by lavender (nearly 80% mortality after 72 h). Out of the ten oils tested for their repellent effect, thyme was the strongest, with nearly 80% of the tested area avoided by mites; oregano caused a 60% avoidance and lavender exhibited an effect close to 40%. All other oils exhibited a repellent effect of less than 30%. None of the experiments showed a repellent effect for HM (commercial alimentary oil) or negative controls. We found that the thyme and lavender essential oils exhibited promising results when tested in vitro for toxic and repellent effects against D. gallinae; thus, we suggest that future experiments focus on in vivo tests using these oils in farm units. Copyright © 2015 Elsevier B.V. All rights reserved.

Overview of data and conceptual approaches for derivation of quantitative structure-activity relationships for ecotoxicological effects of organic chemicals.

PubMed

Bradbury, Steven P; Russom, Christine L; Ankley, Gerald T; Schultz, T Wayne; Walker, John D

2003-08-01

The use of quantitative structure-activity relationships (QSARs) in assessing potential toxic effects of organic chemicals on aquatic organisms continues to evolve as computational efficiency and toxicological understanding advance. With the ever-increasing production of new chemicals, and the need to optimize resources to assess thousands of existing chemicals in commerce, regulatory agencies have turned to QSARs as essential tools to help prioritize tiered risk assessments when empirical data are not available to evaluate toxicological effects. Progress in designing scientifically credible QSARs is intimately associated with the development of empirically derived databases of well-defined and quantified toxicity endpoints, which are based on a strategic evaluation of diverse sets of chemical structures, modes of toxic action, and species. This review provides a brief overview of four databases created for the purpose of developing QSARs for estimating toxicity of chemicals to aquatic organisms. The evolution of QSARs based initially on general chemical classification schemes, to models founded on modes of toxic action that range from nonspecific partitioning into hydrophobic cellular membranes to receptor-mediated mechanisms is summarized. Finally, an overview of expert systems that integrate chemical-specific mode of action classification and associated QSAR selection for estimating potential toxicological effects of organic chemicals is presented.

The chemical nature of phenolic compounds determines their toxicity and induces distinct physiological responses in Saccharomyces cerevisiae in lignocellulose hydrolysates

PubMed Central

2014-01-01

We investigated the severity of the inhibitory effects of 13 phenolic compounds usually found in spruce hydrolysates (4-hydroxy-3-methoxycinnamaldehyde, homovanilyl alcohol, vanillin, syringic acid, vanillic acid, gallic acid, dihydroferulic acid, p-coumaric acid, hydroquinone, ferulic acid, homovanillic acid, 4-hydroxybenzoic acid and vanillylidenacetone). The effects of the selected compounds on cell growth, biomass yield and ethanol yield were studied and the toxic concentration threshold was defined for each compound. Using Ethanol Red, the popular industrial strain of Saccharomyces cerevisiae, we found the most toxic compound to be 4-hydroxy-3-methoxycinnamaldehyde which inhibited growth at a concentration of 1.8 mM. We also observed that toxicity did not generally follow a trend based on the aldehyde, acid, ketone or alcohol classification of phenolic compounds, but rather that other structural properties such as additional functional groups attached to the compound may determine its toxicity. Three distinctive growth patterns that effectively clustered all the compounds involved in the screening into three categories. We suggest that the compounds have different cellular targets, and that. We suggest that the compounds have different cellular targets and inhibitory mechanisms in the cells, also compounds who share similar pattern on cell growth may have similar inhibitory effect and mechanisms of inhibition. PMID:24949277

De Novo Synthesized Estradiol Protects against Methylmercury-Induced Neurotoxicity in Cultured Rat Hippocampal Slices

PubMed Central

Ishihara, Yasuhiro; Komatsu, Shota; Munetsuna, Eiji; Onizaki, Masahiro; Ishida, Atsuhiko; Kawato, Suguru; Mukuda, Takao

2013-01-01

Background Estrogen, a class of female sex steroids, is neuroprotective. Estrogen is synthesized in specific areas of the brain. There is a possibility that the de novo synthesized estrogen exerts protective effect in brain, although direct evidence for the neuroprotective function of brain-synthesized estrogen has not been clearly demonstrated. Methylmercury (MeHg) is a neurotoxin that induces neuronal degeneration in the central nervous system. The neurotoxicity of MeHg is region-specific, and the molecular mechanisms for the selective neurotoxicity are not well defined. In this study, the protective effect of de novo synthesized 17β-estradiol on MeHg-induced neurotoxicity in rat hippocampus was examined. Methodology/Principal Findings Neurotoxic effect of MeHg on hippocampal organotypic slice culture was quantified by propidium iodide fluorescence imaging. Twenty-four-hour treatment of the slices with MeHg caused cell death in a dose-dependent manner. The toxicity of MeHg was attenuated by pre-treatment with exogenously added estradiol. The slices de novo synthesized estradiol. The estradiol synthesis was not affected by treatment with 1 µM MeHg. The toxicity of MeHg was enhanced by inhibition of de novo estradiol synthesis, and the enhancement of toxicity was recovered by the addition of exogenous estradiol. The neuroprotective effect of estradiol was inhibited by an estrogen receptor (ER) antagonist, and mimicked by pre-treatment of the slices with agonists for ERα and ERβ, indicating the neuroprotective effect was mediated by ERs. Conclusions/Significance Hippocampus de novo synthesized estradiol protected hippocampal cells from MeHg-induced neurotoxicity via ERα- and ERβ-mediated pathways. The self-protective function of de novo synthesized estradiol might be one of the possible mechanisms for the selective sensitivity of the brain to MeHg toxicity. PMID:23405170

Acute toxicity of subcutaneously administered vitamin E isomers delta- and gamma-tocotrienol in mice.

PubMed

Swift, Sibyl N; Pessu, Roli L; Chakraborty, Kushal; Villa, Vilmar; Lombardini, Eric; Ghosh, Sanchita P

2014-01-01

The toxicity of parenterally administered vitamin E isomers, delta-tocotrienol (DT3) and gamma-tocotrienol (GT3), was evaluated in male and female CD2F1 mice. In an acute toxicity study, a single dose of DT3 or GT3 was administered subcutaneously in a dose range of 200 to 800 mg/kg. A mild to moderately severe dermatitis was observed clinically and microscopically in animals at the injection site at doses above 200 mg/kg. The severity of the reaction was reduced when the drug concentration was lowered. Neither drug produced detectable toxic effects in any other tissue at the doses tested. Based on histopathological analysis for both DT3 and GT3, and macroscopic observations of inflammation at the injection site, a dose of 300 mg/kg was selected as the lowest toxic dose in a 30-day toxicity study performed in male mice. At this dose, a mild skin irritation occurred at the injection site that recovered completely by the end of the experimental period. At a dose of 300 mg/kg of DT3 or GT3, no adverse effects were observed in any tissues or organs. © The Author(s) 2014.

[Evaluation of Brodifacoum-induced Toxicity by Metabonomics Approach Based on HPLC-TOF-MS].

PubMed

Yan, H; Zhuo, X Y; Shen, B H; Xiang, P; Shen, M

2017-06-01

To analyse the metabolic changes in urine of rats with brodifacoum intoxication, and to reveal the molecular mechanism of brodifacoum-induced toxicity on rats. By establishing a brodifacoum poisoning rats model, the urine metabolic profiling data of rats were acquired using high performance liquid chromatography-time of flight mass spectrometry （HPLC-TOF-MS）. The orthogonal partial least squares analysis-discrimination analysis （OPLS-DA） was applied for the multivariate statistics and the discovery of differential metabolites closely related to toxicity of brodifacoum. OPLS-DA score plot showed that the urinary metabolic at different time points before and after drug administration had good similarity within time period and presented clustering phenomenon. Comparing the urine samples of rats before drug administration with which after drug administration, twenty-two metabolites related to brodifacoum-induced toxicity were selected. The toxic effect of brodifacoum worked by disturbing the metabolic pathways in rats such as tricarboxylic cycle, glycolysis, sphingolipid metabolism and tryptophan metabolism, and the toxicity of brodifacoum is characterized of accumulation effect. The metabonomic method based on urine HPLC-TOF-MS can provide a novel insight into the study on molecular mechanism of brodifacoum-induced toxicity. Copyright© by the Editorial Department of Journal of Forensic Medicine

The Role of Therapeutic Drugs on Acquired Mitochondrial Toxicity.

PubMed

Morén, Constanza; Juárez-Flores, Diana Luz; Cardellach, Francesc; Garrabou, Glòria

2016-01-01

Certain therapeutic drugs used in medical practice may trigger mitochondrial toxicity leading to a wide range of clinical symptoms including deafness, neuropathy, myopathy, hyperlactatemia, lactic acidosis, pancreatitis and lipodystrophy, among others, which could even compromise the life of the patient. The aim of this work is to review the potential mitochondrial toxicity derived from drugs used in health care, including anesthetics, antiepileptics, neuroleptics, antidepressants, antivirals, antibiotics, antifungals, antimalarics, antineoplastics, antidiabetics, hypolipemiants, antiarrhythmics, anti-inflammatories and nitric oxide. We herein have reviewed data from experimental and clinical studies to document the molecular mitochondrial basis, potential biomarkers and putative clinical symptoms associated to secondary effects of drugs. One hundred and forty-five articles were selected and the information was organized by means of the primary target to which pharmacologic drugs were directed. Adverse toxic events were classified depending on the mitochondrial offtarget effect and whether they had been demonstrated in the experimental or clinical setting. Since treatment of acquired mitochondriopathies remains supportive and therapeutic interventions cannot be avoided, information of molecular and clinical consequences of toxic exposure becomes fundamental to assess riskbenefit imbalance of treatment prescription. Additionally, there is a crucial need to develop less mitochondrial toxic compounds, novel biomarkers to follow up mitochondrial toxicity (or implement those already proposed) and new approaches to prevent or revert unintended mitochondrial damage.

Development of a Multi-Species Biotic Ligand Model Predicting the Toxicity of Trivalent Chromium to Barley Root Elongation in Solution Culture

PubMed Central

Song, Ningning; Zhong, Xu; Li, Bo; Li, Jumei; Wei, Dongpu; Ma, Yibing

2014-01-01

Little knowledge is available about the influence of cation competition and metal speciation on trivalent chromium (Cr(III)) toxicity. In the present study, the effects of pH and selected cations on the toxicity of trivalent chromium (Cr(III)) to barley (Hordeum vulgare) root elongation were investigated to develop an appropriate biotic ligand model (BLM). Results showed that the toxicity of Cr(III) decreased with increasing activity of Ca2+ and Mg2+ but not with K+ and Na+. The effect of pH on Cr(III) toxicity to barley root elongation could be explained by H+ competition with Cr3+ bound to a biotic ligand (BL) as well as by the concomitant toxicity of CrOH2+ in solution culture. Stability constants were obtained for the binding of Cr3+, CrOH2+, Ca2+, Mg2+ and H+ with binding ligand: log KCrBL 7.34, log KCrOHBL 5.35, log KCaBL 2.64, log KMgBL 2.98, and log KHBL 4.74. On the basis of those estimated parameters, a BLM was successfully developed to predict Cr(III) toxicity to barley root elongation as a function of solution characteristics. PMID:25119269

Development of a multi-species biotic ligand model predicting the toxicity of trivalent chromium to barley root elongation in solution culture.

PubMed

Song, Ningning; Zhong, Xu; Li, Bo; Li, Jumei; Wei, Dongpu; Ma, Yibing

2014-01-01

Little knowledge is available about the influence of cation competition and metal speciation on trivalent chromium (Cr(III)) toxicity. In the present study, the effects of pH and selected cations on the toxicity of trivalent chromium (Cr(III)) to barley (Hordeum vulgare) root elongation were investigated to develop an appropriate biotic ligand model (BLM). Results showed that the toxicity of Cr(III) decreased with increasing activity of Ca(2+) and Mg(2+) but not with K(+) and Na(+). The effect of pH on Cr(III) toxicity to barley root elongation could be explained by H(+) competition with Cr(3+) bound to a biotic ligand (BL) as well as by the concomitant toxicity of CrOH(2+) in solution culture. Stability constants were obtained for the binding of Cr(3+), CrOH(2+), Ca(2+), Mg(2+) and H(+) with binding ligand: log KCrBL 7.34, log KCrOHBL 5.35, log KCaBL 2.64, log KMgBL 2.98, and log KHBL 4.74. On the basis of those estimated parameters, a BLM was successfully developed to predict Cr(III) toxicity to barley root elongation as a function of solution characteristics.

Screening of Toxic Effects of Bisphenol A and Products of Its Degradation: Zebrafish (Danio rerio) Embryo Test and Molecular Docking.

PubMed

Makarova, Katerina; Siudem, Pawel; Zawada, Katarzyna; Kurkowiak, Justyna

2016-10-01

Bisphenol A (BPA) acts as an endocrine-disrupting compound even at a low concentration. Degradation of BPA could lead to the formation of toxic products. In this study, we compare the toxicity of BPA and seven intermediate products of its degradation. The accuracy of three molecular docking programs (Surflex, Autodock, and Autodock Vina) in predicting the binding affinities of selected compounds to human (ERα, ERβ, and ERRγ) and zebrafish (ERα, ERRγA, and ERRγB) estrogen and estrogen-related receptors was evaluated. The docking experiments showed that 4-isopropylphenol could have similar toxicity to that of BPA due to its high affinity to ERRγ and ERRγB and high octanol-water partitioning coefficient. The least toxic compounds were hydroquinone and phenol. Those compounds as well as BPA were screened in the zebrafish (Danio rerio) embryo test. 4-isopropylphenol had the strongest toxic effect on zebrafish embryos and caused 100% lethality shortly after exposure. BPA caused the delay in development, multiple deformations, and low heartbeats (30 bps), whereas hydroquinone had no impact on the development of the zebrafish embryo. Thus, the results of zebrafish screening are in good agreement with our docking experiment. The molecular docking could be used to screen the toxicity of other xenoestrogens and their products of degradation.

Toxicity Ranking and Toxic Mode of Action Evaluation of Commonly Used Agricultural Adjuvants on the Basis of Bacterial Gene Expression Profiles

PubMed Central

Nobels, Ingrid; Spanoghe, Pieter; Haesaert, Geert; Robbens, Johan; Blust, Ronny

2011-01-01

The omnipresent group of pesticide adjuvants are often referred to as “inert” ingredients, a rather misleading term since consumers associate this term with “safe”. The upcoming new EU regulation concerning the introduction of plant protection products on the market (EC1107/2009) includes for the first time the demand for information on the possible negative effects of not only the active ingredients but also the used adjuvants. This new regulation requires basic toxicological information that allows decisions on the use/ban or preference of use of available adjuvants. In this study we obtained toxicological relevant information through a multiple endpoint reporter assay for a broad selection of commonly used adjuvants including several solvents (e.g. isophorone) and non-ionic surfactants (e.g. ethoxylated alcohols). The used assay allows the toxicity screening in a mechanistic way, with direct measurement of specific toxicological responses (e.g. oxidative stress, DNA damage, membrane damage and general cell lesions). The results show that the selected solvents are less toxic than the surfactants, suggesting that solvents may have a preference of use, but further research on more compounds is needed to confirm this observation. The gene expression profiles of the selected surfactants reveal that a phenol (ethoxylated tristyrylphenol) and an organosilicone surfactant (ethoxylated trisiloxane) show little or no inductions at EC20 concentrations, making them preferred surfactants for use in different applications. The organosilicone surfactant shows little or no toxicity and good adjuvant properties. However, this study also illustrates possible genotoxicity (induction of the bacterial SOS response) for several surfactants (POEA, AE, tri-EO, EO FA and EO NP) and one solvent (gamma-butyrolactone). Although the number of compounds that were evaluated is rather limited (13), the results show that the used reporter assay is a promising tool to rank commonly used agricultural adjuvants based on toxicity and toxic mode of action data. PMID:22125591

Effect-Based Tools for Monitoring and Predicting the Ecotoxicological Effects of Chemicals in the Aquatic Environment

PubMed Central

Connon, Richard E.; Geist, Juergen; Werner, Inge

2012-01-01

Ecotoxicology faces the challenge of assessing and predicting the effects of an increasing number of chemical stressors on aquatic species and ecosystems. Herein we review currently applied tools in ecological risk assessment, combining information on exposure with expected biological effects or environmental water quality standards; currently applied effect-based tools are presented based on whether exposure occurs in a controlled laboratory environment or in the field. With increasing ecological relevance the reproducibility, specificity and thus suitability for standardisation of methods tends to diminish. We discuss the use of biomarkers in ecotoxicology including ecotoxicogenomics-based endpoints, which are becoming increasingly important for the detection of sublethal effects. Carefully selected sets of biomarkers allow an assessment of exposure to and effects of toxic chemicals, as well as the health status of organisms and, when combined with chemical analysis, identification of toxicant(s). The promising concept of “adverse outcome pathways (AOP)” links mechanistic responses on the cellular level with whole organism, population, community and potentially ecosystem effects and services. For most toxic mechanisms, however, practical application of AOPs will require more information and the identification of key links between responses, as well as key indicators, at different levels of biological organization, ecosystem functioning and ecosystem services. PMID:23112741

Gossypol Toxicity from Cottonseed Products

PubMed Central

Gadelha, Ivana Cristina N.; Fonseca, Nayanna Brunna S.; Oloris, Silvia Catarina S.; Melo, Marília M.

2014-01-01

Gossypol is a phenolic compound produced by pigment glands in cotton stems, leaves, seeds, and flower buds (Gossypium spp.). Cottonseed meal is a by-product of cotton that is used for animal feeding because it is rich in oil and proteins. However, gossypol toxicity limits cottonseed use in animal feed. High concentrations of free gossypol may be responsible for acute clinical signs of gossypol poisoning which include respiratory distress, impaired body weight gain, anorexia, weakness, apathy, and death after several days. However, the most common toxic effects is the impairment of male and female reproduction. Another important toxic effect of gossypol is its interference with immune function, reducing an animal's resistance to infections and impairing the efficiency of vaccines. Preventive procedures to limit gossypol toxicity involve treatment of the cottonseed product to reduce the concentration of free gossypol with the most common treatment being exposure to heat. However, free gossypol can be released from the bound form during digestion. Agronomic selection has produced cotton varieties devoid of glands producing gossypol, but these varieties are not normally grown because they are less productive and are more vulnerable to attacks by insects. PMID:24895646

Intranasal melatonin nanoniosomes: pharmacokinetic, pharmacodynamics and toxicity studies.

PubMed

Priprem, Aroonsri; Johns, Jeffrey R; Limsitthichaikoon, Sucharat; Limphirat, Wanwisa; Mahakunakorn, Pramote; Johns, Nutjaree Prateepawanit

2017-06-01

Intranasal melatonin encapsulated in nanosized niosomes was preclinically evaluated. A formula of melatonin niosomes (MN) was selected through physicochemical and cytotoxic data for pharmacokinetic, pharmacodynamics and toxicity studies in male Wistar rats. Intranasal MN was bioequivalent to intravenous injection of melatonin, providing therapeutic level doses. Acute and subchronic toxicity screening showed no abnormal signs, symptoms or hematological effects in any animals. Transient nasal irritations with no inflammation were observed with intranasal MN, leading it to be categorized as relatively harmless. The intranasal MN could deliver melatonin to the brain to induce sleep and provide delayed systemic circulation, relative to intravenous injection and also distribute to peripheral tissue.

Regenerative toxicology: the role of stem cells in the development of chronic toxicities.

PubMed

Canovas-Jorda, David; Louisse, Jochem; Pistollato, Francesca; Zagoura, Dimitra; Bremer, Susanne

2014-01-01

Human stem cell lines and their derivatives, as alternatives to the use of animal cells or cancer cell lines, have been widely discussed as cellular models in predictive toxicology. However, the role of stem cells in the development of long-term toxicities and carcinogenesis has not received great attention so far, despite growing evidence indicating the relationship of stem cell damage to adverse effects later in life. However, testing this in vitro is a scientific/technical challenge in particular due to the complex interplay of factors existing under physiological conditions. Current major research programs in stem cell toxicity are not aiming to demonstrate that stem cells can be targeted by toxicants. Therefore, this knowledge gap needs to be addressed in additional research activities developing technical solutions and defining appropriate experimental designs. The current review describes selected examples of the role of stem cells in the development of long-term toxicities in the brain, heart or liver and in the development of cancer. The presented examples illustrate the need to analyze the contribution of stem cells to chronic toxicity in order to make a final conclusion whether stem cell toxicities are an underestimated risk in mechanism-based safety assessments. This requires the development of predictive in vitro models allowing the assessment of adverse effects to stem cells on chronic toxicity and carcinogenicity.

The reclamation of Indian and Abrams creeks in Great Smoky Mountains National Park

USGS Publications Warehouse

Lennon, Robert E.; Parker, Phillip S.

1959-01-01

A complete program of stream reclamation was developed and applied on Indian and Abrams creeks in Great Smoky Mountains National Park. A salt-resistivity technique was used to estimate the dilution and velocity of a toxicant in running water. Streamside toxicity trials on resident fishes established minimal, effective concentrations of the rotenone material. The successful removals of undesirable fish were followed by restocking with selected strains of eastern brook trout and rainbow trout. Post-reclamation observations demonstrated enhanced survival, growth, reproduction, and catch of trout. Factors which might limit the effectiveness of stream reclamation programs ar e discussed.

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.

Single and joint toxic effects of five selected pesticides on the early life stages of zebrafish (Denio rerio).

PubMed

Wang, Yanhua; Lv, Lu; Yu, Yijun; Yang, Guiling; Xu, Zhenlan; Wang, Qiang; Cai, Leiming

2017-03-01

Instead of individual ones, pesticides are usually detected in water environment as mixtures of contaminants. Laboratory tests were conducted in order to investigate the effects of individual and joint pesticides (phoxim, atrazine, chlorpyrifos, butachlor and λ-cyhalothrin) on zebrafish (Denio rerio). Results from 96-h semi-static toxicity test indicated that λ-cyhalothrin had the greatest toxicity to the three life stages (embryonic, larval and juvenile stages) of D. rerio with LC 50 values ranging from 0.0031 (0.0017-0.0042) to 0.38 (0.21-0.53) mg a.i. L -1 , followed by butachlor and chlorpyrifos with LC 50 values ranging from 0.45 (0.31-0.59) to 1.93 (1.37-3.55) and from 0.28 (0.13-0.38) to 13.03 (7.54-19.71) mg a.i. L -1 , respectively. In contrast, atrazine showed the least toxicity with LC 50 values ranging from 6.09 (3.34-8.35) to 34.19 (24.42-51.9) mg a.i. L -1 . The larval stage of D. rerio was a vulnerable period to most of the selected pesticides in the multiple life stages tested. Pesticide mixtures containing phoxim and λ-cyhalothrin exerted synergistic effects on the larvae of D. rerio. Moreover, the binary mixture of phoxim-atrazine also displayed synergistic response to zebrafish. It has been assumed that most chemicals are additive in toxicity. Therefore, it is crucial to clarify the synergistic interaction for pesticide regulators and environment managers. In the present study, our data provided a clear picture on ecological risk of these pesticide mixtures to aquatic organisms. Moreover, joint effects play a more important role than individual ones, which require more attention when defining standard for water environment quality and risk assessment protocols. Copyright © 2016 Elsevier Ltd. All rights reserved.

Accelerated hematopoietic toxicity by high energy (56)Fe radiation.

PubMed

Datta, Kamal; Suman, Shubhankar; Trani, Daniela; Doiron, Kathryn; Rotolo, Jimmy A; Kallakury, Bhaskar V S; Kolesnick, Richard; Cole, Michael F; Fornace, Albert J

2012-03-01

There is little information on the relative toxicity of highly charged (Z) high-energy (HZE) radiation in animal models compared to γ or X-rays, and the general assumption based on in vitro studies has been that acute toxicity is substantially greater. C57BL/6J mice were irradiated with (56)Fe ions (1 GeV/nucleon), and acute (within 30 d) toxicity compared to that of γ rays or protons (1 GeV). To assess relative hematopoietic and gastrointestinal toxicity, the effects of (56)Fe ions were compared to γ rays using complete blood count (CBC), bone marrow granulocyte-macrophage colony forming unit (GM-CFU), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay for apoptosis in bone marrow, and intestinal crypt survival. Although onset was more rapid, (56)Fe ions were only slightly more toxic than γ rays or protons with lethal dose (LD)(50/30) (a radiation dose at which 50% lethality occurs at 30-day) values of 5.8, 7.25, and 6.8 Gy, respectively, with relative biologic effectiveness for (56)Fe ions of 1.25 and 1.06 for protons. (56)Fe radiation caused accelerated and more severe hematopoietic toxicity. Early mortality correlated with more profound leukopenia and subsequent sepsis. Results indicate that there is selective enhanced toxicity to bone marrow progenitor cells, which are typically resistant to γ rays, and bone marrow stem cells, because intestinal crypt cells did not show increased HZE toxicity.

Accelerated Hematopoietic Toxicity by High Energy 56Fe Radiation

PubMed Central

Datta, Kamal; Suman, Shubhankar; Trani, Daniela; Doiron, Kathryn; Rotolo, Jimmy A.; Kallakury, Bhaskar V. S.; Kolesnick, Richard; Cole, Michael F.; Fornace, Albert J.

2013-01-01

Purpose There is little information on the relative toxicity of highly charged (Z) high-energy (HZE) radiation in animal models compared to γ or x-rays, and the general assumption based on in vitro studies has been that acute toxicity is substantially greater. Methods C57BL/6J mice were irradiated with 56Fe ions (1 GeV/nucleon), and acute (within 30 d) toxicity compared to that of γ rays or protons (1 GeV). To assess relative hematopoietic and gastrointestinal toxicity, the effects of 56Fe ions were compared to γ rays using complete blood count (CBC), bone marrow granulocyte-macrophage colony forming unit (GM-CFU), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay for apoptosis in bone marrow, and intestinal crypt survival. Results Although onset was more rapid, 56Fe ions were only slightly more toxic than γ rays or protons with lethal dose (LD)50/30 (a radiation dose at which 50% lethality occurs at 30-day) values of 5.8, 7.25, and 6.8 Gy respectively with relative biologic effectiveness for 56Fe ions of 1.25 and 1.06 for protons. Conclusions 56Fe radiation caused accelerated and more severe hematopoietic toxicity. Early mortality correlated with more profound leukopenia and subsequent sepsis. Results indicate that there is selective enhanced toxicity to bone marrow progenitor cells, which are typically resistant to γ rays, and bone marrow stem cells, because intestinal crypt cells did not show increased HZE toxicity. PMID:22077279

Receptor-mediated cytotoxicity of alpha-MSH fragments containing melphalan in a human melanoma cell line.

PubMed

Morandini, R; Süli-Vargha, H; Libert, A; Loir, B; Botyánszki, J; Medzihradszky, K; Ghanem, G

1994-01-02

Four alpha-MSH drug conjugates have been synthesized, 2 C-terminal (Pep 3 and 4) and 2 central fragments (Pep 1 and 2), the latter being the 4-10 sequence known to be the main alpha-MSH-receptor-recognition site. Melphalan was introduced into each sequence at different locations. Their ability to recognize alpha-MSH receptors as well as their cytotoxic effects were compared in 3 cell lines: melanoma, carcinoma and fibroblast cells. Pep 1 and 2 were able to specifically bind to MSH receptors on melanoma cells by displacing labelled alpha-MSH from its binding sites at concentrations similar to the 4-10 heptapeptide sequence known to contain the main receptor-recognition site. They subsequently penetrate the cell, most probably by a receptor internalization mechanism, since about half of their effect could be inhibited by competition at the receptor level. Significant and selective cytotoxic effects to melanoma cells could be observed after only 2 hr exposure to the drug conjugates. Interestingly, these 2 conjugates, differing only in melphalan position, showed completely different cytotoxicity in terms of IC50 values, Pep 1 being 24 times more toxic to all cells; but the 2 were equally specific to melanoma cells. However, they both were less toxic to all cells than melphalan itself. Furthermore, Pep 1 and 2 were able to block the receptor and, unlike Pep 3 and 4, their cytotoxic effect could be significantly inhibited by an alpha-MSH agonist. Pep 3 and 4 were 5 to 10 times less toxic than melphalan to melanoma and carcinoma cells and 50 times less to fibroblast cells, and did not show any cell-type selectivity. They were less toxic than Pep 1 to melanoma and carcinoma cells by a factor of 2, but equally toxic to fibroblasts. In contrast, they were more toxic than Pep 2 to fibroblasts, melanoma and carcinoma by a factor of 3, 10 and 24 respectively. Our data strongly suggest a receptor-mediated cytotoxicity mechanism occurring with alpha-MSH central fragments in human melanoma cells due to the presence of alpha-MSH-specific receptors. This mechanism appeared to be both peptide- and cell-type-specific.

Chronic toxicity of selected polycyclic aromatic hydrocarbons to algae and crustaceans using passive dosing.

PubMed

Bragin, Gail E; Parkerton, Thomas F; Redman, Aaron D; Letinksi, Daniel J; Butler, Josh D; Paumen, Miriam Leon; Sutherland, Cary A; Knarr, Tricia M; Comber, Mike; den Haan, Klaas

2016-12-01

Because of the large number of possible aromatic hydrocarbon structures, predictive toxicity models are needed to support substance hazard and risk assessments. Calibration and evaluation of such models requires toxicity data with well-defined exposures. The present study has applied a passive dosing method to generate reliable chronic effects data for 8 polycyclic aromatic hydrocarbons (PAHs) on the green algae Pseudokirchneriella subcapitata and the crustacean Ceriodaphnia dubia. The observed toxicity of these substances on algal growth rate and neonate production were then compared with available literature toxicity data for these species, as well as target lipid model and chemical activity-based model predictions. The use of passive dosing provided well-controlled exposures that yielded more consistent data sets than attained by past literature studies. Results from the present study, which were designed to exclude the complicating influence of ultraviolet light, were found to be well described by both target lipid model and chemical activity effect models. The present study also found that the lack of chronic effects for high molecular weight PAHs was consistent with the limited chemical activity that could be achieved for these compounds in the aqueous test media. Findings from this analysis highlight that variability in past literature toxicity data for PAHs may be complicated by both poorly controlled exposures and photochemical processes that can modulate both exposure and toxicity. Environ Toxicol Chem 2016;35:2948-2957. © 2016 SETAC. © 2016 SETAC.

Integration of biological responses from a suite of bioassays for the Venice Lagoon (Italy) through sediment toxicity index - part A: development and comparison of two methodological approaches.

PubMed

Losso, Chiara; Novelli, Alessandra Arizzi; De Salvador, Davide; Ghetti, Pier Francesco; Ghirardini, Annamaria Volpi

2010-12-01

Marine and coastal quality assessment, based on test batteries involving a wide array of endpoints, organisms and test matrices, needs for setting up toxicity indices that integrate multiple toxicological measures for decision-making processes and that classify the continuous toxicity response into discrete categories according to the European Water Framework Directive. Two toxicity indices were developed for the lagoon environment such as the Venice Lagoon. Stepwise procedure included: the construction of a database that identified test-matrix pairs (indicators); the selection of a minimum number of ecotoxicological indicators, called toxicological core metrics (CMs-tox) on the basis of specific criteria; the development of toxicity scores for each CM-tox; the integration of the CMs-tox into two indices, the Toxicity Effect Index (TEI), based on the transformation of Toxic Unit (TU) data that were integrated as logarithmic sum, and the Weighted Average Toxicity Index (WATI), starting from toxicity classes integrated as weighted mean. Results from the indices are compared; advantages and drawbacks of both approaches are discussed. Copyright © 2010. Published by Elsevier Ltd.

Investigation of olive mill wastewater (OMW) ozonation efficiency with the use of a battery of selected ecotoxicity and human toxicity assays.

PubMed

Siorou, Sofia; Vgenis, Theodoros T; Dareioti, Margarita A; Vidali, Maria-Sophia; Efthimiou, Ioanna; Kornaros, Michael; Vlastos, Dimitris; Dailianis, Stefanos

2015-07-01

The effects of olive mill wastewater (OMW) on a battery of biological assays, before and during the ozonation process, were investigated in order to assess ozone's efficiency in removing phenolic compounds from OMW and decreasing the concomitant OMW toxicity. Specifically, ozonated-OMW held for 0, 60, 120, 300, 420, 540min in a glass bubble reactor, showed a drastic reduction of OMW total phenols (almost 50%) after 300min of ozonation with a concomitant decrease of OMW toxicity. In particular, the acute toxicity test primarily performed in the fairy shrimp Thamnocephalus platyurus (Thamnotoxkit F™ screening toxicity test) showed a significant attenuation of OMW-induced toxic effects, after ozonation for a period of 120 and in a lesser extent 300min, while further treatment resulted in a significant enhancement of ozonated-OMW toxic effects. Furthermore, ozonated-OMW-treated mussel hemocytes showed a significant attenuation of the ability of OMW to cause cytotoxic (obtained by the use of NRRT assay) effects already after an ozonation period of 120 and to a lesser extent 300min. In accordance with the latter, OMW-mediated oxidative (enhanced levels of superoxide anions and lipid peroxidation by-products) and genotoxic (induction of DNA damage) effects were diminished after OMW ozonation for the aforementioned periods of time. The latter was also revealed by the use of cytokinesis block micronucleus (CBMN) assay in human lymphocytes exposed to different concentrations of both raw- and ozonated-OMW for 60, 120 and 300min. Those findings revealed for a first time the existence of a critical time point during the OMW ozonation process that could be fundamentally used for evaluating OMW ozonation as a pretreatment method of OMW. Copyright © 2015 Elsevier B.V. All rights reserved.

Pharmacogenetics of posttransplant diabetes mellitus.

PubMed

Lancia, P; Adam de Beaumais, T; Jacqz-Aigrain, E

2017-06-01

Many factors (physiological, pathological, environmental or genetic) are associated with variability in drug effect. Most patients respond to a standard treatment but the drug may be ineffective or toxic. In this review, we focused on genetic markers of posttransplant diabetes mellitus (PTDM) after renal transplantation, a frequent complication of immunosuppressive therapy and important risk factor of graft loss and mortality. An initial literature search identified 100 publications and among them 32 association studies were retrieved under 'Pharmacogenetics and PTDM'. Thirty-five variants in 25 genes with an impact on insulin secretion, disposition or effect were significantly associated with PTDM. The population studied, immunosuppressive regimen, follow-up, PTDM diagnostic and genetic variations tested were highly variable between studies. Although pharmacogenetic biomarkers are key tools of great promise for preventing toxicities and improving event-free survival rates, replication studies are required to select validated biomarkers linked to the occurrence of PTDM and select appropriate immusuppressive treatment to improve renal graft and patient outcome.

Heavy metal toxicity to bacteria - are the existing growth media accurate enough to determine heavy metal toxicity?

PubMed

Rathnayake, I V N; Megharaj, Mallavarapu; Krishnamurti, G S R; Bolan, Nanthi S; Naidu, Ravi

2013-01-01

A new minimal medium was formulated considering the limitations of the existing media for testing heavy metal sensitivity to bacteria. Toxicity of cadmium and copper to three bacteria was investigated in the new medium and compared with three other media commonly used to study the effect of the toxic metals. Based on speciation data arrived at using ion-selective electrodes, the available free-metal concentration in solution was highest in the MES-buffered medium. This finding was strongly supported by the estimated EC(50) values for the metals tested based on the toxicity bioassays. The free-ionic cadmium and copper concentrations in the medium provide more accurate determination of metal concentrations that affects the bacteria, than with most of other existing media. This will avoid doubts on other media and misleading conclusions relevant to the toxicity of heavy metals to bacteria and provides a better option for the study of metal-bacteria interactions. Copyright © 2012 Elsevier Ltd. 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

Selection of a battery of rapid toxicity sensors for drinking water evaluation.

PubMed

van der Schalie, William H; James, Ryan R; Gargan, Thomas P

2006-07-15

Comprehensive identification of chemical contaminants in Army field water supplies can be a lengthy process, but rapid analytical methods suitable for field use are limited. A complementary approach is to directly measure toxicity instead of individual chemical constituents. Ten toxicity sensors utilizing enzymes, bacteria, or vertebrate cells were tested to determine the minimum number of sensors that could rapidly identify toxicity in water samples containing one of 12 industrial chemicals. The ideal sensor would respond at a concentration just exceeding the Military Exposure Guideline (MEG) level for the chemical (an estimated threshold for adverse effects) but below the human lethal concentration. Chemical solutions were provided to testing laboratories as blind samples. No sensors responded to deionized water blanks, and only one sensor responded to a hard water blank. No single toxicity sensor responded to more than six chemicals in the desired response range, and one chemical (nicotine) was not detected by any sensor with the desired sensitivity. A combination of three sensors (Microtox, the Electric Cell Substrate Impedance Sensing (ECIS) test, and the Hepatocyte low density lipoprotein (LDL) uptake test) responded appropriately to nine of twelve chemicals. Adding a fourth sensor (neuronal microelectrode array) to the test battery allowed detection of two additional chemicals (aldicarb and methamidophos), but the neuronal microelectrode array was overly sensitive to paraquat. Evaluating sensor performance using a standard set of chemicals and a desired sensitivity range provides a basis both for selecting among available toxicity sensors and for evaluating emerging sensor technologies. Recommendations for future toxicity sensor evaluations are discussed.

Global concentration additivity and prediction of mixture toxicities, taking nitrobenzene derivatives as an example.

PubMed

Li, Tong; Liu, Shu-Shen; Qu, Rui; Liu, Hai-Ling

2017-10-01

The toxicity of a mixture depends not only on the mixture concentration level but also on the mixture ratio. For a multiple-component mixture (MCM) system with a definite chemical composition, the mixture toxicity can be predicted only if the global concentration additivity (GCA) is validated. The so-called GCA means that the toxicity of any mixture in the MCM system is the concentration additive, regardless of what its mixture ratio and concentration level. However, many mixture toxicity reports have usually employed one mixture ratio (such as the EC 50 ratio), the equivalent effect concentration ratio (EECR) design, to specify several mixtures. EECR mixtures cannot simulate the concentration diversity and mixture ratio diversity of mixtures in the real environment, and it is impossible to validate the GCA. Therefore, in this paper, the uniform design ray (UD-Ray) was used to select nine mixture ratios (rays) in the mixture system of five nitrobenzene derivatives (NBDs). The representative UD-Ray mixtures can effectively and rationally describe the diversity in the NBD mixture system. The toxicities of the mixtures to Vibrio qinghaiensis sp.-Q67 were determined by the microplate toxicity analysis (MTA). For each UD-Ray mixture, the concentration addition (CA) model was used to validate whether the mixture toxicity is additive. All of the UD-Ray mixtures of five NBDs are global concentration additive. Afterwards, the CA is employed to predict the toxicities of the external mixtures from three EECR mixture rays with the NOEC, EC 30 , and EC 70 ratios. The predictive toxicities are in good agreement with the experimental toxicities, which testifies to the predictability of the mixture toxicity of the NBDs. Copyright © 2017. Published by Elsevier Inc.

A look at treatment strategies for relapsed multiple myeloma.

PubMed

Cetani, Giusy; Boccadoro, Mario; Oliva, Stefania

2018-05-16

Multiple myeloma treatment considerably improved during the past decade, thanks to novel effective drugs, a better understanding of myeloma biology and clonal heterogeneity, and an improved management of toxicities. The choice of regimen at relapse is usually based on prior response, toxicities, age and comorbidities of relapsed patients. Areas covered: A review was performed of the most recent and effective therapeutic strategies for the relapsed myeloma setting, by documenting the latest clinical evidence from phase II and III clinical trials. Of note, new drugs, such as carfilzomib, ixazomib, pomalidomide, daratumumab and elotuzumab, alone or in combinations in doublet or triplet regimens, have greatly increased the treatment armamentarium against myeloma. Expert Commentary: Impressive results have been obtained with new drugs in relapsed patients. Besides number of prior therapies and previous response, other factors play a crucial role in the selection of therapy. Re-challenge with previous drugs can be adopted if previous responses lasted at least 6 months and therapy had induced low toxicity. Patients' risk status can further help to appropriately select therapy at relapse, and clinical trials will allow physicians to use newer targeted therapies and immune-therapies, thus delaying palliative approaches to later relapse stages.

Sensitivity of some nitrogen fixers and the target pest Fusarium oxysporum to fungicide thiram.

PubMed

Osman, Awad G; Sherif, Ashraf M; Elhussein, Adil A; Mohamed, Afrah T

2012-03-01

This study was carried out to investigate the toxic effects of the fungicide thiram (TMTD) against five nitrogen fixers and the thiram target pest Fusarium oxysporum under laboratory conditions. Nitrogen fixing bacteria Falvobacterium showed the highest values of LD(50) and proved to be the most resistant to the fungicide followed by Fusarium oxysporum, while Pseudomonas aurentiaca was the most affected microorganism. LD(50) values for these microorganisms were in 2-5 orders of magnitude lower in comparison with LD(50) value for Fusarium oxysporum. Thiram was most toxic to Pseudomonas aurentiaca followed by Azospirillum. The lowest toxicity index was recorded for Fusarium oxysporum and Flavobacterium. The slope of the curve for Azomonas, Fusarium oxysporum and Flavobacterium is more steep than that of the other curves, suggesting that even a slight increase of the dose of the fungicide can cause a very strong negative effect. Thiram was more selective to Pseudomonas aurentiaca followed by Azospirillum, Rhizobium meliloti and Azomonas. The lowest selectivity index of the fungicide was recorded for Falvobacterium followed by Fusarium oxysporum. The highest safety coefficient of the fungicide was assigned for Flavobacterium, while Pseudomonas aurentiaca showed the lowest value.

Evaluation of toxic and interactive toxic effects of three agrochemicals and copper using a battery of microbiotests.

PubMed

Kungolos, A; Emmanouil, C; Tsiridis, V; Tsiropoulos, N

2009-08-01

Three commonly used test organisms of different trophic levels (Vibrio fischeri, Pseudokirchneriella subcapitata and Daphnia magna) were exposed to selected agrochemicals (fosthiazate, metalaxyl-M, imidacloprid) and copper, in single doses or in binary mixtures. The toxicity of each single compound varied up to two orders of magnitude, depending on the test species examined. V. fischeri was the most sensitive test organism regarding fosthiazate and metalaxyl-M, indicating an IC(50) value of 0.20 mg/L (0.17-0.25 mg/L) and 0.88 mg/L (0.35-1.57 mg/L), respectively. Imidacloprid was the least toxic compound, indicating an EC(50) value on D. magna of 64.6 mg/L (43.3-122.5 mg/L) and an IC(50) value on V. fischeri of 226 mg/L (159-322 mg/L), while for imidacloprid at a concentration of 1000 mg/L the effect on P. subcapitata was lower than 50%. Copper was the most toxic compound towards all test organisms exhibiting the highest toxic effect on P. subcapitata, with an IC(50) value of 0.05 mg/L (0.003-0.008 mg/L). The toxic effects of the binary mixtures have been compared to the theoretically expected effect, resulting from a simple mathematical model based on the theory of probabilities. The independent action model was used in order to predict the theoretically expected effect. The interactive effects were mostly antagonistic or additive, while in few cases (interactive effects of metalaxyl-M and copper on V. fischeri) a synergistic mode of action was observed for some concentration combinations. Experiments showed that interactive effects of chemicals may vary depending on the test species used as well as on the chemicals and their respective concentrations. Although most of the concentrations of chemicals tested in this study are higher than the ones usually found in natural environment, the evaluation of their interactive toxic effects using a battery of bioassays may comprise a useful tool for the estimation of the environmental hazard of chemicals.

Using early life stages of marine animals to screen the toxicity of priority hazardous and noxious substances.

PubMed

Cunha, Isabel; Torres, Tiago; Oliveira, Helena; Martins, Rosário; McGowan, Thomas; Sheahan, David; Santos, Miguel Machado

2017-04-01

This study provides toxicity values for early life stages (ELS) of two phylogenetically distinct marine animal taxa, the sea urchin (Paracentrotus lividus), a deuterostome invertebrate, and the turbot (Scophthalmus maximus), a vertebrate (teleost), when challenged by six hazardous and noxious substances (HNS): aniline, butyl acrylate, m-cresol, cyclohexylbenzene, hexane and trichloroethylene. The aim of the study was to provide preliminary information on toxic effects of representative and relevant priority HNS to assess the risk posed by spills to marine habitats and therefore improve preparedness and the response at the operational level. Selection criteria to include each compound in the study were (1) inclusion in the HASREP (2005) list; (2) presence on the priority list established by Neuparth et al. (2011); (3) paucity of toxicological data (TOXnet and ECOTOX) for marine organisms; (4) behaviour in the water according to the categories defined by the European Behaviour classification system (GESAMP 2002), by selecting compounds with different behaviours in water; and (5) physicochemical and toxicological properties, where available, in order to anticipate the most toxic compounds. Aniline and m-cresol were the most toxic compounds with no observed apical effect concentration (NOAEC) values for sea urchin ranging between 0.01 and 0.1 mg/L, followed by butyl acrylate and cyclohexylbenzene with NOAECs ranging between 0.1 and 1.0 mg/L and trichloroethylene with NOAEC values that were in the range between 1 and 10 mg/L, reflecting their behaviour in water, mostly vapour pressure, but also solubility and log Kow. Hexane was toxic only for turbot embryos, due to its neurotoxic effects, and not for sea urchin larvae, at concentrations in the range between 1 and 10 mg/L. The concentrations tested were of the same order of magnitude for both species, and it was observed that sea urchin embryos (length of the longest arm) are more sensitive than turbot eggs larvae (hatching and cumulative mortality rates) to the HNS tested (except hexane). For this specific compound, concentrations up to 70 mg/L were tested in sea urchin larvae and no effects were observed on the length of the larvae. Both tests were found to be complementary depending on behaviour in water and toxicity target of the compounds analysed.

Identification of a Potent Phosphoinositide 3-Kinase Pan Inhibitor Displaying a Strategic Carboxylic Acid Group and Development of Its Prodrugs.

PubMed

Pirali, Tracey; Ciraolo, Elisa; Aprile, Silvio; Massarotti, Alberto; Berndt, Alex; Griglio, Alessia; Serafini, Marta; Mercalli, Valentina; Landoni, Clarissa; Campa, Carlo Cosimo; Margaria, Jean Piero; Silva, Rangel L; Grosa, Giorgio; Sorba, Giovanni; Williams, Roger; Hirsch, Emilio; Tron, Gian Cesare

2017-09-21

Activation of the phosphoinositide 3-kinase (PI3K) pathway is a key signaling event in cancer, inflammation, and other proliferative diseases. PI3K inhibitors are already approved for some specific clinical indications, but their systemic on-target toxicity limits their larger use. In particular, whereas toxicity is tolerable in acute treatment of life-threatening diseases, this is less acceptable in chronic conditions. In the past, the strategy to overcome this drawback was to block selected isoforms mainly expressed in leukocytes, but redundancy within the PI3K family members challenges the effectiveness of this approach. On the other hand, decreasing exposure to selected target cells represents a so-far unexplored alternative to circumvent systemic toxicity. In this manuscript, we describe the generation of a library of triazolylquinolones and the development of the first prodrug pan-PI3K inhibitor. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Multiple factors govern the association between pharmacology and toxicity in a class of drugs: toward a unification of class effect terminology.

PubMed

Smith, Dennis A; Harrison, Anthony; Morgan, Paul

2011-04-18

The term class effect has gained in use to describe a side effect including toxicity common to a series of drugs. There is no definition of what constitutes a class effect, and it is not applied against a rigid set of criteria.Thus, the finding of toxicity in one of a series of drugs can raise the concern of a class effect, especially if one or more of the others shows findings even slightly related or at very much lower incidence. This is particularly problematic when the term is used loosely or speculatively on initial events that are themselves of low incidence and serious. This speculation exaggerates and distorts the scientific process in establishing the true benefit risk of the individual drugs and can lead to lengthy development times, or highly restrictive labeling, to the detriment of patient welfare. To provide better definition and application of the term, we suggest that the term class effect toxicity is only used when a clear mechanistic link has been established between a safety concern and drug class based on (I) where the primary pharmacology delivers a clear rationale for the observed findings and toxicities; and (II) where the secondary pharmacology is obligate to the class of the molecule and not subject to variation of structure, and the selectivity cannot be impacted significantly by variations in potency introduced by structural manipulation. With these categorizations, we believe class effect toxicity will be mainly confined to I with examples such as the tetracycline class of antibacterials which inhibit protein synthesis both as a mechanism of antibacterial activity and to produce hepatic injury by mitochondrial injury in the liver.

Chemical characterization and in vitro toxicity of diesel exhaust particulate matter generated under varying conditions

PubMed Central

Cox, David P.; Drury, Bertram E.; Gould, Timothy R.; Kavanagh, Terrance J.; Paulsen, Michael H.; Sheppard, Lianne; Simpson, Christopher D.; Stewart, James A.; Larson, Timothy V.; Kaufman, Joel D.

2014-01-01

Epidemiologic studies have linked diesel exhaust (DE) to cardiovascular and respiratory morbidity and mortality, as well as lung cancer. DE composition is known to vary with many factors, although it is unclear how this influences toxicity. We generated eight DE atmospheres by applying a 2×2×2 factorial design and altering three parameters in a controlled exposure facility: (1) engine load (27 vs 82 %), (2) particle aging (residence time ~5 s vs ~5 min prior to particle collection), and (3) oxidation (with or without ozonation during dilution). Selected exposure concentrations of both diesel exhaust particles (DEPs) and DE gases, DEP oxidative reactivity via DTT activity, and in vitro DEP toxicity in murine endothelial cells were measured for each DE atmosphere. Cell toxicity was assessed via measurement of cell proliferation (colony formation assay), cell viability (MTT assay), and wound healing (scratch assay). Differences in DE composition were observed as a function of engine load. The mean 1-nitropyrene concentration was 15 times higher and oxidative reactivity was two times higher for low engine load versus high load. There were no substantial differences in measured toxicity among the three DE exposure parameters. These results indicate that alteration of applied engine load shifts the composition and can modify the biological reactivity of DE. While engine conditions did not affect the selected in vitro toxicity measures, the change in oxidative reactivity suggests that toxicological studies with DE need to take into account engine conditions in characterizing biological effects. PMID:26539254

Graphene oxide selectively targets cancer stem cells, across multiple tumor types: Implications for non-toxic cancer treatment, via “differentiation-based nano-therapy”

PubMed Central

Fiorillo, Marco; Verre, Andrea F.; Iliut, Maria; Peiris-Pagés, Maria; Ozsvari, Bela; Gandara, Ricardo; Cappello, Anna Rita; Sotgia, Federica; Vijayaraghavan, Aravind; Lisanti, Michael P.

2015-01-01

Tumor-initiating cells (TICs), a.k.a. cancer stem cells (CSCs), are difficult to eradicate with conventional approaches to cancer treatment, such as chemo-therapy and radiation. As a consequence, the survival of residual CSCs is thought to drive the onset of tumor recurrence, distant metastasis, and drug-resistance, which is a significant clinical problem for the effective treatment of cancer. Thus, novel approaches to cancer therapy are needed urgently, to address this clinical need. Towards this end, here we have investigated the therapeutic potential of graphene oxide to target cancer stem cells. Graphene and its derivatives are well-known, relatively inert and potentially non-toxic nano-materials that form stable dispersions in a variety of solvents. Here, we show that graphene oxide (of both big and small flake sizes) can be used to selectively inhibit the proliferative expansion of cancer stem cells, across multiple tumor types. For this purpose, we employed the tumor-sphere assay, which functionally measures the clonal expansion of single cancer stem cells under anchorage-independent conditions. More specifically, we show that graphene oxide effectively inhibits tumor-sphere formation in multiple cell lines, across 6 different cancer types, including breast, ovarian, prostate, lung and pancreatic cancers, as well as glioblastoma (brain). In striking contrast, graphene oxide is non-toxic for “bulk” cancer cells (non-stem) and normal fibroblasts. Mechanistically, we present evidence that GO exerts its striking effects on CSCs by inhibiting several key signal transduction pathways (WNT, Notch and STAT-signaling) and thereby inducing CSC differentiation. Thus, graphene oxide may be an effective non-toxic therapeutic strategy for the eradication of cancer stem cells, via differentiation-based nano-therapy. PMID:25708684

Selectivity assessment of two biorational insecticides, azadirachtin and pyriproxyfen, in comparison to a neonicotinoid, acetamiprid, on pupae and adults of a Neotropical strain Eretmocerus mundus Mercet.

PubMed

Francesena, Natalia; Schneider, Marcela Inés

2018-05-02

Assessment of the susceptibility of natural enemies of pests to selective pesticides is relevant for a sustainable agriculture with low impact on the environment. The aim of this study was to assess the toxicity of two biorational insecticides, azadirachtin and pyriproxyfen in comparison to a neonicotinoid insecticide, acetamiprid, on pupae and adults of a Neotropical strain of Eretmocerus mundus. Adult emergence and survival were evaluated as lethal effects whereas the sublethal effects were assessed through the reproductive capacity, sex ratio, and longevity of the surviving first progeny. Adult emergence from treated pupae was reduced by all three insecticides, but azadirachtin at its maximum field recommended concentration (MFRC) proved the most toxic insecticide. The survival probability of emerged adults was reduced by the three insecticides below than 50% from 2 to 5 days after the adult emergence. Malformations in nonemerged adults from treated pupal hosts were observed at the MFRC of all three insecticides. Sublethal effects on survivors from pupal treatment could be evaluated at only the lowest azadirachtin concentration. At that concentration, though azadirachtin did not affect the reproductive capacity of females, the sex ratio and the longevity of the first progeny were disrupted. The survival of parasitoid adults after adult exposure was reduced by all three insecticides, pyriproxyfen at the MFRC being the most toxic. All insecticides at their half of MFRCs induced sublethal effects in the survivors' adults, with pyriproxyfen being the most harmful to the reproductive capacity of females. In conclusion, both biorational insecticides were toxic to E. mundus. Copyright © 2018 Elsevier Ltd. All rights reserved.

A targeted and adjuvanted nanocarrier lowers the effective dose of liposomal amphotericin B and enhances adaptive immunity in murine cutaneous leishmaniasis.

PubMed

Daftarian, Pirouz M; Stone, Geoffrey W; Kovalski, Leticia; Kumar, Manoj; Vosoughi, Aram; Urbieta, Maitee; Blackwelder, Pat; Dikici, Emre; Serafini, Paolo; Duffort, Stephanie; Boodoo, Richard; Rodríguez-Cortés, Alhelí; Lemmon, Vance; Deo, Sapna; Alberola, Jordi; Perez, Victor L; Daunert, Sylvia; Ager, Arba L

2013-12-01

Amphotericin B (AmB), the most effective drug against leishmaniasis, has serious toxicity. As Leishmania species are obligate intracellular parasites of antigen presenting cells (APC), an immunopotentiating APC-specific AmB nanocarrier would be ideally suited to reduce the drug dosage and regimen requirements in leishmaniasis treatment. Here, we report a nanocarrier that results in effective treatment shortening of cutaneous leishmaniasis in a mouse model, while also enhancing L. major specific T-cell immune responses in the infected host. We used a Pan-DR-binding epitope (PADRE)-derivatized-dendrimer (PDD), complexed with liposomal amphotericin B (LAmB) in an L. major mouse model and analyzed the therapeutic efficacy of low-dose PDD/LAmB vs full dose LAmB. PDD was shown to escort LAmB to APCs in vivo, enhanced the drug efficacy by 83% and drug APC targeting by 10-fold and significantly reduced parasite burden and toxicity. Fortuitously, the PDD immunopotentiating effect significantly enhanced parasite-specific T-cell responses in immunocompetent infected mice. PDD reduced the effective dose and toxicity of LAmB and resulted in elicitation of strong parasite specific T-cell responses. A reduced effective therapeutic dose was achieved by selective LAmB delivery to APC, bypassing bystander cells, reducing toxicity and inducing antiparasite immunity.

Relative toxicity testing of spacecraft materials. 2: Aircraft materials

NASA Technical Reports Server (NTRS)

Lawrence, W. H.

1980-01-01

The relative toxicity of thermodegradation (pyrolysis/combustion) products of aircraft materials was studied. Two approaches were taken to assess the biological activity of the pyrolysis/combustion products of these materials: (1) determine the acute lethality to rats from inhalation of these pyrolysates and (2) examine the tendency for sublethal exposure to the pyrolysates to disrupt behavioral (shock avoidance) performance of exposed rats. The ralative importance of lethality vs. behavioral effects in selection of a material may be dictated by whether or not individuals potentially exposed to such products, would have an opportunity to escape if they were behaviorally capable of doing so. If so, the second parameter would assume greater importance, but if not the first parameter may be of much greater importance in selecting materials.

Analysis of Hypericin-Mediated Effects and Implications for Targeted Photodynamic Therapy

PubMed Central

Mühleisen, Laura; Alev, Magdalena; Unterweger, Harald; Subatzus, Daniel; Pöttler, Marina; Friedrich, Ralf P.; Alexiou, Christoph; Janko, Christina

2017-01-01

The phototoxic effect of hypericin can be utilized for Photodynamic Therapy (PDT) of cancer. After intravenous application and systemic distribution of the drug in the patient’s body, the tumor site is exposed to light. Subsequently, toxic reactive oxygen species (ROS) are generated, inducing tumor cell death. To prevent unwanted activation of the drug in other regions of the body, patients have to avoid light during and after the treatment cycles, consequently impairing quality of life. Here, we characterize toxicity and hypericin-mediated effects on cancer cells in vitro and confirm that its effect clearly depends on concentration and illumination time. To reduce side effects and to increase therapy success, selective accumulation of hypericin in the tumor region is a promising solution. Loading hypericin on superparamagnetic iron oxide nanoparticles (SPIONs) and guiding them to the desired place using an external magnetic field might accomplish this task (referred to as Magnetic Drug Targeting (MDT)). Thus, using a double targeting strategy, namely magnetic accumulation and laser induced photoactivation, might improve treatment effectivity as well as specificity and reduce toxic side effects in future clinical applications. PMID:28661430

Analysis of Hypericin-Mediated Effects and Implications for Targeted Photodynamic Therapy.

PubMed

Mühleisen, Laura; Alev, Magdalena; Unterweger, Harald; Subatzus, Daniel; Pöttler, Marina; Friedrich, Ralf P; Alexiou, Christoph; Janko, Christina

2017-06-29

The phototoxic effect of hypericin can be utilized for Photodynamic Therapy (PDT) of cancer. After intravenous application and systemic distribution of the drug in the patient's body, the tumor site is exposed to light. Subsequently, toxic reactive oxygen species (ROS) are generated, inducing tumor cell death. To prevent unwanted activation of the drug in other regions of the body, patients have to avoid light during and after the treatment cycles, consequently impairing quality of life. Here, we characterize toxicity and hypericin-mediated effects on cancer cells in vitro and confirm that its effect clearly depends on concentration and illumination time. To reduce side effects and to increase therapy success, selective accumulation of hypericin in the tumor region is a promising solution. Loading hypericin on superparamagnetic iron oxide nanoparticles (SPIONs) and guiding them to the desired place using an external magnetic field might accomplish this task (referred to as Magnetic Drug Targeting (MDT)). Thus, using a double targeting strategy, namely magnetic accumulation and laser induced photoactivation, might improve treatment effectivity as well as specificity and reduce toxic side effects in future clinical applications.

AQUIRE: Aquatic Toxicity Information Retrieval data base. Data file

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

Anderson, E.; Pilli, A.

The purpose of Aquatic Toxicity Information Retrieval (AQUIRE) data base is to provide scientists and managers quick access to a comprehensive, systematic, computerized compilation of aquatic toxicity data. Scientific papers published both nationally and internationally on the toxicity of chemicals to aquatic organisms and plants are collected and reviewed for AQUIRE. Independently compiled data files that meet AQUIRE parameter and quality assurance criteria are also included. Selected toxicity-test results and related testing information for any individual chemical from laboratory and field aquatic toxicity tests are extracted and added to AQUIRE. Acute, sublethal, and bioconcentration effects are included for tests withmore » freshwater and marine organisms. The total number of data records in AQUIRE now equals 104,500. This includes data from 6000 references, for 5200 chemicals and 2400 test species. A major data file, Acute Toxicity of Organic Chemicals (ATOC), has been incorporated into AQUIRE. The ATOC file contains laboratory acute test data on 525 organic chemicals using juvenile fathead minnows. The complete data file can be accessed by requesting review code 5 as a search parameter.« less

Selective cytoprotective effect of histamine on doxorubicin-induced hepatic and cardiac toxicity in animal models

PubMed Central

Lamas, DJMartinel; Nicoud, MB; Sterle, HA; Carabajal, E; Tesan, F; Perazzo, JC; Cremaschi, GA; Rivera, ES; Medina, VA

2015-01-01

The aim of the present work was to evaluate the potential protective effect of histamine on Doxorubicin (Dox)-induced hepatic and cardiac toxicity in different rodent species and in a triple-negative breast tumor-bearing mice model. Male Sprague Dawley rats and Balb/c mice were divided into four groups: control (received saline), histamine (5 mg/kg for rats and 1 mg/kg for mice, daily subcutaneous injection starting 24 h before treatment with Dox), Dox (2 mg/kg, intraperitoneally injected three times a week for 2 weeks) and Dox+histamine (received both treatments). Tissue toxicity was evaluated by histopathological studies and oxidative stress and biochemical parameters. The combined effect of histamine and Dox was also investigated in vitro and in vivo in human MDA-MB-231 triple-negative breast cancer model. Heart and liver of Dox-treated animals displayed severe histological damage, loss of tissue weight, increased TBARS levels and DNA damage along with an augment in serum creatine kinase-myocardial band. Pretreatment with histamine prevented Dox-induced tissue events producing a significant preservation of the integrity of both rat and mouse myocardium and liver, through the reduction of Dox-induced oxidative stress and apoptosis. Histamine treatment preserved anti-tumor activity of Dox, exhibiting differential cytotoxicity and increasing the Dox-induced inhibition of breast tumor growth. Findings provide preclinical evidence indicating that histamine could be a promising candidate as a selective cytoprotective agent for the treatment of Dox-induced cardiac and hepatic toxicity, and encourage the translation to clinical practice. PMID:27551485

The Installation Restoration Program Toxicology Guide. Volume 4

DTIC Science & Technology

1989-07-01

64.15 64-5 JP-4 Fuel-Water Partition Coefficients (K,) for Selected Hydrocarbons .......................... 64-20 04-6 Acute Toxicity of Components of JP...65.11 65-3 Equilibrium Partitioning of Select Gasoline Hydrocarbons in Model Environments ............... 65-14 65-4 Acute Toxicity of Components o...66-27 66-5 Acute Toxicity of Components of Fuel Oils ............ 66-37 67-1 Composition Dat,- for Stoddard Solvent

LC-MS based metabolomics and chemometrics study of the toxic effects of copper on Saccharomyces cerevisiae.

PubMed

Farrés, Mireia; Piña, Benjamí; Tauler, Romà

2016-08-01

Copper containing fungicides are used to protect vineyards from fungal infections. Higher residues of copper in grapes at toxic concentrations are potentially toxic and affect the microorganisms living in vineyards, such as Saccharomyces cerevisiae. In this study, the response of the metabolic profiles of S. cerevisiae at different concentrations of copper sulphate (control, 1 mM, 3 mM and 6 mM) was analysed by liquid chromatography coupled to mass spectrometry (LC-MS) and multivariate curve resolution-alternating least squares (MCR-ALS) using an untargeted metabolomics approach. Peak areas of the MCR-ALS resolved elution profiles in control and in Cu(ii)-treated samples were compared using partial least squares regression (PLSR) and PLS-discriminant analysis (PLS-DA), and the intracellular metabolites best contributing to sample discrimination were selected and identified. Fourteen metabolites showed significant concentration changes upon Cu(ii) exposure, following a dose-response effect. The observed changes were consistent with the expected effects of Cu(ii) toxicity, including oxidative stress and DNA damage. This research confirmed that LC-MS based metabolomics coupled to chemometric methods are a powerful approach for discerning metabolomics changes in S. cerevisiae and for elucidating modes of toxicity of environmental stressors, including heavy metals like Cu(ii).

Human health risk assessment database, "the NHSRC toxicity value database": supporting the risk assessment process at US EPA's National Homeland Security Research Center.

PubMed

Moudgal, Chandrika J; Garrahan, Kevin; Brady-Roberts, Eletha; Gavrelis, Naida; Arbogast, Michelle; Dun, Sarah

2008-11-15

The toxicity value database of the United States Environmental Protection Agency's (EPA) National Homeland Security Research Center has been in development since 2004. The toxicity value database includes a compilation of agent property, toxicity, dose-response, and health effects data for 96 agents: 84 chemical and radiological agents and 12 biotoxins. The database is populated with multiple toxicity benchmark values and agent property information from secondary sources, with web links to the secondary sources, where available. A selected set of primary literature citations and associated dose-response data are also included. The toxicity value database offers a powerful means to quickly and efficiently gather pertinent toxicity and dose-response data for a number of agents that are of concern to the nation's security. This database, in conjunction with other tools, will play an important role in understanding human health risks, and will provide a means for risk assessors and managers to make quick and informed decisions on the potential health risks and determine appropriate responses (e.g., cleanup) to agent release. A final, stand alone MS ACESSS working version of the toxicity value database was completed in November, 2007.

MOVES2014: Fuel Effects, Toxics Emissions, Total Organic Gases (TOG) and PM Speciation Analysis

EPA Science Inventory

The report updates fuel effects applied in MOVES2013 for selected fuel content and bulk fuel properties in gasolines containing up to 20% ethanol for gasoline fuel sulfur content and for fuel ethanol content for E85 and similar blends. These adjustments are applied to vehicle exh...

Effectiveness of Hexazinone as a Forestry Herbicide

Treesearch

Jerry L. Michael

1985-01-01

Hexuinone has proven to be a useful herbicide in southern forestry. Its effectiveness in controlling many woody and herbaceour weeds at application rates tolerated by pines provides foresters with a selective vegetation management tool. Hexazinone is an environmentally safe chemical because lt is low in toxicity, is degraded readily, does not bioaccumulate; and does...

Toxic impact of aldrin on acid and alkaline phosphatase activity of penaeid prawn, Metapenaeus monoceros: In vitro study

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

Reddy, M.S.; Jayaprada, P.; Rao, K.V.R.

1991-03-01

The increasing contamination of the aquatic environment by the indiscriminate and widespread use of different kinds of pesticides is a serious problem for environmental biologists. Organochlorine insecticides are more hazardous since they are not only more toxic but also leave residues in nature. The deleterious effects of aldrin on several crustaceans have been studied. But studies concerning the impact of aldrin on biochemical aspects of crustaceans are very much limited. The present study is aimed at probing the in vitro effects of aldrin on the acid and alkaline phosphatase activity levels in selected tissues of penaeid prawn, Metapenaeus monoceros (Fabricius).

Influence of Select Antibiotics on Vibrio fischeri and Desmodesmus subspicatus at μg L-1 Concentrations.

PubMed

de Vasconcelos, E C; Dalke, C R; de Oliveira, C M R

2017-07-01

The presence of pharmaceuticals in the aquatic environment is a contemporary reality and it is necessary to understand more about the effects of this presence on organisms. The purpose of this work was to assess the ecotoxicity of antibiotics metronidazole, nitrofurantoin, trimethoprim, and sulphamethoxazole (single and mixture) in Vibrio fischeri and Desmodesmus subspicatus at μg L -1 concentrations. The evaluation of the toxic effect of the antibiotics on V. fischeri and D. subspicatus was based on fluorescence and bioluminescence tests, respectively, using nominal concentrations. When tested individually, the four antibiotics gave rise to a toxic effect on the evaluated organisms. Sulphamethoxazole caused a higher toxic effect on V. fischeri and D. subspicatus from 7.81 to 500 μg L -1 . Trimethoprim and sulphamethoxazole showed hormesis for the concentrations, which ranged from 7.81 to 62.5 μg L -1 . The mixture of antibiotics induced a toxic effect on the V. fischeri and D. subspicatus organisms (from 0.03 to 1 μg L -1 concentrations) than when the antibiotics were evaluated individually. These results were significant since water quality problems are widespread all over the word, and emerging pollutants such as antibiotics have been detected in the aquatic environment in very low concentrations.

Integrated ecological risk assessment of pesticides in tropical ecosystems: a case study with carbofuran in Brazil.

PubMed

Chelinho, Sónia; Lopes, Isabel; Natal-da-Luz, Tiago; Domene, Xaxier; Nunes, Maria Edna Tenorio; Espíndola, Evaldo L G; Ribeiro, Rui; Sousa, Jose P

2012-02-01

The aim of the present study is to contribute an ecologically relevant assessment of the ecotoxicological effects of pesticide applications in agricultural areas in the tropics, using an integrated approach with information gathered from soil and aquatic compartments. Carbofuran, an insecticide/nematicide used widely on sugarcane crops, was selected as a model substance. To evaluate the toxic effects of pesticide spraying for soil biota, as well as the potential indirect effects on aquatic biota resulting from surface runoff and/or leaching, field and laboratory (using a cost-effective simulator of pesticide applications) trials were performed. Standard ecotoxicological tests were performed with soil (Eisenia andrei, Folsomia candida, and Enchytraeus crypticus) and aquatic (Ceriodaphnia silvestrii) organisms, using serial dilutions of soil, eluate, leachate, and runoff samples. Among soil organisms, sensitivity was found to be E. crypticus < E. andrei < F. candida. Among the aqueous extracts, mortality of C. silvestrii was extreme in runoff samples, whereas eluates were by far the least toxic samples. A generally higher toxicity was found in the bioassays performed with samples from the field trial, indicating the need for improvements in the laboratory simulator. However, the tool developed proved to be valuable in evaluating the toxic effects of pesticide spraying in soils and the potential risks for aquatic compartments. Copyright © 2011 SETAC.

Gastroprotective effects of several H2RAs on ibuprofen-induced gastric ulcer in rats.

PubMed

Liu, Jing; Sun, Dan; He, Jinfeng; Yang, Chengli; Hu, Tingting; Zhang, Lijing; Cao, Hua; Tong, Ai-Ping; Song, Xiangrong; Xie, Yongmei; He, Gu; Guo, Gang; Luo, Youfu; Cheng, Ping; Zheng, Yu

2016-03-15

Ibuprofen is the first line of treatment for osteoarthritis and arthritis. The main side effects of ibuprofen especially in long-term treatment include gastric ulcer, duodenal ulcer and indigestion etc. Therefore, screening drugs with effective gastric protective effects and low toxicity for combination therapy with ibuprofen is necessary. The mechanism of gastric damage induced by ibuprofen is still unclear, however, cell damage caused by reactive oxygen species (ROS) is considered as the main reason. Preliminary screening of literature with the criteria of low toxicity led to four histamine-2 receptor antagonists (H2RAs): nizatidine, famotidine, lafutidine, and roxatidine acetate, which were selected for further investigation. These drugs were evaluated systemically by examining the gastric ulcer index, lipid peroxidation (LPO), membrane permeability, toxicity to main organs, and the influence on the activity of antioxidant enzymes, and myeloperoxidase (MPO). Nizatidine was found to be the best gastric protective agent. It exhibited excellent protective effect by increasing antioxidant enzyme activity, decreasing MPO activity, reducing LPO, and membrane permeability. Combination treatment with nizatidine and ibuprofen did not show any significant toxicity. Nizatidine was considered as a good option for combination therapy with ibuprofen especially for diseases that require long-term treatment such as arthritis and osteoarthritis. Copyright © 2016 Elsevier Inc. All rights reserved.

Management of Side Effects of Novel Therapies for Multiple Myeloma: Consensus Statements Developed by the International Myeloma Foundation’s Nurse Leadership Board

PubMed Central

Bertolotti, Page; Bilotti, Elizabeth; Colson, Kathleen; Curran, Kathleen; Doss, Deborah; Faiman, Beth; Gavino, Maria; Jenkins, Bonnie; Lilleby, Kathy; Love, Ginger; Mangan, Patricia A.; McCullagh, Emily; Miceli, Teresa; Miller, Kena; Rogers, Kathryn; Rome, Sandra; Sandifer, Stacey; Smith, Lisa C.; Tariman, Joseph D.; Westphal, Jeanne

2014-01-01

Nurses play an essential role in managing the care of patients with multiple myeloma, who require education and support to receive and adhere to optimal therapy. The International Myeloma Foundation created a Nurse Leadership Board comprised of oncology nurses from leading cancer centers and community practices. An assessment survey identified the need for specific recommendations for managing key side effects of novel antimyeloma agents. Myelosuppression, thromboembolic events, peripheral neuropathy, steroid toxicities, and gastrointestinal side effects were selected for the first consensus statements. The board developed recommendations for healthcare providers in any medical setting, including grading of side-effect toxicity and strategies for managing the side effects in general, with specific recommendations pertaining to the novel agents. PMID:18490252

A Novel Inhibitor Of Topoisomerase I is Selectively Toxic For A Subset of Non-Small Cell Lung Cancer Cell Lines | Office of Cancer Genomics

Cancer.gov

SW044248, identified through a screen for chemicals that are selectively toxic for NSCLC cell lines, was found to rapidly inhibit macromolecular synthesis in sensitive, but not in insensitive cells. SW044248 killed approximately 15% of a panel of 74 NSCLC cell lines and was non-toxic to immortalized human bronchial cell lines.

Effect of AL2O3 and TiO2 nanoparticles on aquatic organisms

NASA Astrophysics Data System (ADS)

Gosteva, I.; Morgalev, Yu; Morgaleva, T.; Morgalev, S.

2015-11-01

Environmental toxicity of aqueous disperse systems of nanoparticles of binary compounds of titanium dioxides (with particle size Δ50=5 nm, Δ50=50 nm, Δ50=90 nm), aluminum oxide alpha-forms (Δ50=7 nm and Δ50=70 nm) and macro forms (TiO2 Δ50=350 nm, Al2O3 A50=4000 nm) were studied using biological testing methods. The bioassay was performed using a set of test organisms representing the major trophic levels. We found the dependence of the toxic effect concentration degree of nTiO2 and nAl2O3 on the fluorescence of the bacterial biosensor "Ekolyum", the chemotactic response of ciliates Paramecium caudatum, the growth of unicellular algae Chlorella vulgaris Beijer and mortality of entomostracans Daphnia magna Straus. We revealed the selective dependence of nTiO2 and nAl2O3 toxicity on the size, concentration and chemical nature of nanoparticles. The minimal concentration causing an organism's response on nTiO2 and nAl2O3 effect depends on the type of the test- organism and the test reaction under study. We specified L(E)C50 and acute toxicity categories for all the studied nanoparticles. We determined that nTiO2 (Δ50=5 nm) belong to the category «Acute toxicity 1», nTiO2 (A50=90 nm) and nAl2O3 (Δ50=70 nm) - to the category «Acute toxicity 2», nAl2O3 (Δ50=7 nm) - to the category «Acute toxicity 3». No acute toxicity was registered for nTiO2 (Δ50=50 nm) and macro form TiO2.

The Impact of Detoxification Costs and Predation Risk on Foraging: Implications for Mimicry Dynamics

PubMed Central

Skelhorn, John; Rowe, Candy; Ruxton, Graeme D.; Higginson, Andrew D.

2017-01-01

Prey often evolve defences to deter predators, such as noxious chemicals including toxins. Toxic species often advertise their defence to potential predators by distinctive sensory signals. Predators learn to associate toxicity with the signals of these so-called aposematic prey, and may avoid them in future. In turn, this selects for mildly toxic prey to mimic the appearance of more toxic prey. Empirical evidence shows that mimicry could be either beneficial (‘Mullerian’) or detrimental (‘quasi-Batesian’) to the highly toxic prey, but the factors determining which are unknown. Here, we use state-dependent models to explore how tri-trophic interactions could influence the evolution of prey defences. We consider how predation risk affects predators’ optimal foraging strategies on aposematic prey, and explore the resultant impact this has on mimicry dynamics between unequally defended species. In addition, we also investigate how the potential energetic cost of metabolising a toxin can alter the benefits to eating toxic prey and thus impact on predators’ foraging decisions. Our model predicts that both how predators perceive their own predation risk, and the cost of detoxification, can have significant, sometimes counterintuitive, effects on the foraging decisions of predators. For example, in some conditions predators should: (i) avoid prey they know to be undefended, (ii) eat more mildly toxic prey as detoxification costs increase, (iii) increase their intake of highly toxic prey as the abundance of undefended prey increases. These effects mean that the relationship between a mimic and its model can qualitatively depend on the density of alternative prey and the cost of metabolising toxins. In addition, these effects are mediated by the predators’ own predation risk, which demonstrates that, higher trophic levels than previously considered can have fundamental impacts on interactions among aposematic prey species. PMID:28045959

Weathering and aging of 2,4,6-trinitrotoluene in soil increases toxicity to potworm Enchytraeus crypticus.

PubMed

Kuperman, Roman G; Checkai, Ronald T; Simini, Michael; Phillips, Carlton T; Kolakowski, Jan E; Kurnas, Carl W

2005-10-01

Energetic materials are employed in a wide range of commercial and military activities and often are released into the environment. Scientifically based ecological soil-screening levels (Eco-SSLs) are needed to identify contaminant explosive levels in soil that present an acceptable ecological risk. Insufficient information for 2,4,6-trinitrotoluene (TNT) to generate Eco-SSLs for soil invertebrates necessitated toxicity testing. We adapted the standardized Enchytraeid Reproduction Test and selected Enchytraeus crypticus for these studies. Tests were conducted in Sassafras sandy loam soil, which supports relatively high bioavailability of TNT. Weathering and aging procedures for TNT amended to test soil were incorporated into the study design to produce toxicity data that better reflect the soil exposure conditions in the field compared with toxicity in freshly amended soils. This included exposing hydrated TNT-amended soils in open glass containers in the greenhouse to alternating wetting and drying cycles. Definitive tests showed that toxicity for E. crypticus adult survival and juvenile production was increased significantly in weathered and aged soil treatments compared with toxicity in freshly amended soil based on 95% confidence intervals. The median effect concentration and 20% effective concentration for reproduction were 98 and 77 mg/kg, respectively, for TNT freshly amended into soil and 48 and 37 mg/kg, respectively, for weathered and aged TNT soil treatments. These findings of increased toxicity to E. crypticus in weathered and aged TNT soil treatments compared with exposures in freshly amended soils show that future investigations should include a weathering and aging component to generate toxicity data that provide more complete information on ecotoxicological effects of energetic contaminants in soil.

Patterns and trends in sediment toxicity in the San Francisco Estuary

USGS Publications Warehouse

Anderson, B.; Hunt, J.; Phillips, B.; Thompson, B.; Lowe, S.; Taberski, K.; Scott, Carr R.

2007-01-01

Widespread sediment toxicity has been documented throughout the San Francisco Estuary since the mid-1980s. Studies conducted in the early 1990s as part of the Bay Protection and Toxic Cleanup Program (BPTCP), and more recently as part of the Regional Monitoring Program (RMP) have continued to find sediment toxicity in the Estuary. Results of these studies have shown a number of sediment toxic hotspots located at selected sites in the margins of the Estuary. Recent RMP monitoring has indicated that the magnitude and frequency of sediment toxicity is greater in the winter wet season than in the summer dry season, which suggests stormwater inputs are associated with sediment toxicity. Additionally, spatial trends in sediment toxicity data indicate that toxic sediments are associated with inputs from urban creeks surrounding the Estuary, and from Central Valley rivers entering the northern Estuary via the Delta. Sediment toxicity has been correlated with a number of contaminants, including selected metals, PAHs and organochlorine pesticides. While toxicity identification evaluations (TIEs) suggest that metals are the primary cause of sediment toxicity to bivalve embryos; TIEs conducted with amphipods have been inconclusive. ?? 2006 Elsevier Inc. All rights reserved.

Selective effects of two systemic fungicides on soil fungi.

PubMed

Abdel-Fattah, H M; Abdel-Kader, M I; Hamida, S

1982-08-20

BAS 317 00F was not toxic to the total count of fungi after 2 days but was regularly significantly toxic at the three doses after 5, 20 and 40 days and toxic at the low and the high doses after 80 days. In the agar medium, it was toxic to the counts of total fungi. Aspergillus, A. terreus, Rhizopus oryzae and Mucor racemosus at the high dose. Only the mycelial growth of Trichoderma viride which was significantly inhibited by the three doses when this fungicide was added to the liquid medium. Polyram-Combi induced two effects on the total population of soil fungi. One inhibitory and this was demonstrated almost regularly after 2, 10 and 40 days and the other stimulatory after 80 days of treatment with the low and the high doses. In the agar medium, this fungicide was very toxic to total fungi and to almost all fungal genera and species at the three doses. Several fungi could survive the high dose. In liquid medium, the test fungi showed variable degree of sensitivity and the most sensitive was Gliocladium roseum which was completely eradicated by the three doses.

Investigation of repeated dose (90 day) oral toxicity, reproductive/developmental toxicity and mutagenic potential of 'Calebin A'.

PubMed

Majeed, Muhammed; Nagabhushanam, Kalyanam; Natarajan, Sankaran; Bani, Sarang; Pandey, Anjali; Karri, Suresh Kumar

2015-01-01

The present work investigated repeated dose and reproductive toxicity of Calebin A in Wistar rats. A study for assessing the mutagenic potential of Calebin A through an AMES test is also described. Calebin A was orally administered to groups of 10 male and/or 10 female Wistar rats each, assigned to three dose levels (20, 50 and 100 mg/kg/body weight) once daily for 90 consecutive days. None of the animals in any of the treatment/control groups exhibited any abnormal clinical signs/behavioral changes, reproductive as well as developmental parameters, or gross and microscopic changes in both male and female rats. Calebin A was also evaluated for its ability to induce reverse mutations at selected loci of Salmonella typhimurium in the presence and absence of Aroclor 1254 induced rat liver S9 cell lines. In conclusion, 100 mg/kg/d of Calebin A is not likely to produce any significant toxic effects in male and female Wistar rats and no reproductive or developmental toxicity was observed at the same dose and hence Calebin A at 100 mg/kg was determined as "No Observed Adverse Effect Level (NOAEL)" under the test conditions.

Subchronic Toxicities of HZ1006, a Hydroxamate-Based Histone Deacetylase Inhibitor, in Beagle Dogs and Sprague-Dawley Rats.

PubMed

Zhang, Xiaofang; Zhang, Xiaodong; Yuan, Bojun; Ren, Lijun; Zhang, Tianbao; Lu, Guocai

2016-11-30

Histone deacetylase inhibitors (HDACIs), such as vorinostat and panobinostat, have been shown to have active effects on many hematologic malignancies, including multiple myeloma and cutaneous T-cell lymphoma. Hydroxamate-based (Hb) HDACIs have very good toxicity profiles and are currently being tested in phases I and II clinical trials with promising results in selected neoplasms, such as bladder carcinoma. One of the Hb-HDACIs, HZ1006, has been demonstrated to be a promising drug for clinical use. The aim of our study was to determine the possible target of toxicity and to identify a non-toxic dose of HZ1006 for clinical use. In our studies, the repeated dosage toxicity of HZ1006 in Beagle dogs and Sprague Dawley (SD) rats was identified. Dogs and rats received HZ1006 orally (0-80 and 0-120 mg/kg/day, respectively) on a continuous daily dosing agenda for 28 days following a 14-day dosage-free period. HZ1006's NOAEL (No Observed Adverse Effect Level) by daily oral administration for dogs and rats was 5 mg/kg and 60 mg/kg, respectively, and the minimum toxic dose was 20 and 120 mg/kg, respectively. All the side effects indicated that the digestive tract, the male reproductive tract, the respiratory tract and the hematological systems might be HZ1006 toxic targets in humans. HZ1006 could be a good candidate or a safe succedaneum to other existing HDACIs for the treatment of some solid tumor and hematologic malignancies.

Gemcitabine: Selective cytotoxicity, induction of inflammation and effects on urothelial function

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

Farr, Stefanie E; Chess-Williams, Russ; McDermott,

Intravesical gemcitabine has recently been introduced for the treatment of superficial bladder cancer and has a favourable efficacy and toxicity profile in comparison to mitomycin c (MMC), the most commonly used chemotherapeutic agent. The aim of this study was to assess the cytotoxic potency of gemcitabine in comparison to MMC in urothelial cell lines derived from non-malignant (UROtsa) and malignant (RT4 and T24) tissues to assess selectivity. Cells were treated with gemcitabine or mitomycin C at concentrations up to the clinical doses for 1 or 2 h respectively (clinical duration). Treatment combined with hyperthermia was also examined. Cell viability, ROSmore » formation, urothelial function (ATP, acetylcholine and PGE2 release) and secretion of inflammatory cytokines were assessed. Gemcitabine displayed a high cytotoxic selectivity for the two malignant cell lines (RT4, T24) compared to the non-malignant urothelial cells (UROtsa, proliferative and non-proliferative). In contrast, the cytotoxic effects of MMC were non-selective with equivalent potency in each of the cell lines. The cytotoxic effect of gemcitabine in the malignant cell lines was associated with an elevation in free radical formation and was significantly decreased in the presence of an equilibrative nucleoside transporter inhibitor. Transient changes in urothelial ATP and PGE{sub 2} release were observed, with significant increase in release of interleukin-6, interleukin-8 and interleukin-1β from urothelial cells treated with gemcitabine. The selectivity of gemcitabine for malignant urothelial cells may account for the less frequent adverse urological effects with comparison to other commonly used chemotherapeutic agents. - Highlights: • Intravesical gemcitabine has recently been introduced to treat bladder cancer. • Gemcitabine is selectively toxic for malignant urothelial cells. • Urothelial ATP, PGE{sub 2} and inflammatory cytokines were altered by gemcitabine. • Selectivity of gemcitabine may account for less frequent urological side effects.« less

Guidance on the selection of cohorts for the extended one-generation reproduction toxicity study (OECD test guideline 443).

PubMed

Moore, Nigel P; Beekhuijzen, Manon; Boogaard, Peter J; Foreman, Jennifer E; North, Colin M; Palermo, Christine; Schneider, Steffen; Strauss, Volker; van Ravenzwaay, Bennard; Poole, Alan

2016-10-01

The extended one-generation reproduction toxicity study (EOGRTS; OECD test guideline 433) is a new and technically complex design to evaluate the putative effects of chemicals on fertility and development, including effects upon the developing nervous and immune systems. In addition to offering a more comprehensive assessment of developmental toxicity, the EOGRTS offers important improvements in animal welfare through reduction and refinement in a modular study design. The challenge to the practitioner is to know how the modular aspects of the study should be triggered on the basis of prior knowledge of a particular chemical, or on earlier findings in the EOGRTS itself, requirements of specific regulatory frameworks notwithstanding. The purpose of this document is to offer guidance on science-based triggers for these extended evaluations. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Comparative studies on ecotoxicology of synthetic detergents.

PubMed

Lal, H; Misra, V; Viswanathan, P N; Krishna Murti, C R

1983-12-01

To predict the comparative toxicological response of synthetic detergents on aquatic ecosystems, the effects of various concentrations of neutralized alkyl benzene sulfonate were studied. The median tolerance limit at 48 hr, 95% confidence limit, slope function, presumable harmless concentration, and rate of survival of different species of aquatic fauna such as water fleas (Daphnia magna), mosquito larvae (Culex pipiens), slug worms (Tubifex rivulorum), snails (Lymnaea vulgaris), tadpoles (Rana cyanophlyctis), and fish fingerlings (Cirrhina mrigala) were followed at 0, 24, 48, 72, and 96 hr. Any effect on quality of the water was also tested after the addition of various concentrations of detergents. The results showed that water fleas are more susceptible to detergent toxicity than fish fingerlings, tadpoles, slug worms, snails, and mosquito larvae. Behavioral changes were also observed as an index for detergent toxicity. The relative toxicity of the detergents to various species is discussed in relation to selective ecotoxicological response.

Planarians in toxicology. Responses of asexual Dugesia dorotocephala to selected metals

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

Kapu, M.M.; Schaeffer, D.J.

1991-08-01

The planarian Dugesia dorotocephala is a freshwater invertebrate found in unpolluted flowing surface waters. Planarians have a sensitive nervous system with synapses and true brain and evidence these in a variety of social and response behaviors. The inclusion of planarians in a screening battery would provide improved sensitivity in detecting toxicity because planarians commonly respond to lower levels of contamination than do other species. Numerous toxicity test have been conducted to determine the acute and chronic effects of toxicants to provide data necessary for the development of water quality criteria. The appropriateness of Illinois water quality standards for metals wasmore » investigated using a 1-hr behavioral test based on the responses of the planarian D. dorotocephala. One possible difficulty with water quality standards for metals is that the standard for each metal is usually established without regard to the effects of other metals present in the receiving water.« less

Evaluation of toxicity and genotoxicity of 2-chlorophenol on bacteria, fish and human cells.

PubMed

Vlastos, Dimitris; Antonopoulou, Maria; Konstantinou, Ioannis

2016-05-01

Due to the extensive use of chlorophenols (CPs) in anthropogenic activities, 2-Chlorophenol (2-CP), among other CPs, can enter aquatic ecosystems and can be harmful to a variety of organisms, including bacteria, fish and humans, that are exposed directly and/or indirectly to such contaminated environments. Based on the existing knowledge and in order to move a step forward, the purpose of this study is to investigate the toxic and mainly the genotoxic effects of 2-CP using a combination of bioassays. The tests include the marine bacterium Vibrio fischeri and micronuclei induction in the erythrocytes of Carassius auratus as well as in cultured human lymphocytes. The results obtained reveal that 2-CP is able to induce dose-dependent toxic and genotoxic effects on the selected tested concentrations under the specific experimental conditions. Copyright © 2016 Elsevier B.V. All rights reserved.

Characterization of selected volatile organic compounds, polycyclic aromatic hydrocarbons and carbonyl compounds at a roadside monitoring station

NASA Astrophysics Data System (ADS)

Ho, K. F.; Lee, S. C.; Chiu, Gloria M. Y.

Volatile organic compounds (VOCs), PAHs and carbonyl compounds are the major toxic components in Hong Kong. Emissions from motor vehicles have been one of the primary pollution sources in the metropolitan areas throughout Hong Kong for a long time. A 1-yr monitoring program for VOCs, PAHs and carbonyl compounds had been performed at a roadside urban station at Hong Kong Polytechnic University in order to determine the variations and correlations of each selected species (VOCs, PAHs and carbonyl compounds). This study is aimed to analyze toxic volatile organic compounds (benzene, toluene, ethylbenzene and xylene), two carbonyl compounds (formaldehyde, acetaldehyde), and selective polycyclic aromatic hydrocarbons. The monitoring program started from 16 April 1999 to 30 March 2000. Ambient VOC concentrations, many of which originate from the same sources as particulate PAHs and carbonyls compounds, show significant quantities of benzene, toluene and xylenes. Correlations and multivariate analysis of selected gaseous and particulate phase organic pollutants were performed. Source identification by principle component analysis and hierarchical cluster analysis allowed the identification of four sources (factors) for the roadside monitoring station. Factor 1 represents the effect of diesel vehicle exhaust. Factor 2 shows the contribution of aromatic compounds. Factor 3 explains photochemical products—formaldehyde and acetaldehyde. Factor 4 explains the effect of gasoline vehicle exhaust.

Combined cyto/genotoxic activity of a selected antineoplastic drug mixture in human circulating blood cells.

PubMed

Gajski, Goran; Gerić, Marko; Domijan, Ana-Marija; Garaj-Vrhovac, Vera

2016-12-01

Antineoplastic drugs are highly cytotoxic chemotherapeutic agents that can often interfere directly or indirectly with the cell's genome. In an environmental or medical setting simultaneous exposure may occur. Such multiple exposures may pose a higher risk than it could be assumed from the studies evaluating the effect of a single substance. Therefore, in the present study we tested the combined cyto/genotoxicity of a mixture of selected antineoplastic drugs with different mechanisms of action (5-fluorouracil, etoposide, and imatinib mesylate) towards human lymphocytes in vitro. The results suggest that the selected antineoplastic drug mixture is potentially cyto/genotoxic and that it can induce cell and genome damage even at low concentrations. Moreover, the changes in the measured oxidative stress parameters suggest the participation of reactive oxygen species in the cyto/genotoxicity of the selected mixture. The obtained results indicate not only that such mixtures may pose a risk to cell and genome integrity, but also that single compound toxicity data are not sufficient for the predicting toxicity in a complex environment. Altogether, the results emphasise the need for further toxicological screening of antineoplastic drug mixtures, especially at low environmentally relevant concentrations, as to avoid any possible adverse effects on the environment and human health. Copyright © 2016 Elsevier Ltd. All rights reserved.

Inhalation toxicology. XI., The effect of elevated temperature on carbon monoxide toxicity.

DOT National Transportation Integrated Search

1990-12-01

Laboratory rats were exposed (a) to experimental concentrations of carbon monoxide in air at ambient temperature, (b) to elevated temperature atmospheres from 40 C to 60 C, and (c) to selected carbon monoxide (CO) concentrations at the elevated tem...

Concentrations and trends of Perfluorinated chemicals in potential indoor sources from 2007 through 2011 in the US

EPA Science Inventory

Certain perfluorinated chemicals in consumer products have been associated with developmental toxicity and other adverse health effects. Temporal trends in the concentrations of selected perfluorinated chemicals (PFCs), including perfluorooctanoic acid (PFOA) and other perfluoroc...

Analyzing Arabidopsis thaliana root proteome provides insights into the molecular bases of enantioselective imazethapyr toxicity

PubMed Central

Qian, Haifeng; Lu, Haiping; Ding, Haiyan; Lavoie, Michel; Li, Yali; Liu, Weiping; Fu, Zhengwei

2015-01-01

Imazethapyr (IM) is a widely used chiral herbicide that inhibits the synthesis of branched-chain amino acids (BCAAs). IM is thought to exert its toxic effects on amino acid synthesis mainly through inhibition of acetolactate synthase activity, but little is known about the potential effects of IM on other key biochemical pathways. Here, we exposed the model plant Arabidospsis thaliana to trace S- and R-IM enantiomer concentrations and examined IM toxicity effects on the root proteome using iTRAQ. Conventional analyses of root carbohydrates, organic acids, and enzyme activities were also performed. We discovered several previously unknown key biochemical pathways targeted by IM in Arabidospsis. 1,322 and 987 proteins were differentially expressed in response to R- and S-IM treatments, respectively. Bioinformatics and physiological analyses suggested that IM reduced the BCAA tissue content not only by strongly suppressing BCAA synthesis but also by increasing BCAA catabolism. IM also affected sugar and starch metabolism, changed the composition of root cell walls, increased citrate production and exudation, and affected the microbial community structure of the rhizosphere. The present study shed new light on the multiple toxicity mechanisms of a selective herbicide on a model plant. PMID:26153126

Analyzing Arabidopsis thaliana root proteome provides insights into the molecular bases of enantioselective imazethapyr toxicity

NASA Astrophysics Data System (ADS)

Qian, Haifeng; Lu, Haiping; Ding, Haiyan; Lavoie, Michel; Li, Yali; Liu, Weiping; Fu, Zhengwei

2015-07-01

Imazethapyr (IM) is a widely used chiral herbicide that inhibits the synthesis of branched-chain amino acids (BCAAs). IM is thought to exert its toxic effects on amino acid synthesis mainly through inhibition of acetolactate synthase activity, but little is known about the potential effects of IM on other key biochemical pathways. Here, we exposed the model plant Arabidospsis thaliana to trace S- and R-IM enantiomer concentrations and examined IM toxicity effects on the root proteome using iTRAQ. Conventional analyses of root carbohydrates, organic acids, and enzyme activities were also performed. We discovered several previously unknown key biochemical pathways targeted by IM in Arabidospsis. 1,322 and 987 proteins were differentially expressed in response to R- and S-IM treatments, respectively. Bioinformatics and physiological analyses suggested that IM reduced the BCAA tissue content not only by strongly suppressing BCAA synthesis but also by increasing BCAA catabolism. IM also affected sugar and starch metabolism, changed the composition of root cell walls, increased citrate production and exudation, and affected the microbial community structure of the rhizosphere. The present study shed new light on the multiple toxicity mechanisms of a selective herbicide on a model plant.

Toxicity data for modeling impacts of oil components in an Arctic ecosystem.

PubMed

Olsen, G H; Klok, C; Hendriks, A J; Geraudie, P; De Hoop, L; De Laender, F; Farmen, E; Grøsvik, B E; Hansen, B H; Hjorth, M; Jansen, C R; Nordtug, T; Ravagnan, E; Viaene, K; Carroll, J

2013-09-01

Ecological impact assessment modeling systems are valuable support tools for managing impacts from commercial activities on marine habitats and species. The inclusion of toxic effects modeling in these systems is predicated on the availability and quality of ecotoxicology data. Here we report on a data gathering exercise to obtain toxic effects data on oil compounds for a selection of cold-water marine species of fish and plankton associated with the Barents Sea ecosystem. Effects data were collated from historical and contemporary literature resources for the endpoints mortality, development, growth, bioaccumulation and reproduction. Evaluating the utility and applicability of these data for modeling, we find that data coverage is limited to a sub-set of the required endpoints. There is a need for new experimental studies for zooplankton focused on the endpoints development and bioaccumulation and for larvae and juvenile fish focused on growth and development. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Toxicological relevance of pharmaceuticals in drinking water.

PubMed

Bruce, Gretchen M; Pleus, Richard C; Snyder, Shane A

2010-07-15

Interest in the public health significance of trace levels of pharmaceuticals in potable water is increasing, particularly with regard to the effects of long-term, low-dose exposures. To assess health risks and establish target concentrations for water treatment, human health risk-based screening levels for 15 pharmaceutically active ingredients and four metabolites were compared to concentrations detected at 19 drinking water treatment plants across the United States. Compounds were selected based on rate of use, likelihood of occurrence, and potential for toxicity. Screening levels were established based on animal toxicity data and adverse effects at therapeutic doses, focusing largely on reproductive and developmental toxicity and carcinogenicity. Calculated drinking water equivalent levels (DWELs) ranged from 0.49 microg/L (risperidone) to 20,000 microg/L (naproxen). None of the 10 detected compounds exceeded their DWEL. Ratios of DWELs to maximum detected concentrations ranged from 110 (phenytoin) to 6,000,000 (sulfamethoxazole). Based on this evaluation, adverse health effects from targeted pharmaceuticals occurring in U.S. drinking water are not expected.

Effect of selected aldehydes found in the corncob hemicellulose hydrolysate on the growth and xylitol fermentation of Candida tropicalis.

PubMed

Wang, Le; Tang, Pingwah; Fan, Xiaoguang; Yuan, Qipeng

2013-01-01

The effects of four aldehydes (furfural, 5-hydroxymethylfurfural, vanillin and syringaldehyde), which were found in the corncob hemicellulose hydrolysate, on the growth and xylitol fermentation of Candida tropicalis were investigated. The results showed that vanillin was the most toxic aldehyde for the xylitol fermentation, followed by syringaldehyde, furfural and 5-hydroxymethylfurfural. Moreover, the binary combination tests revealed that furfural amplified the toxicity of other aldehydes and the toxicities of other binary combinations without furfural were simply additive. Based on the fermentation experiments, it was demonstrated that the inhibition of aldehydes could be alleviated by prolonging the fermentation incubation, increasing the initial cell concentration, enhancing the initial pH value and minimizing the furfural levels in the hydrolysate evaporation process. The strategies that we proposed to suppress the inhibitory effects of the aldehydes successfully avoided the complicated and costly detoxifications. Our findings could be potentially adopted for the industrial xylitol fermentation from hydrolysates. © 2013 American Institute of Chemical Engineers.

Dempster-Shafer theory applied to regulatory decision process for selecting safer alternatives to toxic chemicals in consumer products.

PubMed

Park, Sung Jin; Ogunseitan, Oladele A; Lejano, Raul P

2014-01-01

Regulatory agencies often face a dilemma when regulating chemicals in consumer products-namely, that of making decisions in the face of multiple, and sometimes conflicting, lines of evidence. We present an integrative approach for dealing with uncertainty and multiple pieces of evidence in toxics regulation. The integrative risk analytic framework is grounded in the Dempster-Shafer (D-S) theory that allows the analyst to combine multiple pieces of evidence and judgments from independent sources of information. We apply the integrative approach to the comparative risk assessment of bisphenol-A (BPA)-based polycarbonate and the functionally equivalent alternative, Eastman Tritan copolyester (ETC). Our results show that according to cumulative empirical evidence, the estimated probability of toxicity of BPA is 0.034, whereas the toxicity probability for ETC is 0.097. However, when we combine extant evidence with strength of confidence in the source (or expert judgment), we are guided by a richer interval measure, (Bel(t), Pl(t)). With the D-S derived measure, we arrive at various intervals for BPA, with the low-range estimate at (0.034, 0.250), and (0.097,0.688) for ETC. These new measures allow a reasonable basis for comparison and a justifiable procedure for decision making that takes advantage of multiple sources of evidence. Through the application of D-S theory to toxicity risk assessment, we show how a multiplicity of scientific evidence can be converted into a unified risk estimate, and how this information can be effectively used for comparative assessments to select potentially less toxic alternative chemicals. © 2013 SETAC.

Antibacterial properties and toxicity from metallic nanomaterials

PubMed Central

Vimbela, Gina V; Ngo, Sang M; Fraze, Carolyn; Yang, Lei; Stout, David A

2017-01-01

The era of antibiotic resistance is a cause of increasing concern as bacteria continue to develop adaptive countermeasures against current antibiotics at an alarming rate. In recent years, studies have reported nanoparticles as a promising alternative to antibacterial reagents because of their exhibited antibacterial activity in several biomedical applications, including drug and gene delivery, tissue engineering, and imaging. Moreover, nanomaterial research has led to reports of a possible relationship between the morphological characteristics of a nanomaterial and the magnitude of its delivered toxicity. However, conventional synthesis of nanoparticles requires harsh chemicals and costly energy consumption. Additionally, the exact relationship between toxicity and morphology of nanomaterials has not been well established. Here, we review the recent advancements in synthesis techniques for silver, gold, copper, titanium, zinc oxide, and magnesium oxide nanomaterials and composites, with a focus on the toxicity exhibited by nanomaterials of multidimensions. This article highlights the benefits of selecting each material or metal-based composite for certain applications while also addressing possible setbacks and the toxic effects of the nanomaterials on the environment. PMID:28579779

Acute and chronic effects of heavy metals and cyanide on Mysidopsis bahia (crustacea:mysidacea)

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

Lussier, S.M.; Gentile, J.H.; Walker, J.

1985-01-01

Acute and whole life-cycle toxicity tests were conducted with the estuarine mysid shrimp, Mysidopsis bahia, exposed to cyanide and selected heavy metals. Acute toxicity values (96h LC50) ranged from 3.5 micrograms/1 for mercury to 3130 micrograms/1 for lead, and were ranked in order of toxicity: (greatest)Hg, Cd, Cu, Cn, Ag, Sn, Ni, As, Cr, and Pb(least). The chronic toxicity values ranged from 1.2 micrograms/1 for mercury to 893 micrograms/1 for arsenic. Chronic values were calculated from either survival, time to first reproduction, or number of young produced. When acute toxicity data for the same chemical are compared, M. bahia ismore » consistently among the more sensitive marine species. Lack of comparable data precludes a similar observation with chronic tests. Examination of the relative sensitivity of the chronic responses indicates that only for cadmium was survival more sensitive than reproduction.« less

Thymidine analogue-sparing highly active antiretroviral therapy (HAART).

PubMed

Nolan, David; Mallal, Simon

2003-02-01

The use of alternative nucleoside reverse transcriptase inhibitors (NRTIs) to the thymidine analogues stavudine (d4T) and zidovudine(ZDV) has been advocated as a means of limiting long-term NRTI-associated toxicity, particularly the development of lipoatrophy or fat wasting. This approach reflects an increasing knowledge of the distinct toxicity profiles of NRTI drugs. However, recent clinical trials have demonstrated that the use of thymidine analogue NRTIs and newer alternative backbone NRTIs, such as tenofovir (TNF) and abacavir (ABC), is associated with comparable short-term efficacy and tolerability. Given the importance of toxicity profile differences in determining clinical management, it is important to recognise that d4T and ZDV cary significantly different risks for long-term NRTI toxicity. Recognising that all NRTIs, including thymidine analogues, have individual toxicity profiles provides a more appropriate basis for selecting optimal antiretroviral therapy. The safety and efficacy of TNF and ABC are also reviewed here, although the available data provide only limited knowledge of the long-term effects of these drugs in terms of toxicity and antiviral durability.

Linking Inflammation and Parkinson Disease: Hypochlorous Acid Generates Parkinsonian Poisons.

PubMed

Jeitner, Thomas M; Kalogiannis, Mike; Krasnikov, Boris F; Gomolin, Irving; Peltier, Morgan R; Moran, Graham R

2016-06-01

Inflammation is a common feature of Parkinson Disease and other neurodegenerative disorders. Hypochlorous acid (HOCl) is a reactive oxygen species formed by neutrophils and other myeloperoxidase-containing cells during inflammation. HOCl chlorinates the amine and catechol moieties of dopamine to produce chlorinated derivatives collectively termed chlorodopamine. Here, we report that chlorodopamine is toxic to dopaminergic neurons both in vivo and in vitro Intrastriatal administration of 90 nmol chlorodopamine to mice resulted in loss of dopaminergic neurons from the substantia nigra and decreased ambulation-results that were comparable to those produced by the same dose of the parkinsonian poison, 1-methyl-4-phenylpyridinium (MPP+). Chlorodopamine was also more toxic to differentiated SH SY5Y cells than HOCl. The basis of this selective toxicity is likely mediated by chlorodopamine uptake through the dopamine transporter, as expression of this transporter in COS-7 cells conferred sensitivity to chlorodopamine toxicity. Pharmacological blockade of the dopamine transporter also mitigated the deleterious effects of chlorodopamine in vivo The cellular actions of chlorodopamine included inactivation of the α-ketoglutarate dehydrogenase complex, as well as inhibition of mitochondrial respiration. The latter effect is consistent with inhibition of cytochrome c oxidase. Illumination at 670 nm, which stimulates cytochrome c oxidase, reversed the effects of chlorodopamine. The observed changes in mitochondrial biochemistry were also accompanied by the swelling of these organelles. Overall, our findings suggest that chlorination of dopamine by HOCl generates toxins that selectively kill dopaminergic neurons in the substantia nigra in a manner comparable to MPP+. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Selective activity of polyene macrolides produced by genetically modified Streptomyces on Trypanosoma cruzi.

PubMed

Rolón, Miriam; Seco, Elena M; Vega, Celeste; Nogal, Juan J; Escario, José A; Gómez-Barrio, Alicia; Malpartida, Francisco

2006-08-01

The growth inhibitory effects on Trypanosoma cruzi of several natural tetraene macrolides and their derivatives were studied and compared with that of amphotericin B. All tetraenes strongly inhibited in vitro multiplication. Proliferation of epimastigotes was arrested by all these drugs at < or =3.6 microM, which were also active on amastigotes proliferating in fibroblasts. Compared with amphotericin B, the compounds were less effective but also less toxic, showing no effect on the proliferation of J774 and NCTC 929 mammalian cells at concentrations active against the parasites. CE-108B (a polyene amide) appeared to be an especially potent trypanocidal compound, with strong in vivo trypanocidal activity and very low or no toxic side effects, and thus should be considered for further studies.

Effect of culture medium on toxic effect of ZnO nanoparticles to freshwater microalgae

NASA Astrophysics Data System (ADS)

Aravantinou, Andriana F.; Tsarpali, Vasiliki; Dailianis, Stefanos; Manariotis, Ioannis D.

2014-05-01

The widely use of nanoparticles (NPs) in many products, is increasing over time. The release of NPs into the environment may affect ecosystems, and therefore it is essential to study their impact on aquatic organisms. The aim of this work was to investigate the effect of zinc oxide (ZnO) NPs on microalgae, cultured in different mediums. Chlorococcum sp. and Scenedesmus rubescens were used as freshwater microalgae model species in order to investigate the toxic effects of ZnO NPs. Microalgae species exposed to ZnO NPs concentrations varying from 0.081 to 810 mg/L for different periods of time (24 to 96 h) and two different culture mediums. The aggregation level and particle size distribution of NPs were also determined during the experiments. The experimental results revealed significant differences on algae growth rates depending on the selected culture medium. Specifically, the toxic effect of ZnO NPs in Chlorococcum sp. was higher in cultures with 1/3N BG-11 medium than in BBM medium, despite the fact that the dissolved zinc concentration was higher in BBM medium. On the other hand, Scenedesmus rubescens exhibited the exact opposite behavior, with the highest toxic effect in cultures with BBM medium. Both species growth was significantly affected by the exposure time, the NPs concentrations, and mainly the culture medium.

Development of phytotoxicity tests using wetland species

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

Nelson, M.K.; Fairchild, J.F.

1994-12-31

Laboratory phytotoxicity tests used to assess contaminant effects may not effectively protect wetland communities. The authors are developing routine culture and testing methods for selected fresh water plants, that can be used in risk assessments and monitoring of existing wetland systems. Utility of these tests includes evaluating the effects of point or non-point source contamination that may cause water or sediment quality degradation. Selected species include algae (blue-green, green), phytoflagellates (Chlamydomonas, Euglena), and floating or submerged vascular plants (milfoil, coontail, wild celery, elodea, duckweed). Algae toxicity tests range from 2-d, 4-d, and 7 day tests, and macrophyte tests from 10-dmore » to 14 days. Metribuzin and boron are the selected contaminants for developing the test methods. Metribuzin, a triazinone herbicide, is a photosystem 11 inhibitor, and is commonly used for control of grass and broad-leaf plants. As a plant micronutrient, boron is required in very small amounts, but excessive levels can result in phytotoxicity or accumulation. The investigations focus on the influence of important factors including the influence of light quality and quantity, and nutrient media. Reference toxicant exposures with potassium chloride are used to establish baseline data for sensitivity and vitality of the plants. These culture and test methods will be incorporated into recommendations for standard phytotoxicity test designs.« less

Oxyfluorfen toxic effect on S. obliquus evaluated by different photosynthetic and enzymatic biomarkers.

PubMed

Geoffroy, L; Dewez, D; Vernet, G; Popovic, R

2003-11-01

The effect of oxyfluorfen was investigated when alga Scenedesmus obliquus has been exposed to different concentrations (7.5, 15, and 22.5 microg x L(-1)) at 12, 24, and 48 hours of exposure. Toxicity test was done by using 13 biomarkers concerning growth rate, chlorophyll content and indicators of photosynthetic and antioxidant enzyme activities. The change of the 13 parameters showed a great variation of sensitivity indicating differences in parameters' suitability to be used as biomarkers when alga culture was exposed to oxyfluorfen toxicity. The order of sensitivity between those biomarkers was: Antenna size (ABS/RC) > Chlorophyll content > Catalase (CAT) > Operational PSII quantum yield (phiS(PSII)) > Glutathione S-transferase (GST) > Functional plastoquinone pool (Q(PQ)) > Glutathione reductase (GR) > Growth rate > Nonphotochemical quenching (QN) > Proton gradient quenching (Q(Emax)) > Ascorbate peroxidase (APX) > Photochemical quenching (Q(p)) > Maximum PSII quantum yield (Phi(PSII)). The effect of oxyfluorfen on the changes of those parameters was interpreted as a result of herbicide mode of action at molecular level of alga cellular system. This study indicated for some photosynthetic and enzymatic biomarkers to be useful indicators of toxicity effect induced in non-target alga species. Determination of biomarkers' sensitivity order may facilitate their selection to be used in environmental risk assessment of polluted water.

The effects of plant essential oils on escape response and mortality rate of Aedes aegypti and Anopheles minimus.

PubMed

Sathantriphop, Sunaiyana; Achee, Nicole L; Sanguanpong, Unchalee; Chareonviriyaphap, Theeraphap

2015-12-01

The High Throughput Screening System (HITSS) has been applied in insecticide behavioral response studies with various mosquito species. In general, chemical or natural compounds can produce a range of insect responses: contact irritancy, spatial repellency, knock-down, and toxicity. This study characterized these actions in essential oils derived from citronella, hairy basil, catnip, and vetiver in comparison to DEET and picaridin against Aedes aegypti and Anopheles minimus mosquito populations. Results indicated the two mosquito species exhibited significantly different (P<0.05) contact irritant escape responses between treatment and control for all tested compound concentrations, except with the minimum dose of picaridin (P>0.05) against Ae. aegypti. Spatial repellency responses were elicited in both mosquito species when exposed to all compounds, but the strength of the repellent response was dependent on compound and concentration. Data show that higher test concentrations had greatest toxic effects on both mosquito populations, but vetiver had no toxic effect on Ae. aegypti and picaridin did not elicit toxicity in either Ae. aegypti or An. minimus at any test concentration. Ultimately, this study demonstrates the ability of the HITSS assay to guide selection of effective plant essential oils for repelling, irritating, and killing mosquitoes. © 2015 The Society for Vector Ecology.

Acute toxicity of anionic and non-ionic surfactants to aquatic organisms.

PubMed

Lechuga, M; Fernández-Serrano, M; Jurado, E; Núñez-Olea, J; Ríos, F

2016-03-01

The environmental risk of surfactants requires toxicity measurements. As different test organisms have different sensitivity to the toxics, it is necessary to establish the most appropriate organism to classify the surfactant as very toxic, toxic, harmful or safe, in order to establish the maximum permissible concentrations in aquatic ecosystems. We have determined the toxicity values of various anionic surfactants ether carboxylic derivatives using four test organisms: the freshwater crustacean Daphnia magna, the luminescent bacterium Vibrio fischeri, the microalgae Selenastrum capricornutum (freshwater algae) and Phaeodactylum tricornutum (seawater algae). In addition, in order to compare and classify the different families of surfactants, we have included a compilation of toxicity data of surfactants collected from literature. The results indicated that V. fischeri was more sensitive to the toxic effects of the surfactants than was D. magna or the microalgae, which was the least sensitive. This result shows that the most suitable toxicity assay for surfactants may be the one using V. fischeri. The toxicity data revealed considerable variation in toxicity responses with the structure of the surfactants regardless of the species tested. The toxicity data have been related to the structure of the surfactants, giving a mathematical relationship that helps to predict the toxic potential of a surfactant from its structure. Model-predicted toxicity agreed well with toxicity values reported in the literature for several surfactants previously studied. Predictive models of toxicity is a handy tool for providing a risk assessment that can be useful to establish the toxicity range for each surfactant and the different test organisms in order to select efficient surfactants with a lower impact on the aquatic environment. Copyright © 2015 Elsevier Inc. All rights reserved.

A Microfluidic Device for Continuous Sensing of Systemic Acute Toxicants in Drinking Water

PubMed Central

Zhao, Xinyan; Dong, Tao

2013-01-01

A bioluminescent-cell-based microfluidic device for sensing toxicants in drinking water was designed and fabricated. The system employed Vibrio fischeri cells as broad-spectrum sensors to monitor potential systemic cell toxicants in water, such as heavy metal ions and phenol. Specifically, the chip was designed for continuous detection. The chip design included two counter-flow micromixers, a T-junction droplet generator and six spiral microchannels. The cell suspension and water sample were introduced into the micromixers and dispersed into droplets in the air flow. This guaranteed sufficient oxygen supply for the cell sensors. Copper (Cu2+), zinc (Zn2+), potassium dichromate and 3,5-dichlorophenol were selected as typical toxicants to validate the sensing system. Preliminary tests verified that the system was an effective screening tool for acute toxicants although it could not recognize or quantify specific toxicants. A distinct non-linear relationship was observed between the zinc ion concentration and the Relative Luminescence Units (RLU) obtained during testing. Thus, the concentration of simple toxic chemicals in water can be roughly estimated by this system. The proposed device shows great promise for an early warning system for water safety. PMID:24300075

Selected Issues Associated with the Risk Assessment Process for Pesticides with Persistent, Bioaccumulative, and Toxic Characteristics

EPA Science Inventory

This Scientific Advisory Panel meeting will address selected scientific issues associated with assessing the potential ecological risks resulting from use of a pesticide active ingredient which has persistent, bioaccumulative, and toxic (PBT) characteristics. EPA will pose speci...

Levels of selected carcinogens and toxicants in vapour from electronic cigarettes.

PubMed

Goniewicz, Maciej Lukasz; Knysak, Jakub; Gawron, Michal; Kosmider, Leon; Sobczak, Andrzej; Kurek, Jolanta; Prokopowicz, Adam; Jablonska-Czapla, Magdalena; Rosik-Dulewska, Czeslawa; Havel, Christopher; Jacob, Peyton; Benowitz, Neal

2014-03-01

Electronic cigarettes, also known as e-cigarettes, are devices designed to imitate regular cigarettes and deliver nicotine via inhalation without combusting tobacco. They are purported to deliver nicotine without other toxicants and to be a safer alternative to regular cigarettes. However, little toxicity testing has been performed to evaluate the chemical nature of vapour generated from e-cigarettes. The aim of this study was to screen e-cigarette vapours for content of four groups of potentially toxic and carcinogenic compounds: carbonyls, volatile organic compounds, nitrosamines and heavy metals. Vapours were generated from 12 brands of e-cigarettes and the reference product, the medicinal nicotine inhaler, in controlled conditions using a modified smoking machine. The selected toxic compounds were extracted from vapours into a solid or liquid phase and analysed with chromatographic and spectroscopy methods. We found that the e-cigarette vapours contained some toxic substances. The levels of the toxicants were 9-450 times lower than in cigarette smoke and were, in many cases, comparable with trace amounts found in the reference product. Our findings are consistent with the idea that substituting tobacco cigarettes with e-cigarettes may substantially reduce exposure to selected tobacco-specific toxicants. E-cigarettes as a harm reduction strategy among smokers unwilling to quit, warrants further study. (To view this abstract in Polish and German, please see the supplementary files online.).

Air quality modeling of selected aromatic and non-aromatic air toxics in the Houston urban and industrial airshed

NASA Astrophysics Data System (ADS)

Coarfa, Violeta Florentina

2007-12-01

Air toxics, also called hazardous air pollutants (HAPs), pose a serious threat to human health and the environment. Their study is important in the Houston area, where point sources, mostly located along the Ship Channel, mobile and area sources contribute to large emissions of such toxic pollutants. Previous studies carried out in this area found dangerous levels of different HAPs in the atmosphere. This thesis presents several studies that were performed for the aromatic and non-aromatic air toxics in the HGA. For these studies we developed several tools: (1) a refined chemical mechanism, which explicitly represents 18 aromatic air toxics that were lumped under two model species by the previous version, based on their reactivity with the hydroxyl radical; (2) an engineering version of an existing air toxics photochemical model that enables us to perform much faster long-term simulations compared to the original model, that leads to a 8--9 times improvement in the running time across different computing platforms; (3) a combined emission inventory based on the available emission databases. Using the developed tools, we quantified the mobile source impact on a few selected air toxics, and analyzed the temporal and spatial variation of selected aromatic and non-aromatic air toxics in a few regions within the Houston area; these regions were characterized by different emissions and environmental conditions.

Effect of chemical treatment on the acute toxicity of two commercial textile dye carriers.

PubMed

Arsian-Alaton, I; Iskender, G; Ozerkan, B; Germirli Babuna, F; Okay, O

2007-01-01

In the present experimental study, the effect of chemical treatment (coagulation-flocculation) on the acute toxicity exerted by two commercial dye carriers (called Carrier A and B herein) often used in the textile industry was investigated. Two different test organisms were selected to elucidate the situations in activated sludge treatment systems (activated sludge microorganisms) as well as in receiving water bodies (ultimate marine discharge). According to the results of a comprehensive analysis covering COD removal efficiencies, sludge settling characteristics and operating costs involved in coagulation-flocculation, the optimum treatment conditions were defined as follows; application of 750 mg/L ferrous sulphate at a pH of 9.0 for Carrier A; and application of 550 mg/L ferrous sulphate at a pH of 9.0 for Carrier B. The acute toxicities of both dye carriers towards marine microalgea Phaeodactylum tricornutum could be reduced significantly after being subjected to coagulation-flocculation. Fair toxicity removals (towards heterotrophic mixed bacterial culture accommodated in activated sludge treatment) were obtained with coagulation-flocculation for both of the carriers under investigation.

Occurrence of Stachybotrys chartarum chemotype S in dried culinary herbs.

PubMed

Biermaier, Barbara; Gottschalk, Christoph; Schwaiger, Karin; Gareis, Manfred

2015-02-01

Stachybotrys (S.) chartarum is an omnipresent cellulolytic mould which produces secondary metabolites, such as the highly toxic macrocyclic trichothecenes. While it is known to occur in animal feed like hay and straw as well as in water-damaged indoor environments, there is little knowledge about the occurrence of S. chartarum and its secondary metabolites in food. The objective of the present study was to examine selected dried culinary herbs for the presence of S. chartarum chemotype S, to assess the potential risk of a contamination of foods with macrocyclic trichothecenes. In total, 50 Stachybotrys isolates from different types of culinary herbs (n=100) such as marjoram (Origanum majorana Linné (L.)), oregano (Origanum vulgare L.), thyme (Thymus vulgaris L.), and savory (Satureja hortensis L.) were examined by MTT-cell culture test (effect-based bioassay), ELISA, and by liquid chromatography tandem mass spectrometry (LC-MS/MS). Selected toxic and non-toxic isolates (n=15) were genetically characterized by PCR and sequencing. Five isolates (10%) were highly toxic in the MTT-cell culture test, and the production of macrocyclic trichothecenes was proven by ELISA and LC-MS/MS. These five isolates were genetically confirmed as S. chartarum chemotype S. To the best of our knowledge, this is the first report about a contamination of dried culinary herbs with toxigenic S. chartarum.

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

Szluha, A.; Morrison, A.; Heckman, C.

Physico-chemical criteria were established and subjected to the chemical compounds listed in CHRIS to select those chemicals which are immiscible and float on water. This information was compiled in a menu-driven data base for easy access. As the result of this work, 294 CHRIS chemicals were found to be floaters. A literature review was conducted also to review available spill containment and recovery equipment and techniques for the application toward floating hazardous chemical spills. No single technology or equipment was found to effectively apply for the containment and recovery of spilled floating chemicals. Specific deficiencies and problems inherent in existingmore » technologies were identified. A hazard and toxicity ranking system was developed and applied to the floating chemicals for groupings by degrees of flammability and toxicity hazards. These groupings include highly flammable through noncombustible and highly toxic through non-toxic and the combination of degrees of hazards.« less

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

Harkema, J.R.

The nasal cavity is susceptible to chemically induced injury as a result of exposure to inhaled irritants. Some responses of the nasal mucosa to inhaled toxicants are species specific. These species-related differences in response may be due to variations in structural, physiologic, and biochemical factors, such as gross nasal cavity structure, distribution of luminal epithelial cell populations along the nasal airway, intranasal airflow patterns, nasal mucociliary apparatus, and nasal xenobiotic metabolism among animal species. This paper reviews the comparative anatomy and irritant-induced pathology of the nasal cavity in laboratory animals. The toxicologist, pathologist, and environmental risk assessor must have amore » good working knowledge of the similarities and differences in normal nasal structure and response to injury among species before they can select animal models for nasal toxicity studies, recognize toxicant-induced lesions in the nasal airway, and extrapolate experimental results to estimate the possible effects of an inhaled toxicant on the human nasal airway.« less

Toxicological characterisation of two novel selective aryl hydrocarbon receptor modulators in Sprague-Dawley rats

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

Mahiout, Selma, E-mail: selma.mahiout@helsinki.fi

The aryl hydrocarbon receptor (AHR) mediates the toxicity of dioxins, but also plays important physiological roles. Selective AHR modulators, which elicit some effects imparted by this receptor without causing the marked toxicity of dioxins, are presently under intense scrutiny. Two novel such compounds are IMA-08401 (N-acetyl-N-phenyl-4-acetoxy-5-chloro-1, 2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide) and IMA-07101 (N-acetyl-N-(4-trifluoromethylphenyl)-4-acetoxy-1, 2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide). They represent, as diacetyl prodrugs, AHR-active metabolites of the drug compounds laquinimod and tasquinimod, respectively, which are intended for the treatment of autoimmune diseases and cancer. Here, we toxicologically assessed the novel compounds in Sprague-Dawley rats, after a single dose (8.75–92.5 mg/kg) and 5-day repeated dosing at the highestmore » doses achievable (IMA-08401: 100 mg/kg/day; and IMA-07101: 75 mg/kg/day). There were no overt clinical signs of toxicity, but body weight gain was marginally retarded, and the treatments induced minimal hepatic extramedullary haematopoiesis. Further, both the absolute and relative weights of the thymus were significantly decreased. Cyp1a1 gene expression was substantially increased in all tissues examined. The hepatic induction profile of other AHR battery genes was distinct from that caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The only marked alterations in serum clinical chemistry variables were a reduction in triglycerides and an increase in 3-hydroxybutyrate. Liver and kidney retinol and retinyl palmitate concentrations were affected largely in the same manner as reported for TCDD. In vitro, the novel compounds activated CYP1A1 effectively in H4IIE cells. Altogether, these novel compounds appear to act as potent activators of the AHR, but lack some major characteristic toxicities of dioxins. They therefore represent promising new selective AHR modulators. - Highlights: • IMA-08401 and IMA-07101 are novel, effective activators of the AHR. • In rats, they lacked the wasting syndrome and thyroid imbalance typical of TCDD. • They also affected the AHR-battery genes in a distinct manner. • Therefore, the compounds appear to represent promising new selective AHR modulators. • They may have potential as drug compound candidates and research tools.« less

REPDOSE: A database on repeated dose toxicity studies of commercial chemicals--A multifunctional tool.

PubMed

Bitsch, A; Jacobi, S; Melber, C; Wahnschaffe, U; Simetska, N; Mangelsdorf, I

2006-12-01

A database for repeated dose toxicity data has been developed. Studies were selected by data quality. Review documents or risk assessments were used to get a pre-screened selection of available valid data. The structure of the chemicals should be rather simple for well defined chemical categories. The database consists of three core data sets for each chemical: (1) structural features and physico-chemical data, (2) data on study design, (3) study results. To allow consistent queries, a high degree of standardization categories and glossaries were developed for relevant parameters. At present, the database consists of 364 chemicals investigated in 1018 studies which resulted in a total of 6002 specific effects. Standard queries have been developed, which allow analyzing the influence of structural features or PC data on LOELs, target organs and effects. Furthermore, it can be used as an expert system. First queries have shown that the database is a very valuable tool.

Review of the Reported Measures of Clinical Validity and Clinical Utility as Arguments for the Implementation of Pharmacogenetic Testing: A Case Study of Statin-Induced Muscle Toxicity.

PubMed

Jansen, Marleen E; Rigter, T; Rodenburg, W; Fleur, T M C; Houwink, E J F; Weda, M; Cornel, Martina C

2017-01-01

Advances from pharmacogenetics (PGx) have not been implemented into health care to the expected extent. One gap that will be addressed in this study is a lack of reporting on clinical validity and clinical utility of PGx-tests. A systematic review of current reporting in scientific literature was conducted on publications addressing PGx in the context of statins and muscle toxicity. Eighty-nine publications were included and information was selected on reported measures of effect, arguments, and accompanying conclusions. Most authors report associations to quantify the relationship between a genetic variation an outcome, such as adverse drug responses. Conclusions on the implementation of a PGx-test are generally based on these associations, without explicit mention of other measures relevant to evaluate the test's clinical validity and clinical utility. To gain insight in the clinical impact and select useful tests, additional outcomes are needed to estimate the clinical validity and utility, such as cost-effectiveness.

The consequences of physical post-treatments (microwave and electron-beam) on food/packaging interactions: A physicochemical and toxicological approach.

PubMed

Riquet, A M; Breysse, C; Dahbi, L; Loriot, C; Severin, I; Chagnon, M C

2016-05-15

The safety of microwave and electron-beam treatments has been demonstrated, in regards to the formation of reaction products that could endanger human health. An integrated approach was used combining the potential toxicity of all the substances likely to migrate to their chemical characterizations. This approach was applied to polypropylene (PP) films prepared with a selection of additives. Components were identified by liquid and gas chromatography using a mass selective detector system. Their potential toxicity was assessed using three in vitro short-term bioassays and their migrations were carried out using a standards-based approach. After the electron-beam treatment some additives decomposed and there was a significant increase in the polyolefin oligomeric saturated hydrocarbons concentration. PP prepared with Irgafos 168 led to a significantly strong cytotoxic effect and PP prepared with Irganox 1076 induced a dose-dependant estrogenic effect in vitro. Migration values were low and below the detection limit of the analytical method applied. Copyright © 2015 Elsevier Ltd. All rights reserved.

Toxicity of selected insecticides applied to western spruce budworm

Treesearch

Jacqueline L. Robertson; Nancy L. Gillette; Melvin Look; Barbara A. Lucas; Robert L. Lyon

1975-01-01

The contact toxicity of 100 insecticides to last stage larvae of Choristoneura occidentalis Freeman was tested by topical application in a 10-yr series of screening experiments. Pyrethroids were generally the most toxic group of chemicals tested. Compounds more toxic than the standard, mexacarbate, at Ld50 were:...

Effective, Facile, and Selective Hydrolysis of the Chemical Warfare Agent VX Using Zr6-Based Metal-Organic Frameworks.

PubMed

Moon, Su-Young; Wagner, George W; Mondloch, Joseph E; Peterson, Gregory W; DeCoste, Jared B; Hupp, Joseph T; Farha, Omar K

2015-11-16

The nerve agent VX is among the most toxic chemicals known to mankind, and robust solutions are needed to rapidly and selectively deactivate it. Herein, we demonstrate that three Zr6-based metal-organic frameworks (MOFs), namely, UiO-67, UiO-67-NH2, and UiO-67-N(Me)2, are selective and highly active catalysts for the hydrolysis of VX. Utilizing UiO-67, UiO-67-NH2, and UiO-67-N(Me)2 in a pH 10 buffered solution of N-ethylmorpholine, selective hydrolysis of the P-S bond in VX was observed. In addition, UiO-67-N(Me)2 was found to catalyze VX hydrolysis with an initial half-life of 1.8 min. This half-life is nearly 3 orders of magnitude shorter than that of the only other MOF tested to date for hydrolysis of VX and rivals the activity of the best nonenzymatic materials. Hydrolysis utilizing Zr-based MOFs is also selective and facile in the absence of pH 10 buffer (just water) and for the destruction of the toxic byproduct EA-2192.

Factors in the Testing and Application of Algicides

PubMed Central

Fitzgerald, George P.

1964-01-01

A review is presented of some of the factors affecting the laboratory testing and practical applications of chemicals toxic to algae. The basic factor demonstrated is that the amount of chemical required to inhibit the growth of algae is dependent on the amount of algae present and not on the volume of water in which the algae are dispersed. It is shown how a chemical can be tested for algistatic or algicidal properties, thus enabling one to decide how best to apply a particular chemical. The selectivity of chemicals and the development of resistance in algae towards certain chemicals is demonstrated. Also, it is shown how certain algae can appear to be resistant to chemical treatments because of their growth habit or their production of extracellular products which affect the toxicity of added chemicals. With a better understanding of how various factors can influence the effectiveness of toxic chemicals, it is hoped that the selection of a chemical and method of application to a particular problem will be more successful. Images FIG. 1 FIG. 2 FIG. 3 FIG. 4 FIG. 5 FIG. 6 PMID:14170963

A preliminary 13-week oral toxicity study of ginger oil in male and female Wistar rats.

PubMed

Jeena, Kottarapat; Liju, Vijayastelter B; Kuttan, Ramadasan

2011-12-01

Zingiber officinale Roscoe, ginger, is a major spice extensively used in traditional medicine. The toxicity profile of ginger oil was studied by subchronic oral administration for 13 weeks at doses of 100, 250, and 500 mg/kg per day to 6 groups of Wistar rats (5/sex per dose). Separate groups of rats (5/sex per group) received either paraffin oil (vehicle) or were untreated and served as comparative control groups. There was no mortality and no decrease in body weight or food consumption as well as selective organ weights during the study period. Administration of ginger oil to rats did not produce any treatment-related changes in hematological parameters, hepatic, renal functions, serum electrolytes, or in histopathology of selected organs. The major component of ginger oil was found to be zingiberene (31.08%), and initial studies indicated the presence of zingiberene in the serum after oral dosing. These results confirmed that ginger oil is not toxic to male and female rats following subchronic oral administrations of up to 500 mg/kg per day (no observed adverse effect level [NOAEL]).

Sediment toxicity identification evaluation (TIE) studies at marine sites suspected of ordnance contamination

USGS Publications Warehouse

Carr, R.S.; Nipper, M.; Biedenbach, J.M.; Hooten, R.L.; Miller, K.; Saepoff, S.

2001-01-01

A sediment quality assessment survey and subsequent toxicity identification evaluation (TIE) study was conducted at several sites in Puget Sound, Washington. The sites were previously suspected of contamination with ordnance compounds. The initial survey employed sea urchin porewater toxicity tests to locate the most toxic stations. Sediments from the most toxic stations were selected for comprehensive chemical analyses. Based on the combined information from the toxicity and chemical data, three adjacent stations in Ostrich Bay were selected for the TIE study. The results of the phase I TIE suggested that organics and metals were primarily responsible for the observed toxicity in the sea urchin fertilization test. In addition to these contaminants, ammonia was also contributing to the toxicity for the sea urchin embryological development test. The phase II TIE study isolated the majority of the toxicity in the fraction containing nonpolar organics with high log Kow, but chemical analyses failed to identify a compound present at a concentration high enough to be responsible for the observed toxicity. The data suggest that some organic or organometallic contaminant(s) that were not included in the comprehensive suite of chemical analyses caused the observed toxicological responses.

Exogenous application of salicylic acid to alleviate the toxic effects of insecticides in Vicia faba L.

PubMed

Singh, Aradhana; Srivastava, Anjil Kumar; Singh, Ashok Kumar

2013-12-01

The present study investigated the possible mediatory role of salicylic acid (SA) in protecting plants from insecticides toxicity. The seeds of Vicia faba var IIVR Selection-1 were treated with different concentrations (1.5, 3.0, and 6.0 ppm) of the insecticides alphamethrin (AM) and endosulfan (ES) for 6 h with and without 12 h conditioning treatment of SA (0.01 mM). Insecticides treatment caused a significant decrease in mitotic index (MI) and induction of different types of chromosomal abnormalities in the meristematic cells of broad bean roots. Pretreatment of seeds with SA resulted in increased MI and significant reduction of chromosomal abnormalities. SA application also regulated proline accumulation and carotenoid content in the leaf tissues. SA resulted in the decrement of insecticides induced increase in proline content and increased the carotenoids content. These results illustrate the ameliorating effect of SA under stress conditions and reveal that SA is more effective in alleviating the toxic effects of insecticides at higher concentrations than that at lower concentrations. Copyright © 2011 Wiley Periodicals, Inc.

Indefinite antithyroid drug therapy in toxic Graves’ disease: What are the cons

PubMed Central

Rajput, Rajesh; Goel, Vasudha

2013-01-01

Existing treatment modalities for Graves’ disease includes antithyroid drugs (ATDs), radioactive iodine, and surgery. There has been a lack of general agreement as to which therapy is the best as none is ideal since all effectively restore euthyroidism, but with some limitations. Previously, therapies were selected with the goal of achieving euthyroidism. Instead, hypothyroidism is now the goal of treatment, to ensure that hyperthyroidism does not recur. Current evidences suggest that high relapse rate and not so rare fatal side effects seen with ATD therapy compel one to consider other definite modes of treatment like radiotherapy and surgery for toxic Graves’ disease after discussing this with the patient. PMID:24251229

Indefinite antithyroid drug therapy in toxic Graves' disease: What are the cons.

PubMed

Rajput, Rajesh; Goel, Vasudha

2013-10-01

Existing treatment modalities for Graves' disease includes antithyroid drugs (ATDs), radioactive iodine, and surgery. There has been a lack of general agreement as to which therapy is the best as none is ideal since all effectively restore euthyroidism, but with some limitations. Previously, therapies were selected with the goal of achieving euthyroidism. Instead, hypothyroidism is now the goal of treatment, to ensure that hyperthyroidism does not recur. Current evidences suggest that high relapse rate and not so rare fatal side effects seen with ATD therapy compel one to consider other definite modes of treatment like radiotherapy and surgery for toxic Graves' disease after discussing this with the patient.

Comparison of Pharmacological Potency and Safety of Glutamate Blocker IEM-1913 and Memantine.

PubMed

Gmiro, V E; Serdyuk, S E; Veselkina, O S

2015-11-01

Adamantane-containing glutamate blocker IEM-1913 (1-amino-4-(1-adamantane-amino)-butane dihydrochloride) equals to memantine in antiparkinsonian potency, but surpasses it in anticonvulsive, antidepressant, and analgesic activities. Moreover, its use is less toxic and safer. IEM-1913 produces significant pharmacological effects at a wide concentration diapason (0.03-1.00 mg/kg), while memantine is effective within a narrow range only (15-20 mg/kg). High pharmacological efficacy and low toxicity of IEM-1913 can be explained by the fact that in contrast to monocationic selective NMDA antagonist memantine, the dicationic glutamate blocker IEM-1913 produces a combined block of cerebral NMDA and AMPA receptors.

O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate.

PubMed

Schoenfeld, Joshua D; Sibenaller, Zita A; Mapuskar, Kranti A; Wagner, Brett A; Cramer-Morales, Kimberly L; Furqan, Muhammad; Sandhu, Sonia; Carlisle, Thomas L; Smith, Mark C; Abu Hejleh, Taher; Berg, Daniel J; Zhang, Jun; Keech, John; Parekh, Kalpaj R; Bhatia, Sudershan; Monga, Varun; Bodeker, Kellie L; Ahmann, Logan; Vollstedt, Sandy; Brown, Heather; Shanahan Kauffman, Erin P; Schall, Mary E; Hohl, Ray J; Clamon, Gerald H; Greenlee, Jeremy D; Howard, Matthew A; Schultz, Michael K; Smith, Brian J; Riley, Dennis P; Domann, Frederick E; Cullen, Joseph J; Buettner, Garry R; Buatti, John M; Spitz, Douglas R; Allen, Bryan G

2017-04-10

Pharmacological ascorbate has been proposed as a potential anti-cancer agent when combined with radiation and chemotherapy. The anti-cancer effects of ascorbate are hypothesized to involve the autoxidation of ascorbate leading to increased steady-state levels of H 2 O 2 ; however, the mechanism(s) for cancer cell-selective toxicity remain unknown. The current study shows that alterations in cancer cell mitochondrial oxidative metabolism resulting in increased levels of O 2 ⋅- and H 2 O 2 are capable of disrupting intracellular iron metabolism, thereby selectively sensitizing non-small-cell lung cancer (NSCLC) and glioblastoma (GBM) cells to ascorbate through pro-oxidant chemistry involving redox-active labile iron and H 2 O 2 . In addition, preclinical studies and clinical trials demonstrate the feasibility, selective toxicity, tolerability, and potential efficacy of pharmacological ascorbate in GBM and NSCLC therapy. Copyright © 2017 Elsevier Inc. All rights reserved.

Rapamycin toxicity in MIN6 cells and rat and human islets is mediated by the inhibition of mTOR complex 2 (mTORC2).

PubMed

Barlow, A D; Xie, J; Moore, C E; Campbell, S C; Shaw, J A M; Nicholson, M L; Herbert, T P

2012-05-01

Rapamycin (sirolimus) is one of the primary immunosuppressants for islet transplantation. Yet there is evidence that the long-term treatment of islet-transplant patients with rapamycin may be responsible for subsequent loss of islet graft function and viability. Therefore, the primary objective of this study was to elucidate the molecular mechanism of rapamycin toxicity in beta cells. Experiments were performed on isolated rat and human islets of Langerhans and MIN6 cells. The effects of rapamycin and the roles of mammalian target of rapamycin complex 2 (mTORC2)/protein kinase B (PKB) on beta cell signalling, function and viability were investigated using cell viability assays, insulin ELISA assays, kinase assays, western blotting, pharmacological inhibitors, small interfering (si)RNA and through the overproduction of a constitutively active mutant of PKB. Rapamycin treatment of MIN6 cells and islets of Langerhans resulted in a loss of cell function and viability. Although rapamycin acutely inhibited mTOR complex 1 (mTORC1), the toxic effects of rapamycin were more closely correlated to the dissociation and inactivation of mTORC2 and the inhibition of PKB. Indeed, the overproduction of constitutively active PKB protected islets from rapamycin toxicity whereas the inhibition of PKB led to a loss of cell viability. Moreover, the selective inactivation of mTORC2 using siRNA directed towards rapamycin-insensitive companion of target of rapamycin (RICTOR), mimicked the toxic effects of chronic rapamycin treatment. This report provides evidence that rapamycin toxicity is mediated by the inactivation of mTORC2 and the inhibition of PKB and thus reveals the molecular basis of rapamycin toxicity and the essential role of mTORC2 in maintaining beta cell function and survival.

"Selective" switching from non-selective to selective non-steroidal anti-inflammatory drugs.

PubMed

Bennett, Kathleen; Teeling, Mary; Feely, John

2003-11-01

Non-steroidal anti inflammatory drugs (NSAIDs) are thought to account for almost 25% of all reported adverse drug reactions, primarily gastrointestinal (GI) toxicity. Selective cyclo-oxygenase-2 (COX-2) inhibitors have been shown to preferentially inhibit activity of the COX-2 enzyme, which maintains anti-inflammatory activity but reduces GI toxicity. To determine the degree of switching from non-selective NSAIDs to COX-2 inhibitors and to examine the factors that were associated with switching. The General Medical Services prescription database (1.2 million people) was examined for NSAID prescriptions from December 1999 through November 2001. All those receiving non-selective NSAIDs and those switching to selective COX-2 inhibitors after at least 1 month on a non-selective NSAID were identified (non-switchers and switchers, respectively). Age, sex, dose of non-selective NSAID and co-prescribing of anti-peptic ulcer (anti-PU) drugs were considered between switchers and non-switchers, and odds ratios (OR) calculated using logistic regression. The effect of chronic use (> or =3 months prescription of a non-selective NSAID during the study period) on switching was also evaluated. A total of 81,538 of 480,573 patients (17%) initially prescribed non-selective NSAIDs were switched to COX-2 inhibitors during the study. The elderly (65 years or older) were more likely to be switched to a COX-2 inhibitor [OR=1.81, 95% confidence interval (CI) 1.79, 1.84]. Women were also more likely to be switched to COX-2 inhibitor therapy (OR=1.25, 95% CI 1.23, 1.27). Previous but not subsequent prescribing of anti-PU drugs was also associated with switching. Chronic users showed similar switching patterns. Prescribers are more likely to switch older female patients and those with a past history of peptic ulcers from non-selective NSAIDs to COX-2 inhibitors. This suggests that doctors take risk factors into consideration when prescribing NSAIDs. The relatively low rate of switching may suggest that prescribers still have concerns over the place of COX-2 inhibitors and reserve their use to those patients particularly at risk of NSAID-induced GI toxicity.

Acute toxicity of polybrominated diphenyl ethers (PBDEs) for turbot (Psetta maxima) early life stages (ELS).

PubMed

Mhadhbi, Lazhar; Fumega, José; Boumaiza, Moncef; Beiras, Ricardo

2012-03-01

The environmental presence of polybrominated diphenyl ethers (PBDEs), among which BDE-47 and BDE-99 are particularly abundant, makes toxicity data necessary to assess the hazard risk posed by PBDE to aquatic organisms. This study examines the effects of BDE-47 and BDE-99 on embryo-larval stages of the marine flatfish turbot. The turbot embryos were exposed at nominal concentrations of BDE-47 and BDE-99 for 6 days. Selected dose levels were relevant for investigating sublethal and lethal effects. Both tested compounds caused lethal toxicity as well as non-lethal malformations during embryo development. We found a high toxic potency of BDE-47 compared to BDE-99 (LC₅₀ values for embryos and larvae, respectively, BDE-47: 27.35 and 14.13 μg L⁻¹; BDE-99: 38.28 and 29.64 μg L⁻¹). The present study shows high sensitivity of fish early life stages (ELS) to PBDE compounds. Based on environmental concentrations of dissolved PBDEs from various aquatic ecosystems, waterborne BDE-47 and BDE-99 pose little risk of acute toxicity to marine fish at relevant environmental concentrations. Turbot fish ELS proved to be an excellent model for the study of ecotoxicity of contaminants in seawater. The results demonstrate harmful effects of PBDE on turbot ELS at concentrations in the range of parts per billion units. In the perspective of risk assessment, ELS endpoints provide rapid, cost-effective and ecologically relevant information, and links should be sought between these short-term tests and effects of long-term exposures in more realistic scenarios.

Derivation of an occupational exposure limit for inorganic borates using a weight of evidence approach.

PubMed

Maier, A; Vincent, M; Hack, E; Nance, P; Ball, W

2014-04-01

Inorganic borates are encountered in many settings worldwide, spurring international efforts to develop exposure guidance (US EPA, 2004; WHO, 2009; ATSDR, 2010) and occupational exposure limits (OEL) (ACGIH, 2005; MAK, 2011). We derived an updated OEL to reflect new data and current international risk assessment frameworks. We assessed toxicity and epidemiology data on inorganic borates to identify relevant adverse effects. International risk assessment frameworks (IPCS, 2005, 2007) were used to evaluate endpoint candidates: reproductive toxicity, developmental toxicity, and sensory irritation. For each endpoint, a preliminary OEL was derived and adjusted based on consideration of toxicokinetics, toxicodynamics, and other uncertainties. Selection of the endpoint point of departures (PODs) is supported by dose-response modeling. Developmental toxicity was the most sensitive systemic effect. An OEL of 1.6mgB/m(3) was estimated for this effect based on a POD of 63mgB/m(3) with an uncertainty factor (UF) of 40. Sensory irritation was considered to be the most sensitive effect for the portal of entry. An OEL of 1.4mgB/m(3) was estimated for this effect based on the identified POD and an UF of 1. An OEL of 1.4mgB/m(3) as an 8-h time-weighted average (TWA) is recommended. Copyright © 2014 Elsevier Inc. All rights reserved.

Plant toxins and trophic cascades alter fire regime and succession on a boral forest landscape

USGS Publications Warehouse

Feng, Zhilan; Alfaro-Murillo, Jorge A.; DeAngelis, Donald L.; Schmidt, Jennifer; Barga, Matthew; Zheng, Yiqiang; Ahmad Tamrin, Muhammad Hanis B.; Olson, Mark; Glaser, Tim; Kielland, Knut; Chapin, F. Stuart; Bryant, John

2012-01-01

Two models were integrated in order to study the effect of plant toxicity and a trophic cascade on forest succession and fire patterns across a boreal landscape in central Alaska. One of the models, ALFRESCO, is a cellular automata model that stochastically simulates transitions from spruce dominated 1 km2 spatial cells to deciduous woody vegetation based on stochastic fires, and from deciduous woody vegetation to spruce based on age of the cell with some stochastic variation. The other model, the ‘toxin-dependent functional response’ model (TDFRM) simulates woody vegetation types with different levels of toxicity, an herbivore browser (moose) that can forage selectively on these types, and a carnivore (wolf) that preys on the herbivore. Here we replace the simple succession rules in each ALFRESCO cell by plant–herbivore–carnivore dynamics from TDFRM. The central hypothesis tested in the integrated model is that the herbivore, by feeding selectively on low-toxicity deciduous woody vegetation, speeds succession towards high-toxicity evergreens, like spruce. Wolves, by keeping moose populations down, can help slow the succession. Our results confirmed this hypothesis for the model calibrated to the Tanana floodplain of Alaska. We used the model to estimate the effects of different levels of wolf control. Simulations indicated that management reductions in wolf densities could reduce the mean time to transition from deciduous to spruce by more than 15 years, thereby increasing landscape flammability. The integrated model can be useful in estimating ecosystem impacts of wolf control and moose harvesting in central Alaska.

Toxicity, sublethal effects, and potential modes of action of select fungicides on freshwater fish and invertebrates

USGS Publications Warehouse

Elskus, Adria A.

2012-01-01

Despite decades of agricultural and urban use of fungicides and widespread detection of these pesticides in surface waters, relatively few data are available on the effects of fungicides on fish and invertebrates in the aquatic environment. Nine fungicides are reviewed in this report: azoxystrobin, boscalid, chlorothalonil, fludioxonil, myclobutanil, fenarimol, pyraclostrobin, pyrimethanil, and zoxamide. These fungicides were identified as emerging chemicals of concern because of their high or increasing global use rates, detection frequency in surface waters, or likely persistence in the environment. A review of the literature revealed significant sublethal effects of fungicides on fish, aquatic invertebrates, and ecosystems, including zooplankton and fish reproduction, fish immune function, zooplankton community composition, metabolic enzymes, and ecosystem processes, such as leaf decomposition in streams, among other biological effects. Some of these effects can occur at fungicide concentrations well below single-species acute lethality values (48- or 96-hour concentration that effects a response in 50 percent of the organisms, that is, effective concentration killing 50 percent of the organisms in 48 or 96 hours) and chronic sublethal values (for example, 21-day no observed adverse effects concentration), indicating that single-species toxicity values may dramatically underestimate the toxic potency of some fungicides. Fungicide modes of toxic action in fungi can sometimes reflect the biochemical and (or) physiological effects of fungicides observed in vertebrates and invertebrates; however, far more studies are needed to explore the potential to predict effects in nontarget organisms based on specific fungicide modes of toxic action. Fungicides can also have additive and (or) synergistic effects when used with other fungicides and insecticides, highlighting the need to study pesticide mixtures that occur in surface waters. For fungicides that partition to organic matter in sediment and soils, it is particularly important to determine their effects on freshwater mussels and other freshwater benthic invertebrates in contact with sediments, as available toxicity studies with pelagic species, mainly Daphnia magna, may not be representative of these benthic organisms. Finally, there is a critical need for studies of the chronic effects of fungicides on reproduction, immunocompetence, and ecosystem function; sublethal endpoints with population and community-level relevance.

SAFETY/TOXICITY ASSESSMENT OF CERIA (A MODEL ENGINEERED NP) TO THE BRAIN

EPA Science Inventory

The results will indicate the influence of the size, shape and various surface chemistry properties of ENMs on their entrance into BBB cells and the brain, compared to selected peripheral organs, the effects they produce in the brain, their biopersistence and biotransformation...

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

Rohrbaugh, Wayne Joseph

Results are reported from an investigation of correlations between molecular structural parameters of selected organophosphorus insecticides and their corresponding toxic effectiveness. The crystal and molecular structures of azinphos-methyl, emidithion, and tetrachlorvinphos were determined via three-dimensional x-ray analysis. Acetylcholinesterase (AChE) in nerve cells was identified as the target for organophosphorus insecticides.

40 CFR 798.4100 - Dermal sensitization.

Code of Federal Regulations, 2014 CFR

2014-07-01

... system selected is recommended; (ii) Animals may act as their own controls or groups of induced animals... CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Specific Organ/Tissue Toxicity § 798.4100 Dermal... hypersensitive state is developed. (3) Induction exposure is an experimental exposure of a subject to a test...

40 CFR 798.4100 - Dermal sensitization.

Code of Federal Regulations, 2012 CFR

2012-07-01

... system selected is recommended; (ii) Animals may act as their own controls or groups of induced animals... CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Specific Organ/Tissue Toxicity § 798.4100 Dermal... hypersensitive state is developed. (3) Induction exposure is an experimental exposure of a subject to a test...

40 CFR 798.4100 - Dermal sensitization.

Code of Federal Regulations, 2013 CFR

2013-07-01

... system selected is recommended; (ii) Animals may act as their own controls or groups of induced animals... CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Specific Organ/Tissue Toxicity § 798.4100 Dermal... hypersensitive state is developed. (3) Induction exposure is an experimental exposure of a subject to a test...

40 CFR 798.4100 - Dermal sensitization.

Code of Federal Regulations, 2011 CFR

2011-07-01

... system selected is recommended; (ii) Animals may act as their own controls or groups of induced animals... CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Specific Organ/Tissue Toxicity § 798.4100 Dermal... hypersensitive state is developed. (3) Induction exposure is an experimental exposure of a subject to a test...

A Model Relating the Uniform Chart of Accounts to Major Disease Categories

DTIC Science & Technology

1985-10-01

THERAPEUTIC ABORTION BOARD - -.- N NURSE MIDWIFERY * . , ,, PSYCHIATRY & NEUROLOGY P PSYCHIATRY , P ADULT _ P ADOLESCENT - P ALCOHOL/ DRUG OTOXIFICATION X P...Substance Induced Organic Disorders MDC 21: Injury, Poisoning, and Toxic Effects of Drugs MDC 22: Burns MDC 23: Selected Factors Influencing Health

Identification of potential isoform-selective histone deacetylase inhibitors for cancer therapy: a combined approach of structure-based virtual screening, ADMET prediction and molecular dynamics simulation assay.

PubMed

Uba, Abdullahi Ibrahim; Yelekçi, Kemal

2017-10-23

Histone deacetylases (HDACs) have gained increased attention as targets for anticancer drug design and development. HDAC inhibitors have proven to be effective for reversing the malignant phenotype in HDAC-dependent cancer cases. However, lack of selectivity of the many HDAC inhibitors in clinical use and trials contributes to toxicities to healthy cells. It is believed that, the continued identification of isoform-selective inhibitors will eliminate these undesirable adverse effects - a task that remains a major challenge to HDAC inhibitor designs. Here, in an attempt to identify isoform-selective inhibitors, a large compound library containing 2,703,000 compounds retrieved from Otava database was screened against class I HDACs by exhaustive approach of structure-based virtual screening using rDOCK and Autodock Vina. A total of 41 compounds were found to show high-isoform selectivity and were further redocked into their respective targets using Autodock4. Thirty-six compounds showed remarkable isoform selectivity and passed drug-likeness and absorption, distribution, metabolism, elimination and toxicity prediction tests using ADMET Predictor™ and admetSAR. Furthermore, to study the stability of ligand binding modes, 10 ns-molecular dynamics (MD) simulations of the free HDAC isoforms and their complexes with respective best-ranked ligands were performed using nanoscale MD software. The inhibitors remained bound to their respective targets over time of the simulation and the overall potential energy, root-mean-square deviation, root-mean-square fluctuation profiles suggested that the detected compounds may be potential isoform-selective HDAC inhibitors or serve as promising scaffolds for further optimization towards the design of selective inhibitors for cancer therapy.

Inhibition of Lithium-Sensitive Phosphatase BPNT-1 Causes Selective Neuronal Dysfunction in C. elegans.

PubMed

Meisel, Joshua D; Kim, Dennis H

2016-07-25

Lithium has been a mainstay for the treatment of bipolar disorder, yet the molecular mechanisms underlying its action remain enigmatic. Bisphosphate 3'-nucleotidase (BPNT-1) is a lithium-sensitive phosphatase that catalyzes the breakdown of cytosolic 3'-phosphoadenosine 5'-phosphate (PAP), a byproduct of sulfation reactions utilizing the universal sulfate group donor 3'-phosphoadenosine 5'-phosphosulfate (PAPS) [1-3]. Loss of BPNT-1 leads to the toxic accumulation of PAP in yeast and non-neuronal cell types in mice [4, 5]. Intriguingly, BPNT-1 is expressed throughout the mammalian brain [4], and it has been hypothesized that inhibition of BPNT-1 could contribute to the effects of lithium on behavior [5]. Here, we show that loss of BPNT-1 in Caenorhabditis elegans results in the selective dysfunction of two neurons, the bilaterally symmetric pair of ASJ chemosensory neurons. As a result, BPNT-1 mutants are defective in behaviors dependent on the ASJ neurons, such as dauer exit and pathogen avoidance. Acute treatment with lithium also causes dysfunction of the ASJ neurons, and we show that this effect is reversible and mediated specifically through inhibition of BPNT-1. Finally, we show that the selective effect of lithium on the nervous system is due in part to the limited expression of the cytosolic sulfotransferase SSU-1 in the ASJ neuron pair. Our data suggest that lithium, through inhibition of BPNT-1 in the nervous system, can cause selective toxicity to specific neurons, resulting in corresponding effects on behavior of C. elegans. Copyright © 2016 Elsevier Ltd. All rights reserved.

Evaluation of Selected Subacute Effects of the Nitrotoluene Group of Munitions Compounds on Fish and Potential Use in Aquatic Toxicity Evaluation.

DTIC Science & Technology

1981-03-01

largemouth bass", Jour. Wildlife Management 22:40-44 (1958). Gardner, G.R. and Yevich, P.P., "Toxicological effects on cadmium on Fundulers heteroclitus... Qaulity Engineering Report No. Aberdeen Proving Ground, MD, pp 25 (1977). Henson, E.V., "Toxicology of some aliphatic ketones", Jour. of Occupational Med

Progressive metabolic impairment underlies the novel nematicidal action of fluensulfone on the potato cyst nematode Globodera pallida.

PubMed

Kearn, James; Lilley, Catherine; Urwin, Peter; O'Connor, Vincent; Holden-Dye, Lindy

2017-10-01

Fluensulfone is a new nematicide with an excellent profile of selective toxicity against plant parasitic nematodes. Here, its effects on the physiology and biochemistry of the potato cyst nematode Globodera pallida have been investigated and comparisons made with its effect on the life-span of the free-living nematode Caenorhabditis elegans to provide insight into its mode of action and its selective toxicity. Fluensulfone exerts acute effects (≤1h; ≥100μM) on stylet thrusting and motility of hatched second stage G. pallida juveniles (J2s). Chronic exposure to lower concentrations of fluensulfone (≥3days; ≤30μM), reveals a slowly developing metabolic insult in which G. pallida J2s sequentially exhibit a reduction in motility, loss of a metabolic marker for cell viability, high lipid content and tissue degeneration prior to death. These effects are absent in adults and dauers of the model genetic nematode Caenorhabditis elegans. The nematicidal action of fluensulfone follows a time-course which progresses from an early impact on motility through to an accumulating metabolic impairment, an inability to access lipid stores and death. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

BIOLOGICAL MONITORING OF TOXIC TRACE METALS. VOLUME 2. TOXIC TRACE METALS IN PLANTS AND ANIMALS OF THE WORLD. PART II

EPA Science Inventory

The needs and priorities in using biological accumulator organisms for monitoring toxic trace metals in plants and animals are analyzed. The toxic trace metals selected for study are antimony, arsenic, beryllium, boron, cadmium, chromium, cobalt, copper, lead, mercury, nickel, se...

BIOLOGICAL MONITORING OF TOXIC TRACE METALS. VOLUME 2. TOXIC TRACE METALS IN PLANTS AND ANIMALS OF THE WORLD. PART I

EPA Science Inventory

The needs and priorities in using biological accumulator organisms for monitoring toxic trace metals in plants and animals are analyzed. The toxic trace metals selected for study are antimony, arsenic, beryllium, boron, cadmium, chromium, cobalt, copper, lead, mercury, nickel, se...

Aluminium Toxicity to Plants as Influenced by the Properties of the Root Growth Environment Affected by Other Co-Stressors: A Review.

PubMed

Siecińska, Joanna; Nosalewicz, Artur

Aluminium toxicity to crops depends on the acidity of the soil and specific plant resistance. However, it is also strongly affected by other environmental factors that have to be considered to properly evaluate the resultant effects on plants. Observed weather perturbations and predicted climate changes will increase the probability of co-occurrence of aluminium toxicity and other abiotic stresses.In this review the mechanisms of plant-aluminium interactions are shown to be influenced by soil mineral nutrients, heavy metals, organic matter, oxidative stress and drought. Described effects of aluminium toxicity include: root growth inhibition, reduction in the uptake of mineral nutrients resulting from the inhibition of transport processes through ion channels; epigenetic changes to DNA resulting in gene silencing. Complex processes occurring in the rhizosphere are highlighted, including the role of soil organic matter and aluminium detoxification by mucilage.There is a considerable research gap in the understanding of root growth in the soil environment in the presence of toxic aluminium concentrations as affected by interactions with abiotic stressors. This knowledge is important for the selection of feasible methods aimed at the reduction of negative consequences of crop production in acidic soils affected by adverse growth environment.

Toxicogenomics concepts and applications to study hepatic effects of food additives and chemicals

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

Stierum, Rob; Heijne, Wilbert; Kienhuis, Anne

2005-09-01

Transcriptomics, proteomics and metabolomics are genomics technologies with great potential in toxicological sciences. Toxicogenomics involves the integration of conventional toxicological examinations with gene, protein or metabolite expression profiles. An overview together with selected examples of the possibilities of genomics in toxicology is given. The expectations raised by toxicogenomics are earlier and more sensitive detection of toxicity. Furthermore, toxicogenomics will provide a better understanding of the mechanism of toxicity and may facilitate the prediction of toxicity of unknown compounds. Mechanism-based markers of toxicity can be discovered and improved interspecies and in vitro-in vivo extrapolations will drive model developments in toxicology. Toxicologicalmore » assessment of chemical mixtures will benefit from the new molecular biological tools. In our laboratory, toxicogenomics is predominantly applied for elucidation of mechanisms of action and discovery of novel pathway-supported mechanism-based markers of liver toxicity. In addition, we aim to integrate transcriptome, proteome and metabolome data, supported by bioinformatics to develop a systems biology approach for toxicology. Transcriptomics and proteomics studies on bromobenzene-mediated hepatotoxicity in the rat are discussed. Finally, an example is shown in which gene expression profiling together with conventional biochemistry led to the discovery of novel markers for the hepatic effects of the food additives butylated hydroxytoluene, curcumin, propyl gallate and thiabendazole.« less

Isolation and toxicity test of Bacillus thuringiensis from Sekayu region soil, South Sumatra on Spodopteralitura

NASA Astrophysics Data System (ADS)

Afriani, S. R.; Pujiastuti, Y.; Irsan, C.; Damiri, N.; Nugraha, S.; Sembiring, E. R.

2018-01-01

This study aimed to obtain bacterial isolates B. thuringiensis potential as a biological control against pests Spodoptera litura. The research was conducted at the Laboratory of Pest and Disease Department, Agricultural Faculty of Sriwijaya University, Campus Inderalaya Ogan Ilir, South Sumatera, from March to June 2017. The study was conducted with survey method and laboratory trial. The results showed that of the 50 soil samples from three villages selected through morphological observation, reaction staining, KOH test, catalase test, producing 13 bacterial isolates. Screening of the 13th toxicity of the isolates suspected B. thuringiensis against S. litura larvae was investigated. Based on the toxicity screening test the following facts were obtained: five isolates ie KJ2M2, KJ3E1, KJ3JB1, KJ3D3 and KJ3D5 were lower toxicity than Dipel, two isolates ie KJ3K4 and KJ3D3 which had the same toxicity to Dipel. Five isolates the KJ3E3, KJ3BW5, KJ3JB5, KJ3D1 and LC2, LC3 known to have effectiveness until the seventh day reached 40%. There was one isolate that is KJ3BW5 which was more effective compared to Dipel as comparison.

Selective toxicity of the mesoionic insecticide, triflumezopyrim, to rice planthoppers and beneficial arthropods.

PubMed

Zhu, Jun; Li, Yao; Jiang, Hua; Liu, Chen; Lu, Weiwei; Dai, Wei; Xu, Jianxiang; Liu, Fang

2018-05-01

The novel mesoionic insecticide triflumezopyrim was highly effective in controlling both imidacloprid-susceptible and resistant planthopper populations in Malaysia. However, the toxicity of triflumezopyrim to planthopper populations and their natural enemies has been under-investigated in China. In this study, the median lethal concentrations (LC 50 ) of triflumezopyrim were determined in eight field populations of Nilaparvata lugens and one population of Sogatella furcifera from China under laboratory conditions. Triflumezopyrim showed higher toxicity to planthopper populations than the commonly-used insecticide, imidacloprid. Furthermore, the lethal effect of triflumezopyrim on eight beneficial arthropods of planthoppers was investigated in the laboratory and compared with three commonly-used insecticides, thiamethoxam, chlorpyrifos and abamectin. Triflumezopyrim was harmless to Anagrus nilaparvatae, Cyrtorhinus lividipennis and Paederus fuscipes, while thiamethoxam, chlorpyrifos and abamectin were moderately harmful or harmful to the insect parasitoid and predators. Triflumezopyrim and thiamethoxam were harmless to the predatory spiders Pirata subpiraticus, Ummeliata insecticeps, Hylyphantes graminicola and Pardosa pseudoannulata, and slightly harmful to Theridion octomaculatum. Chlorpyrifos caused slight to high toxicity to four spider species except U. insecticeps. Abamectin was moderately to highly toxic to all five spider species. Our results indicate that triflumezopyrim has high efficacy for rice planthoppers populations and is compatibile with their natural enemies in China.

Mixture Toxicity of SN2-Reactive Soft Electrophiles: 2—Evaluation of Mixtures Containing Ethyl α-Halogenated Acetates

PubMed Central

Mooneyham, T.; Jeyaratnam, J.; Schultz, T. W.; Pöch, G.

2011-01-01

Four ethyl α-halogenated acetates were tested in (1) sham and (2) nonsham combinations and (3) with a nonreactive nonpolar narcotic. Ethyl iodoacetate (EIAC), ethyl bromoacetate (EBAC), ethyl chloroacetate (ECAC), and ethyl fluoroacetate (EFAC), each considered to be an SN2-H-polar soft electrophile, were selected for testing based on their differences in electro(nucleo)philic reactivity and time-dependent toxicity (TDT). Agent reactivity was assessed using the model nucleophile glutathione, with EIAC and EBAC showing rapid reactivity, ECAC being less reactive, and EFAC lacking reactivity at ≤250 mM. The model nonpolar narcotic, 3-methyl-2-butanone (3M2B), was not reactive. Toxicity of the agents alone and in mixture was assessed using the Microtox acute toxicity test at three exposure durations: 15, 30 and 45 min. Two of the agents alone (EIAC and EBAC) had TDT values >100%. In contrast, ECAC (74 to 99%) and EFAC (9 to 12%) had partial TDT, whereas 3M2B completely lacked TDT (<0%). In mixture testing, sham combinations of each agent showed a combined effect consistent with predicted effects for dose-addition at each time point, as judged by EC50 dose-addition quotient values. Mixture toxicity results for nonsham ethyl acetate combinations were variable, with some mixtures being inconsistent with the predicted effects for dose-addition and/or independence. The ethyl acetate–3M2B combinations were somewhat more toxic than predicted for dose-addition, a finding differing from that observed previously for α-halogenated acetonitriles with 3M2B. PMID:21452006

Fish embryo toxicity test: identification of compounds with weak toxicity and analysis of behavioral effects to improve prediction of acute toxicity for neurotoxic compounds.

PubMed

Klüver, Nils; König, Maria; Ortmann, Julia; Massei, Riccardo; Paschke, Albrecht; Kühne, Ralph; Scholz, Stefan

2015-06-02

The fish embryo toxicity test has been proposed as an alternative for the acute fish toxicity test, but concerns have been raised for its predictivity given that a few compounds have been shown to exhibit a weak acute toxicity in the fish embryo. In order to better define the applicability domain and improve the predictive capacity of the fish embryo test, we performed a systematic analysis of existing fish embryo and acute fish toxicity data. A correlation analysis of a total of 153 compounds identified 28 compounds with a weaker or no toxicity in the fish embryo test. Eleven of these compounds exhibited a neurotoxic mode of action. We selected a subset of eight compounds with weaker or no embryo toxicity (cyanazine, picloram, aldicarb, azinphos-methyl, dieldrin, diquat dibromide, endosulfan, and esfenvalerate) to study toxicokinetics and a neurotoxic mode of action as potential reasons for the deviating fish embryo toxicity. Published fish embryo LC50 values were confirmed by experimental analysis of zebrafish embryo LC50 according to OECD guideline 236. Except for diquat dibromide, internal concentration analysis did not indicate a potential relation of the low sensitivity of fish embryos to a limited uptake of the compounds. Analysis of locomotor activity of diquat dibromide and the neurotoxic compounds in 98 hpf embryos (exposed for 96 h) indicated a specific effect on behavior (embryonic movement) for the neurotoxic compounds. The EC50s of behavior for neurotoxic compounds were close to the acute fish toxicity LC50. Our data provided the first evidence that the applicability domain of the fish embryo test (LC50s determination) may exclude neurotoxic compounds. However, neurotoxic compounds could be identified by changes in embryonic locomotion. Although a quantitative prediction of acute fish toxicity LC50 using behavioral assays in fish embryos may not yet be possible, the identification of neurotoxicity could trigger the conduction of a conventional fish acute toxicity test or application of assessment factors while considering the very good fish embryo-acute fish toxicity correlation for other compounds.

Toxicity of inhaled traffic related particulate matter

NASA Astrophysics Data System (ADS)

Gerlofs-Nijland, Miriam E.; Campbell, Arezoo; Miller, Mark R.; Newby, David E.; Cassee, Flemming R.

2009-02-01

Traffic generated ultrafine particulates may play a major role in the development of adverse health effects. However, little is known about harmful effects caused by recurring exposure. We hypothesized that repeated exposure to particulate matter results in adverse pulmonary and systemic toxic effects. Exposure to diesel engine exhaust resulted in signs of oxidative stress in the lung, impaired coagulation, and changes in the immune system. Pro-inflammatory cytokine levels were decreased in some regions of the brain but increased in the striatum implying that exposure to diesel engine exhaust may selectively aggravate neurological impairment. Data from these three studies suggest that exposure to traffic related PM can mediate changes in the vasculature and brain of healthy rats. To what extent these changes may contribute to chronic neurodegenerative or vascular diseases is at present unclear.

Pharmacogenetics of toxicity of 5-fluorouracil, doxorubicin and cyclophosphamide chemotherapy in breast cancer patients

PubMed Central

Tecza, Karolina; Pamula-Pilat, Jolanta; Lanuszewska, Joanna; Butkiewicz, Dorota; Grzybowska, Ewa

2018-01-01

The differences in patients’ response to the same medication, toxicity included, are one of the major problems in breast cancer treatment. Chemotherapy toxicity makes a significant clinical problem due to decreased quality of life, prolongation of treatment and reinforcement of negative emotions associated with therapy. In this study we evaluated the genetic and clinical risk factors of FAC chemotherapy-related toxicities in the group of 324 breast cancer patients. Selected genes and their polymorphisms were involved in FAC drugs transport (ABCB1, ABCC2, ABCG2,SLC22A16), metabolism (ALDH3A1, CBR1, CYP1B1, CYP2C19, DPYD, GSTM1, GSTP1, GSTT1, MTHFR,TYMS), DNA damage recognition, repair and cell cycle control (ATM, ERCC1, ERCC2, TP53, XRCC1). The multifactorial risk models that combine genetic risk modifiers and clinical characteristics were constructed for 12 toxic symptoms. The majority of toxicities was dependent on the modifications in components of more than one pathway of FAC drugs, while the impact level of clinical factors was comparable to the genetic ones. For the carriers of multiple high risk factors the chance of developing given symptom was significantly elevated which proved the factor-dosage effect. We found the strongest associations between concurrent presence of clinical factors - overall and recurrent anemia, nephrotoxicity and early nausea and genetic polymorphisms in genes responsible for DNA repair, drugs metabolism and transport pathways. These results indicate the possibility of selection of the patients with expected high tolerance to FAC treatment and consequently with high chance of chemotherapy completion without the dose reduction, treatment delays and decline in the quality of life. PMID:29507678

Selected flavonoids potentiate the toxicity of cisplatin in human lung adenocarcinoma cells: a role for glutathione depletion.

PubMed

Kachadourian, Remy; Leitner, Heather M; Day, Brian J

2007-07-01

Adjuvant therapies that enhance the anti-tumor effects of cis-diammineplatinum(II) dichloride (cisplatin, CDDP) are actively being pursued. Growing evidence supports the involvement of mitochondrial dysfunction in the anti-cancer effect of cisplatin. We examined the potential of using selective flavonoids that are effective in depleting tumor cells of glutathione (GSH) to potentiate cisplatin-mediated cytotoxicity in human lung adenocarcinoma (A549) cells. We found that cisplatin (40 microM, 48-h treatment) disrupts the steady-state levels of mitochondrial respiratory complex I, which correlates with elevated mitochondrial reactive oxygen species (ROS) production and cytochrome c release. The flavonoids, 2',5'-dihydroxychalcone (2',5'-DHC, 20 microM) and chrysin (20 microM) potentiated the cytotoxicity of cisplatin (20 microM), which could be blocked by supplementation of the media with exogenous GSH (500 microM). Both 2',5'-DHC and chrysin were more effective than the specific inhibitor of GSH synthesis, L-buthionine sulfoximine (BSO, 20 microM), in inducing GSH depletion and potentiating the cytotoxic effect of cisplatin. These data suggest that the flavonoid-induced potentiation of cisplatin's toxicity is due, in part, to synergetic pro-oxidant effects of cisplatin by inducing mitochondrial dysfunction, and the flavonoids by depleting cellular GSH, an important antioxidant defense.

Quantitative trait loci controlling aluminum tolerance in soybean: candidate gene and SNP marker discovery

USDA-ARS?s Scientific Manuscript database

Aluminum (Al) toxicity is an important abiotic stress that affects soybean production in acidic soils. Development of Al-tolerant cultivars is an efficient and environmentally friendly solution to the problem. Effective selection of Al-tolerant genotypes in applied breeding requires an understanding...

An Evaluation of 25 Selected ToxCast Chemicals in Medium-Throughput Assays to Detect Genotoxicity

EPA Science Inventory

ABSTRACTToxCast is a multi-year effort to develop a cost-effective approach for the US EPA to prioritize chemicals for toxicity testing. Initial evaluation of more than 500 high-throughput (HT) microwell-based assays without metabolic activation showed that most lacked high speci...

Forage and breed effects on behavior and temperament of pregnant beef heifers

USDA-ARS?s Scientific Manuscript database

Integration of behavioral observations with traditional selection schemes may lead to enhanced animal well-being and more profitable forage-based cattle production systems. Brahman-influenced (BR; n=64) and Gelbvieh x Angus (GA; n=64) heifers consumed either toxic endophyte-infected tall fescue (E+)...

Considerations in Use of the EPA’s ToxCast Data for Environmental Toxicology (SETAC)

EPA Science Inventory

The US EPA has developed the ToxCast program to prioritize chemicals for selective toxicity testing. ToxCast relies on extensive bioactivity profiling using a panel of biochemical and cellular assays that measure chemicals effects on potential molecular initiating events and key ...

THE EFFECTS OF FUNCTIONALIZED AND NON-FUNCTIONALIZED CARBON NANOTUBES ON ROOT ELONGATION OF SELECTED CROP SPECIES

EPA Science Inventory

Single-walled carbon nanotubes (SWNT) have many potential beneficial uses with additional applications constantly being investigated. However, these unique properties create a potential cause for concern of toxicity, not only in humans and animals, but also in plants. Root elong...

Toxicity of selected insecticides and insecticide mixtures to adult brown stink bug (Heteroptera: Pentatomidae)

USDA-ARS?s Scientific Manuscript database

Glass vial bioassay were conducted to evaluate the toxicity of selected insecticides and insecticide mixtures to the brown stink bug (BSB), Euschistus servus (Say) collected from blacklight traps, cotton plants and weeds in farming areas in the Brazos Valley of Texas. Dicrotophos was 5- and 18-fold...

RELATIONSHIPS OF QUANTITATIVE STRUCTURE-ACTIVITY TO COMPARATIVE TOXICITY OF SELECTED PHENOLS IN THE 'PIMEPHALES PROMELAS' AND 'TETRAHYMENA PYRIFORMIS' TEST SYSTEMS

EPA Science Inventory

The relative toxic response of 27 selected phenols in the 96-hr acute flowthrough Pimephales promelas (fathead minnow) and the 48- to 60-hr chronic static Tetrahymena pyriformis (ciliate protozoan) test systems was evaluated. Log Kow-dependent linear regression analyses revealed ...

Selective removal of organic contaminants from sediments: A methodology for toxicity identification evaluations (TIEs)

USGS Publications Warehouse

Lebo, J.A.; Huckins, J.N.; Petty, J.D.; Ho, K.T.; Stern, E.A.

2000-01-01

Aqueous slurries of a test sediment spiked with dibenz[a,h]anthracene, 2,4,5,2′,4′,5′-hexachlorobiphenyl, p,p′-DDE, or phenanthrene were subjected to decontamination experimentation. The spiked sediments were agitated at elevated temperatures for at least 96 h in the presence of either of the two contaminant-absorbing media: clusters of polyethylene membrane or lipid-containing semipermeable membrane devices (SPMDs). The effects of treatment temperature and surface area of media on the removal of contaminants were explored. This work is part of a larger methodology for whole-sediment toxicity identification evaluation (TIE). A method is being sought that is capable of detoxifying sediments with respect to organic contaminants while leaving toxicity attributable to inorganic contaminants unaffected.

Anti-digoxin Fab variants generated by phage display.

PubMed

Murata, Viviane Midori; Schmidt, Mariana Costa Braga; Kalil, Jorge; Tsuruta, Lilian Rumi; Moro, Ana Maria

2013-06-01

Digoxin is a pharmaceutical used in the control of cardiac dysfunction. Its therapeutic window is narrow, with effect dosage very close to the toxic dosage. To counteract the toxic effect, polyclonal Fab fragments are commercially available. Our study is based on a monoclonal anti-digoxin antibody, which would provide a product with a specific potency and more precise dosage for the detoxification of patients under digoxin treatment. Phage display technology was used to select variants with high affinity. From an anti-digoxin hybridoma, RNA was extracted for subsequent cDNA synthesis. Specific primers were used for the LC and Fd amplifications, then cloned sequentially in a phagemid vector (pComb3X) for the combinatorial Fab library construction. Clones were selected for their ability to bind to digoxin-BSA. The presence of light and heavy chains was checked, randomly selected clones then sequenced and induced to produce soluble Fabs, and subsequently analyzed for anti-digoxin expression. Out of ten clones randomly chosen, six resulted positive expression of the product. The sequencing of these revealed two identical clones and one presenting a pseudogene in the LC. Four clones presenting variations in the framework1 showed binding to digoxin-BSA by ELISA and western blotting. The specific binding was further confirmed by Biacore(®), which allowed ranking of the clones. The development of these clones allowed the selection of variants with higher affinity than the original version.

Embryonic Zebrafish Model - A Well-Established Method for Rapidly Assessing the Toxicity of Homeopathic Drugs: - Toxicity Evaluation of Homeopathic Drugs Using Zebrafish Embryo Model.

PubMed

Gupta, Himanshu R; Patil, Yogesh; Singh, Dipty; Thakur, Mansee

2016-12-01

Advancements in nanotechnology have led to nanoparticle (NP) use in various fields of medicine. Although the potential of NPs is promising, the lack of documented evidence on the toxicological effects of NPs is concerning. A few studies have documented that homeopathy uses NPs. Unfortunately, very few sound scientific studies have explored the toxic effects of homeopathic drugs. Citing this lack of high-quality scientific evidence, regulatory agencies have been reluctant to endorse homeopathic treatment as an alternative or adjunct treatment. This study aimed to enhance our insight into the impact of commercially-available homeopathic drugs, to study the presence of NPs in those drugs and any deleterious effects they might have, and to determine the distribution pattern of NPs in zebrafish embryos ( Danio rerio ). Homeopathic dilutions were studied using high-resolution transmission electron microscopy with selected area electron diffraction (SAED). For the toxicity assessment on Zebrafish, embryos were exposed to a test solution from 4 - 6 hours post-fertilization, and embryos/larvae were assessed up to 5 days post-fertilization (dpf) for viability and morphology. Toxicity was recorded in terms of mortality, hatching delay, phenotypic defects and metal accumulation. Around 5 dpf was found to be the optimum developmental stage for evaluation. The present study aimed to conclusively prove the presence of NPs in all high dilutions of homeopathic drugs. Embryonic zebrafish were exposed to three homeopathic drugs with two potencies (30CH, 200CH) during early embryogenesis. The resulting morphological and cellular responses were observed. Exposure to these potencies produced no visibly significant malformations, pericardial edema, and mortality and no necrotic and apoptotic cellular death. Our findings clearly demonstrate that no toxic effects were observed for these three homeopathic drugs at the potencies and exposure times used in this study. The embryonic zebrafish model is recommended as a well-established method for rapidly assessing the toxicity of homeopathic drugs.

In Vivo Protection against Strychnine Toxicity in Mice by the Glycine Receptor Agonist Ivermectin

PubMed Central

Radwan, Rasha

2014-01-01

The inhibitory glycine receptor, a ligand-gated ion channel that mediates fast synaptic inhibition in mammalian spinal cord and brainstem, is potently and selectively inhibited by the alkaloid strychnine. The anthelminthic and anticonvulsant ivermectin is a strychnine-independent agonist of spinal glycine receptors. Here we show that ivermectin is an effective antidote of strychnine toxicity in vivo and determine time course and extent of ivermectin protection. Mice received doses of 1 mg/kg and 5 mg/kg ivermectin orally or intraperitoneally, followed by an intraperitoneal strychnine challenge (2 mg/kg). Ivermectin, through both routes of application, protected mice against strychnine toxicity. Maximum protection was observed 14 hours after ivermectin administration. Combining intraperitoneal and oral dosage of ivermectin further improved protection, resulting in survival rates of up to 80% of animals and a significant delay of strychnine effects in up to 100% of tested animals. Strychnine action developed within minutes, much faster than ivermectin, which acted on a time scale of hours. The data agree with a two-compartment distribution of ivermectin, with fat deposits acting as storage compartment. The data demonstrate that toxic effects of strychnine in mice can be prevented if a basal level of glycinergic signalling is maintained through receptor activation by ivermectin. PMID:25317421

Determinants of Toxicity of Environmental Asbestos Fibers ...

EPA Pesticide Factsheets

Recent EPA-led studies have addressed the comparative toxicity and pathological mechanisms of environmental asbestos samples from Libby, Montana and other communities in the United States. Longer amosite fibers induce a 4-10 fold greater induction of pro-inflammatory mediators COX-2 and HO-1 than Libby fibers in human airway epithelial cells, as well as a number of other genes involved in cellular stress and toxicity. Similarly, equal mass doses of longer amosite fibers administered intratracheally to F344 rats cause greater pathological effects than Libby fibers, from 1 day to 2 years post-exposure. However, both intratracheal and inhalation studies show comparable effects of Libby fibers and shorter UICC amosite fibers. Dosimetry modeling and potency analysis studies are using these data to predict effects in humans. Libby fibers induce an acute phase response and systemic increases in selected markers of inflammation, and induce components of the NALP-3 inflammasome in the lung, while surface complexed iron inhibits these responses. Libby fibers alter genes involved in inflammation, immune regulation, and cell-cycle control, and also induce autoimmune responses in a rat model. Comparative toxicity studies showed that chrysotile fibers from Sumas Mountain, Washington caused greater lung interstitial fibrosis than Libby fibers, which were significantly more potent than tremolite fibers from El Dorado, California and actinolite “cleavage fragments” from

Coupling of OECD standardized test and immunomarkers to select the most environmentally benign ionic liquids option--towards an innovative "safety by design" approach.

PubMed

Bado-Nilles, Anne; Diallo, Alpha-Oumar; Marlair, Guy; Pandard, Pascal; Chabot, Laure; Geffard, Alain; Len, Christophe; Porcher, Jean-Marc; Sanchez, Wilfried

2015-01-01

This paper proposed a potential industrial accompaniment to reduce ionic liquid harmfulness by a novel combination of OECD Daphnia magna standardized test and fish immunomarkers. The combination of these two tests allowed multicriteria examination of ILs impacts in different organisms and trophic levels. The work provided new data for legislation and opened a door towards an integrative environmental evaluation due to direct implications of immune system in fish and ecosystem health. Whatever the species, each IL tested induced deleterious effects suggesting that toxic impact was especially due to IL lipophilicity properties. Nevertheless, cation moieties of ILs seemed to draw overall toxicity of ILs to significant extent as supported by lower cell mortality shown with imidazolium-based ILs compared to phosphonium-based ILs. However, the anions moieties have some additional effect, as revealed by quite dissimilar toxicity within same IL family. Concerning the more integrative biomarkers, the cationic-based ILs tested possessed also dissimilar effect on immune system of fish, especially on leucocyte distribution, lysosomal membrane integrity and phagocytosis activity. These results confirm that ILs toxicity could be influenced by design and that chemical engineering processes can integrate ecological footprint reduction strategies for successful IL utilization in the future. Copyright © 2014 Elsevier B.V. All rights reserved.

Disentangling taste and toxicity in aposematic prey

PubMed Central

Holen, Øistein Haugsten

2013-01-01

Many predators quickly learn to avoid attacking aposematic prey. If the prey vary in toxicity, the predators may alternatively learn to capture and taste-sample prey carefully before ingesting or rejecting them (go-slow behaviour). An increase in prey toxicity is generally thought to decrease predation on prey populations. However, while prey with a higher toxin load are more harmful to ingest, they may also be easier to recognize and reject owing to greater distastefulness, which can facilitate a taste-sampling foraging strategy. Here, the classic diet model is used to study the separate effects of taste and toxicity on predator preferences. The taste-sampling process is modelled using signal detection theory. The model is applicable to automimicry and Batesian mimicry. It shows that when the defensive toxin is sufficiently distasteful, a mimicry complex may be less profitable to the predator and better protected against predation if the models are moderately toxic than if they are highly toxic. Moreover, taste mimicry can reduce the profitability of the mimicry complex and increase protection against predation. The results are discussed in relation to the selection pressures acting on prey defences and the evolution of mimicry. PMID:23256198

Disentangling taste and toxicity in aposematic prey.

PubMed

Holen, Øistein Haugsten

2013-02-22

Many predators quickly learn to avoid attacking aposematic prey. If the prey vary in toxicity, the predators may alternatively learn to capture and taste-sample prey carefully before ingesting or rejecting them (go-slow behaviour). An increase in prey toxicity is generally thought to decrease predation on prey populations. However, while prey with a higher toxin load are more harmful to ingest, they may also be easier to recognize and reject owing to greater distastefulness, which can facilitate a taste-sampling foraging strategy. Here, the classic diet model is used to study the separate effects of taste and toxicity on predator preferences. The taste-sampling process is modelled using signal detection theory. The model is applicable to automimicry and batesian mimicry. It shows that when the defensive toxin is sufficiently distasteful, a mimicry complex may be less profitable to the predator and better protected against predation if the models are moderately toxic than if they are highly toxic. Moreover, taste mimicry can reduce the profitability of the mimicry complex and increase protection against predation. The results are discussed in relation to the selection pressures acting on prey defences and the evolution of mimicry.

Relationship between Composition and Toxicity of Motor Vehicle Emission Samples

PubMed Central

McDonald, Jacob D.; Eide, Ingvar; Seagrave, JeanClare; Zielinska, Barbara; Whitney, Kevin; Lawson, Douglas R.; Mauderly, Joe L.

2004-01-01

In this study we investigated the statistical relationship between particle and semivolatile organic chemical constituents in gasoline and diesel vehicle exhaust samples, and toxicity as measured by inflammation and tissue damage in rat lungs and mutagenicity in bacteria. Exhaust samples were collected from “normal” and “high-emitting” gasoline and diesel light-duty vehicles. We employed a combination of principal component analysis (PCA) and partial least-squares regression (PLS; also known as projection to latent structures) to evaluate the relationships between chemical composition of vehicle exhaust and toxicity. The PLS analysis revealed the chemical constituents covarying most strongly with toxicity and produced models predicting the relative toxicity of the samples with good accuracy. The specific nitro-polycyclic aromatic hydrocarbons important for mutagenicity were the same chemicals that have been implicated by decades of bioassay-directed fractionation. These chemicals were not related to lung toxicity, which was associated with organic carbon and select organic compounds that are present in lubricating oil. The results demonstrate the utility of the PCA/PLS approach for evaluating composition–response relationships in complex mixture exposures and also provide a starting point for confirming causality and determining the mechanisms of the lung effects. PMID:15531438

Reproductive and developmental toxicity of the components of gasoline.

PubMed Central

Skalko, R G

1993-01-01

The reproductive, developmental, and postnatal toxicity of 14 select chemicals and mixtures that are components of gasoline has been reviewed. The majority of experimental analyses have been performed as either variations of the accepted segment 2 protocol or as traditional teratology studies. Specific deficiencies in the present database have been identified and are most obvious in the evaluation of reproductive and postnatal effects. It is recommended that future studies address the continuing need for assessment in multiple species and over a range of dosages with specific emphasis on the impact of route of administration on the results obtained. PMID:8020438

Principles and procedures in forensic toxicology.

PubMed

Wyman, John F

2012-09-01

The principles and procedures employed in a modern forensic toxicology lab are detailed in this review. Aspects of Behavioral and Postmortem toxicology, including certification of analysts and accreditation of labs, chain of custody requirements, typical testing services provided, rationale for specimen selection, and principles of quality assurance are discussed. Interpretation of toxicology results in postmortem specimens requires the toxicologist and pathologist to be cognizant of drug-drug interactions, drug polymorphisms and pharmacogenomics, the gross signs of toxic pathology, postmortem redistribution, confirmation of systemic toxicity in suspected overdoses, the possibility of developed tolerance, and the effects of decomposition on drug concentration.

ECOSAR model performance with a large test set of industrial chemicals.

PubMed

Reuschenbach, Peter; Silvani, Maurizio; Dammann, Martina; Warnecke, Dietmar; Knacker, Thomas

2008-05-01

The widely used ECOSAR computer programme for QSAR prediction of chemical toxicity towards aquatic organisms was evaluated by using large data sets of industrial chemicals with varying molecular structures. Experimentally derived toxicity data covering acute effects on fish, Daphnia and green algae growth inhibition of in total more than 1,000 randomly selected substances were compared to the prediction results of the ECOSAR programme in order (1) to assess the capability of ECOSAR to correctly classify the chemicals into defined classes of aquatic toxicity according to rules of EU regulation and (2) to determine the number of correct predictions within tolerance factors from 2 to 1,000. Regarding ecotoxicity classification, 65% (fish), 52% (Daphnia) and 49% (algae) of the substances were correctly predicted into the classes "not harmful", "harmful", "toxic" and "very toxic". At all trophic levels about 20% of the chemicals were underestimated in their toxicity. The class of "not harmful" substances (experimental LC/EC(50)>100 mg l(-1)) represents nearly half of the whole data set. The percentages for correct predictions of toxic effects on fish, Daphnia and algae growth inhibition were 69%, 64% and 60%, respectively, when a tolerance factor of 10 was allowed. Focussing on those experimental results which were verified by analytically measured concentrations, the predictability for Daphnia and algae toxicity was improved by approximately three percentage points, whereas for fish no improvement was determined. The calculated correlation coefficients demonstrated poor correlation when the complete data set was taken, but showed good results for some of the ECOSAR chemical classes. The results are discussed in the context of literature data on the performance of ECOSAR and other QSAR models.

Cumulative toxicity of neonicotinoid insecticide mixtures to Chironomus dilutus under acute exposure scenarios.

PubMed

Maloney, Erin M; Morrissey, Christy A; Headley, John V; Peru, Kerry M; Liber, Karsten

2017-11-01

Extensive agricultural use of neonicotinoid insecticide products has resulted in the presence of neonicotinoid mixtures in surface waters worldwide. Although many aquatic insect species are known to be sensitive to neonicotinoids, the impact of neonicotinoid mixtures is poorly understood. In the present study, the cumulative toxicities of binary and ternary mixtures of select neonicotinoids (imidacloprid, clothianidin, and thiamethoxam) were characterized under acute (96-h) exposure scenarios using the larval midge Chironomus dilutus as a representative aquatic insect species. Using the MIXTOX approach, predictive parametric models were fitted and statistically compared with observed toxicity in subsequent mixture tests. Single-compound toxicity tests yielded median lethal concentration (LC50) values of 4.63, 5.93, and 55.34 μg/L for imidacloprid, clothianidin, and thiamethoxam, respectively. Because of the similar modes of action of neonicotinoids, concentration-additive cumulative mixture toxicity was the predicted model. However, we found that imidacloprid-clothianidin mixtures demonstrated response-additive dose-level-dependent synergism, clothianidin-thiamethoxam mixtures demonstrated concentration-additive synergism, and imidacloprid-thiamethoxam mixtures demonstrated response-additive dose-ratio-dependent synergism, with toxicity shifting from antagonism to synergism as the relative concentration of thiamethoxam increased. Imidacloprid-clothianidin-thiamethoxam ternary mixtures demonstrated response-additive synergism. These results indicate that, under acute exposure scenarios, the toxicity of neonicotinoid mixtures to C. dilutus cannot be predicted using the common assumption of additive joint activity. Indeed, the overarching trend of synergistic deviation emphasizes the need for further research into the ecotoxicological effects of neonicotinoid insecticide mixtures in field settings, the development of better toxicity models for neonicotinoid mixture exposures, and the consideration of mixture effects when setting water quality guidelines for this class of pesticides. Environ Toxicol Chem 2017;36:3091-3101. © 2017 SETAC. © 2017 SETAC.

UGT1A1*6 and UGT1A1*28 polymorphisms are correlated with irinotecan-induced toxicity: A meta-analysis.

PubMed

Yang, Yuwei; Zhou, MengMeng; Hu, Mingjun; Cui, Yanjie; Zhong, Qi; Liang, Ling; Huang, Fen

2018-06-22

Previous articles explored the role of UGT1A1 polymorphism on predicting irinotecan-induced toxicity, but the conclusions were still inconsistent and not comprehensive. We performed this meta-analysis to investigate the association between UGT1A1 polymorphism and irinotecan-induced toxicity. PubMed and Web of Science were searched for articles before July 2017. Inclusion and exclusion criteria were set to select eligible articles, and corresponding data were extracted from those articles. Subgroup analyses based on different cancer categories, doses and races were carried out to achieve comprehensive results. Statistical analyses were conducted using STATA 11.0. A total of 38 studies with 6742 cases were included after reading full text. Both UGT1A1*6 and UGT1A1*28 polymorphism are significantly associated with severe irinotecan-induced toxicity. Both Asian and Caucasian cancer patients with UGT1A1*28 variant had an increased risk. Compared with heterozygous variant, patients with homozygous variant suffered from a higher risk of toxicity. The effect of UGT1A1*28 polymorphism on diarrhea was less than on neutropenia. Subgroup analysis exhibited that for UGT1A1*6 polymorphism, patients treated with low-dose irinotecan were at a notable risk of toxicity. Moreover, the association between UGT1A1*6 polymorphism and irinotecan-induced toxicity was found in patients suffering from respiratory system cancers. Both UGT1A1*6 and UGT1A1*28 polymorphisms can be considered as predictors of irinotecan-induced toxicity, with effect varying by race, cancer type and irinotecan dose. © 2018 John Wiley & Sons Australia, Ltd.

Balancing risk and benefit for first-line treatment of metastatic colorectal cancer: a graphic communication tool for patients and physicians.

PubMed

Sanatani, Michael S; Vincent, Mark D

2007-01-01

Advances in the treatment of metastatic colorectal cancer have improved overall survival (OS); however, this might come at the cost of increased toxicity. Health-related quality of life, a significant concern closely related to toxicity and important when discussing palliative therapy, is infrequently assessed and reported in older clinical trials. As the number of tested regimens increases, the question arises on how to best present palliative treatment options. We present a simple way to compare treatment options in terms of potential risks and benefits. The literature was surveyed for reports of first-line systemic chemotherapies for metastatic colorectal cancer. The largest recent reports with detailed toxicity data were selected as representative for a regimen. Toxicity sum of a regimen was calculated as percent occurrences in the study cohort of severe adverse effects: diarrhea, mucositis, neurocutaneous conditions (excluding alopecia), vomiting, and febrile neutropenia. Limitations of toxicity reporting precluded inclusion of other or milder adverse events. Benefits (OS and progression-free survival [PFS]) were plotted graphically as benefit versus toxicity sum. Thirty-four regimens were found. Overall survival, PFS, and toxicity sum ranged from 8.9-24.7 months, 4.9-9.2 months, and 12-70 months, respectively. Weaknesses of our study include omission of some specific toxicities and of symptom control benefit, as well as heterogeneity of trial design and study populations. Furthermore, more recent OS data might reflect the availability of more lines of therapy rather than the effect of the first-line regimen, as comparison with PFS outcomes show. Our comparative tool helps physicians discuss the large number of available options with a patient in order to arrive at the treatment plan most appropriate to the individual and improve informed consent and disclosure, while highlighting limitations in available evidence.

Essential oils and Beauveria bassiana against Dermanyssus gallinae (Acari: Dermanyssidae): Towards new natural acaricides.

PubMed

Immediato, Davide; Figueredo, Luciana Aguiar; Iatta, Roberta; Camarda, Antonio; de Luna, Rafaela Lira Nogueira; Giangaspero, Annunziata; Brandão-Filho, Sinval Pinto; Otranto, Domenico; Cafarchia, Claudia

2016-10-15

Essential oils (EOs) and entomopathogenic fungi such as Beauveria bassiana (Bb) strains have the potential to be used as alternative insecticides and acaricides for controlling ectoparasites as Dermanyssus gallinae. These compounds have some limitations in their use: the acaricidal effect of EOs is rapid, but short-lived, whilst that of Bb is delayed, but long-lived. To evaluate the effect of both compounds combined against D. gallinae, the non-toxic dose of Eucalyptus globulus, Eucalyptus citriodora, Thymus vulgaris and Eugenia caryophyllata essential oils were firstly calculated for "native" strains of Bb. Subsequently, the effects of the combination of selected EOs with Bb against nymph and adult poultry red mites (PRMs) was assessed. EO concentrations ranging from 0.0015 to 8% v/v (i.e., nine double dilutions) were used to evaluate their effect on germination, sporulation and vegetative growth rates of native strains of Bb. A total of 1440 mites (720 nymphs and 720 adults) were divided into three-treated group (TGs) and one control group (CG). In TGs, mites were exposed to Bb in combination with the selected EO (TG1), EO alone (TG2) or Bb (TG3) alone. In the CG, mites were exposed to 0.1% tween 80 plus EO solvent (CG). E. globulus and E. citriodora were toxic for Bb in concentrations higher than 0.2% and 0.003% respectively, whilst E. caryophyllata and T. vulgaris were toxic at all concentrations tested against Bb. Based on the results of the toxicity assays against Bb, E. globulus was chosen to be tested as acaricide resulting non-toxic for Bb at concentration lower than 0.4%. Increased mortality of D. gallinae adults was recorded in TG1 than those in other TGs from 4days post-infection (T+4DPI). A 100% mortality of D. gallinae was recorded in adults at T+9DPI and at T+10DPI in nymphs in TG1 and later than T+11DPI in the other TGs. Used in combination with E. globulus, Bb displayed an earlier acaricidal effect towards both haematophagous D. gallinae stages. The combination of B. bassiana and E. globulus at 0.2% might be used for controlling arthropods of medical and veterinary importance as D. gallinae. Copyright © 2016 Elsevier B.V. All rights reserved.

Exposure to Nicotine and Selected Toxicants in Cigarette Smokers Who Switched to Electronic Cigarettes: A Longitudinal Within-Subjects Observational Study

PubMed Central

Gawron, Michal; Smith, Danielle M.; Peng, Margaret; Jacob, Peyton; Benowitz, Neal L.

2017-01-01

Introduction: Electronic cigarettes (e-cigarettes) are purported to deliver nicotine aerosol without any toxic combustion products present in tobacco smoke. In this longitudinal within-subjects observational study, we evaluated the effects of e-cigarettes on nicotine delivery and exposure to selected carcinogens and toxicants. Methods: We measured seven nicotine metabolites and 17 tobacco smoke exposure biomarkers in the urine samples of 20 smokers collected before and after switching to pen-style M201 e-cigarettes for 2 weeks. Biomarkers were metabolites of 13 major carcinogens and toxicants in cigarette smoke: one tobacco-specific nitrosamine (NNK), eight volatile organic compounds (1,3-butadiene, crotonaldehyde, acrolein, benzene, acrylamide, acrylonitrile, ethylene oxide, and propylene oxide), and four polycyclic aromatic hydrocarbons (naphthalene, fluorene, phenanthrene, and pyrene). Changes in urine biomarkers concentration were tested using repeated measures analysis of variance. Results: In total, 45% of participants reported complete abstinence from cigarette smoking at 2 weeks, while 55% reported continued smoking. Levels of total nicotine and some polycyclic aromatic hydrocarbon metabolites did not change after switching from tobacco to e-cigarettes. All other biomarkers significantly decreased after 1 week of using e-cigarettes (p < .05). After 1 week, the greatest percentage reductions in biomarkers levels were observed for metabolites of 1,3-butadiene, benzene, and acrylonitrile. Total NNAL, a metabolite of NNK, declined by 57% and 64% after 1 and 2 weeks, respectively, while 3-hydroxyfluorene levels declined by 46% at week 1, and 34% at week 2. Conclusions: After switching from tobacco to e-cigarettes, nicotine exposure remains unchanged, while exposure to selected carcinogens and toxicants is substantially reduced. Implications: To our knowledge, this is the first study that demonstrates that substituting tobacco cigarettes with an e-cigarette may reduce user exposure to numerous toxicants and carcinogens otherwise present in tobacco cigarettes. Data on reduced exposure to harmful constituents that are present in tobacco cigarettes and e-cigarettes can aid in evaluating e-cigarettes as a potential harm reduction device. PMID:27613896

Exposure to Nicotine and Selected Toxicants in Cigarette Smokers Who Switched to Electronic Cigarettes: A Longitudinal Within-Subjects Observational Study.

PubMed

Goniewicz, Maciej L; Gawron, Michal; Smith, Danielle M; Peng, Margaret; Jacob, Peyton; Benowitz, Neal L

2017-02-01

Electronic cigarettes (e-cigarettes) are purported to deliver nicotine aerosol without any toxic combustion products present in tobacco smoke. In this longitudinal within-subjects observational study, we evaluated the effects of e-cigarettes on nicotine delivery and exposure to selected carcinogens and toxicants. We measured seven nicotine metabolites and 17 tobacco smoke exposure biomarkers in the urine samples of 20 smokers collected before and after switching to pen-style M201 e-cigarettes for 2 weeks. Biomarkers were metabolites of 13 major carcinogens and toxicants in cigarette smoke: one tobacco-specific nitrosamine (NNK), eight volatile organic compounds (1,3-butadiene, crotonaldehyde, acrolein, benzene, acrylamide, acrylonitrile, ethylene oxide, and propylene oxide), and four polycyclic aromatic hydrocarbons (naphthalene, fluorene, phenanthrene, and pyrene). Changes in urine biomarkers concentration were tested using repeated measures analysis of variance. In total, 45% of participants reported complete abstinence from cigarette smoking at 2 weeks, while 55% reported continued smoking. Levels of total nicotine and some polycyclic aromatic hydrocarbon metabolites did not change after switching from tobacco to e-cigarettes. All other biomarkers significantly decreased after 1 week of using e-cigarettes (p < .05). After 1 week, the greatest percentage reductions in biomarkers levels were observed for metabolites of 1,3-butadiene, benzene, and acrylonitrile. Total NNAL, a metabolite of NNK, declined by 57% and 64% after 1 and 2 weeks, respectively, while 3-hydroxyfluorene levels declined by 46% at week 1, and 34% at week 2. After switching from tobacco to e-cigarettes, nicotine exposure remains unchanged, while exposure to selected carcinogens and toxicants is substantially reduced. To our knowledge, this is the first study that demonstrates that substituting tobacco cigarettes with an e-cigarette may reduce user exposure to numerous toxicants and carcinogens otherwise present in tobacco cigarettes. Data on reduced exposure to harmful constituents that are present in tobacco cigarettes and e-cigarettes can aid in evaluating e-cigarettes as a potential harm reduction device. © The Author 2016. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Predictors of Severe Acute and Late Toxicities in Patients With Localized Head-and-Neck Cancer Treated With Radiation Therapy

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

Meyer, Francois, E-mail: francois.meyer@chuq.qc.ca; Fortin, Andre; Wang, Chang Shu

2012-03-15

Purpose: Radiation therapy (RT) causes acute and late toxicities that affect various organs and functions. In a large cohort of patients treated with RT for localized head and neck cancer (HNC), we prospectively assessed the occurrence of RT-induced acute and late toxicities and identified characteristics that predicted these toxicities. Methods and Materials: We conducted a randomized trial among 540 patients treated with RT for localized HNC to assess whether vitamin E supplementation could improve disease outcomes. Adverse effects of RT were assessed using the Radiation Therapy Oncology Group Acute Radiation Morbidity Criteria during RT and one month after RT, andmore » the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer Late Radiation Morbidity Scoring Scheme at six and 12 months after RT. The most severe adverse effect among the organs/tissues was selected as an overall measure of either acute or late toxicity. Grade 3 and 4 toxicities were considered as severe. Stepwise multivariate logistic regression models were used to identify all independent predictors (p < 0.05) of acute or late toxicity and to estimate odds ratios (OR) for severe toxicity with their 95% confidence intervals (CI). Results: Grade 3 or 4 toxicity was observed in 23% and 4% of patients, respectively, for acute and late toxicity. Four independent predictors of severe acute toxicity were identified: sex (female vs. male: OR = 1.72, 95% confidence interval [CI]: 1.06-2.80), Karnofsky Performance Status (OR = 0.67 for a 10-point increment, 95% CI: 0.52-0.88), body mass index (above 25 vs. below: OR = 1.88, 95% CI: 1.22-2.90), TNM stage (Stage II vs. I: OR = 1.91, 95% CI: 1.25-2.92). Two independent predictors were found for severe late toxicity: female sex (OR = 3.96, 95% CI: 1.41-11.08) and weight loss during RT (OR = 1.26 for a 1 kg increment, 95% CI: 1.12-1.41). Conclusions: Knowledge of these predictors easily collected in a clinical setting could help tailoring therapies to reduce toxicities among patients treated with RT for HNC.« less

In Vitro and In Vivo Evaluation of Lactobacillus delbrueckii subsp. bulgaricus KLDS1.0207 for the Alleviative Effect on Lead Toxicity

PubMed Central

Li, Bailiang; Jin, Da; Yu, Shangfu; Etareri Evivie, Smith; Muhammad, Zafarullah; Huo, Guicheng; Liu, Fei

2017-01-01

Lead (Pb) is a toxic contaminating heavy metal that can cause a variety of hazardous effects to both humans and animals. In the present study, Lactobacillus delbrueckii subsp. bulgaricus KLDS1.0207 (L. bulgaricus KLDS1.0207), which has a remarkable Pb binding capacity and Pb tolerance, was selected for further study. It was observed that the thermodynamic and kinetic model of L. bulgaricus KLDS1.0207 Pb binding respectively fit with the Langmuir–Freundlich model and the pseudo second-order kinetic model. Scanning electron microscopy and energy dispersive spectroscopy analysis disclosed that the cell surfaces were covered with Pb and that carbon and oxygen elements were chiefly involved in Pb binding. Combined with Fourier transform infrared spectroscopy analysis, it was revealed that the carboxyl, phosphoryl, hydroxyl, amino and amide groups were the main functional groups involved in the Pb adsorption. The protective effects of L. bulgaricus KLDS1.0207 against acute Pb toxicity in mice was evaluated by prevention and therapy groups, the results in vivo showed that L. bulgaricus KLDS1.0207 treatment could reduce mortality rates, effectively increase Pb levels in the feces, alleviate tissue Pb enrichment, improve the antioxidant index in the liver and kidney, and relieve renal pathological damage. Our findings show that L. bulgaricus KLDS1.0207 can be used as a potential probiotic against acute Pb toxicity. PMID:28786945

In Vitro and In Vivo Evaluation of Lactobacillus delbrueckii subsp. bulgaricus KLDS1.0207 for the Alleviative Effect on Lead Toxicity.

PubMed

Li, Bailiang; Jin, Da; Yu, Shangfu; Etareri Evivie, Smith; Muhammad, Zafarullah; Huo, Guicheng; Liu, Fei

2017-08-08

Lead (Pb) is a toxic contaminating heavy metal that can cause a variety of hazardous effects to both humans and animals. In the present study, Lactobacillus delbrueckii subsp. bulgaricus KLDS1.0207 ( L. bulgaricus KLDS1.0207), which has a remarkable Pb binding capacity and Pb tolerance, was selected for further study. It was observed that the thermodynamic and kinetic model of L. bulgaricus KLDS1.0207 Pb binding respectively fit with the Langmuir-Freundlich model and the pseudo second-order kinetic model. Scanning electron microscopy and energy dispersive spectroscopy analysis disclosed that the cell surfaces were covered with Pb and that carbon and oxygen elements were chiefly involved in Pb binding. Combined with Fourier transform infrared spectroscopy analysis, it was revealed that the carboxyl, phosphoryl, hydroxyl, amino and amide groups were the main functional groups involved in the Pb adsorption. The protective effects of L. bulgaricus KLDS1.0207 against acute Pb toxicity in mice was evaluated by prevention and therapy groups, the results in vivo showed that L. bulgaricus KLDS1.0207 treatment could reduce mortality rates, effectively increase Pb levels in the feces, alleviate tissue Pb enrichment, improve the antioxidant index in the liver and kidney, and relieve renal pathological damage. Our findings show that L. bulgaricus KLDS1.0207 can be used as a potential probiotic against acute Pb toxicity.

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

Belinsky, S. A.; Hoover, M. D.; Bradley, P. L.

This document from the Inhalation Toxicology Research Institute includes annual reports in the following general areas: (I) Aerosol Technology and Characterization of Airborne Materials; (II) Deposition, transport, and clearance of inhaled Toxicants; (III) Metabolism and Markers of Inhaled Toxicants; (IV) Carcinogenic Responses to Toxicants; (V) Mechanisms of carcinogenic response to Toxicants; (VI) Non carcinogenic responses to inhaled toxicants; (VII) Mechanisms of noncarcinogenic Responses to Inhaled Toxicants; (VIII) The application of Mathematical Modeling to Risk Estimates. 9 appendices are also included. Selected papers are indexed separately for inclusion in the Energy Science and Technology Database.

Toxicity of Silver Nanoparticles at the Air-Liquid Interface

PubMed Central

Holder, Amara L.; Marr, Linsey C.

2013-01-01

Silver nanoparticles are one of the most prevalent nanomaterials in consumer products. Some of these products are likely to be aerosolized, making silver nanoparticles a high priority for inhalation toxicity assessment. To study the inhalation toxicity of silver nanoparticles, we have exposed cultured lung cells to them at the air-liquid interface. Cells were exposed to suspensions of silver or nickel oxide (positive control) nanoparticles at concentrations of 2.6, 6.6, and 13.2 μg cm−2 (volume concentrations of 10, 25, and 50 μg ml−1) and to 0.7 μg cm−2 silver or 2.1 μg cm−2 nickel oxide aerosol at the air-liquid interface. Unlike a number of in vitro studies employing suspensions of silver nanoparticles, which have shown strong toxic effects, both suspensions and aerosolized nanoparticles caused negligible cytotoxicity and only a mild inflammatory response, in agreement with animal exposures. Additionally, we have developed a novel method using a differential mobility analyzer to select aerosolized nanoparticles of a single diameter to assess the size-dependent toxicity of silver nanoparticles. PMID:23484109

Reduction of aflatoxin B1 to aflatoxicol: a comprehensive DFT study provides clues to its toxicity.

PubMed

Karabulut, Sedat; Paytakov, Guvanchmyrat; Leszczynski, Jerzy

2014-12-01

Aflatoxicol (AFL) is one of most the important metabolites of aflatoxin B1 (AFB1). AFL can be formed through enzymatic or synthetic reduction of AFB1. Various experimental and theoretical studies have been focused on the AFB1 due to its high toxicity and carcinogenicity. The selective reduction of AFB1 carbonyls, molecular structure of AFL and its effect on toxicity has been studied here by the density functional theory (DFT) method. Although the toxicity of AFL is 18 times lower than that of AFB1, it has been concluded that both molecular structures have similar potency to form an exo-epoxide (AFEP) analogue which can bind to DNA. Calculations revealed that only one of the three possible tautomers of AFL is stable, both in the gas phase and water. The electronic properties of aflatoxicol are calculated as similar to aflatoxin B1 and this may be an explanation of similar carcinogenicity and toxicity of these compounds, which has been proved by experimental results. © 2014 Society of Chemical Industry.

[Efectiveness of topical therapies in patients with breast cancer that experience radiodermatitis. A systematic review].

PubMed

Fernández-Castro, Mercedes; Martín-Gil, Belén

2015-01-01

After radiation therapy most patients experience acute skin toxicity to some degree. The purpose of this systematic review is to assess the available evidence concerning the effectivity of topical therapies on patients with breast cancer that experience radiodermatitis after radiotherapy. The review included clinical trials aimed to evaluate topical therapies for prevention or treatment of acute radiodermatitis in women with breast cancer, which were published between 2009 and 2014. The bibliographic search was carried out in the following databases: PubMed, Cinahl, Cochrane Plus, IBECS and LILACS. The studies were selected independently by peer reviewers using the Critical Appraisal Skills Programme in its Spanish version. 86 bibliographical references were identified. Twenty full-text articles of clinical trials were assessed and two were excluded because they were not completed; 12 of clinical trials evaluated topical treatment with creams and ointments, three with corticosteroid creams and other three with dressings. The effectivity of human epidermal growth factor cream, linoleic acid emulsion, topical silver sulfadiazine, corticosteroids creams and polyurethane dressings has been shown in these clinical trials. Given that radiodermatitis is a dynamic process, these topical agents were effective in different stages of skin toxicity. Some of them delayed the onset, others decreased the development and severity of acute skin toxicity degree and others improved the subjective symptoms (itching, pain, burning). Only polyurethane dressings suggest effectiveness in all stages of skin toxicity, in prevention, management of the different skin toxicity degrees and improvement of wellbeing. Copyright © 2015. Published by Elsevier España, S.L.U.

Tamoxifen Provides Structural and Functional Rescue in Murine Models of Photoreceptor Degeneration

PubMed Central

Wang, Xu; Ma, Wenxin; Gonzalez, Shaimar R.; Kretschmer, Friedrich; Badea, Tudor C.

2017-01-01

Photoreceptor degeneration is a cause of irreversible vision loss in incurable blinding retinal diseases including retinitis pigmentosa (RP) and atrophic age-related macular degeneration. We found in two separate mouse models of photoreceptor degeneration that tamoxifen, a selective estrogen receptor modulator and a drug previously linked with retinal toxicity, paradoxically provided potent neuroprotective effects. In a light-induced degeneration model, tamoxifen prevented onset of photoreceptor apoptosis and atrophy and maintained near-normal levels of electroretinographic responses. Rescue effects were correlated with decreased microglial activation and inflammatory cytokine production in the retina in vivo and a reduction of microglia-mediated toxicity to photoreceptors in vitro, indicating a microglia-mediated mechanism of rescue. Tamoxifen also rescued degeneration in a genetic (Pde6brd10) model of RP, significantly improving retinal structure, electrophysiological responses, and visual behavior. These prominent neuroprotective effects warrant the consideration of tamoxifen as a drug suitable for being repurposed to treat photoreceptor degenerative disease. SIGNIFICANCE STATEMENT Photoreceptor degeneration is a cause of irreversible blindness in a number of retinal diseases such as retinitis pigmentosa (RP) and atrophic age-related macular degeneration. Tamoxifen, a selective estrogen receptor modulator approved for the treatment of breast cancer and previously linked to a low incidence of retinal toxicity, was unexpectedly found to exert marked protective effects against photoreceptor degeneration. Structural and functional protective effects were found for an acute model of light-induced photoreceptor injury and for a genetic model for RP. The mechanism of protection involved the modulation of microglial activation and the production of inflammatory cytokines, highlighting the role of inflammatory mechanisms in photoreceptor degeneration. Tamoxifen may be suitable for clinical study as a potential treatment for diseases involving photoreceptor degeneration. PMID:28235894

Plant toxicity, adaptive herbivory, and plant community dynamics

USGS Publications Warehouse

Feng, Z.; Liu, R.; DeAngelis, D.L.; Bryant, J.P.; Kielland, K.; Stuart, Chapin F.; Swihart, R.K.

2009-01-01

We model effects of interspecific plant competition, herbivory, and a plant's toxic defenses against herbivores on vegetation dynamics. The model predicts that, when a generalist herbivore feeds in the absence of plant toxins, adaptive foraging generally increases the probability of coexistence of plant species populations, because the herbivore switches more of its effort to whichever plant species is more common and accessible. In contrast, toxin-determined selective herbivory can drive plant succession toward dominance by the more toxic species, as previously documented in boreal forests and prairies. When the toxin concentrations in different plant species are similar, but species have different toxins with nonadditive effects, herbivores tend to diversify foraging efforts to avoid high intakes of any one toxin. This diversification leads the herbivore to focus more feeding on the less common plant species. Thus, uncommon plants may experience depensatory mortality from herbivory, reducing local species diversity. The depensatory effect of herbivory may inhibit the invasion of other plant species that are more palatable or have different toxins. These predictions were tested and confirmed in the Alaskan boreal forest. ?? 2009 Springer Science+Business Media, LLC.

Contact toxicity and residual effects of selected insecticides against the adult Paederus fuscipes (Coleoptera: Staphylinidae).

PubMed

Bong, Lee-Jin; Neoh, Kok-Boon; Jaal, Zairi; Lee, Chow-Yang

2013-12-01

The contact toxicity of four insecticide formulations (deltamethrin, fipronil, fenitrothion, and imidacloprid) applied on three different substrates (tile, plywood, and concrete) against the adult rove beetle, Paederus fuscipes Curtis, was evaluated. The relative order of speed of killing effects was as follows: deltamethrin > imidacloprid > fipronil > fenitrothion. Although deltamethrin showed the fastest action against P. fuscipes, the recovery rate of rove beetles at 48 h posttreatment was moderate (approximately 25%) on the tile surface to high (approximately 80%) on the plywood surface. Thus, it is likely that the insects did not pick up the lethal dose especially on porous surfaces. In contrast, fipronil demonstrated delayed toxicity that might promote maximal uptake by the insects. More than 80% mortality was registered for tile and plywood surfaces up to 4 wk after exposure. High mortality (almost 100%) was recorded for imidacloprid-exposed P. fuscipes at 48 h posttreatment, but only on the tile surface. Among the four insecticides tested, fenitrothion was the least effective against P. fuscipes because low percentage to no mortality was recorded in the fenitrothion treatment.

URBAN STORMWATER TOXIC POLLUTANTS: ASSESSMENT, SOURCES, AND TREATABILITY

EPA Science Inventory

This paper summarizes an investigation to characterize and treat selected storm water contaminants that are listed as toxic pollutants (termed toxicants in this paper) in the Clean Water Act, Section 307 (Arbuckle et al., 1991). The first project phase investigated typical toxica...

TOXIC TRACE METALS IN MAMMALIAN HAIR AND NAILS

EPA Science Inventory

Data have been compiled from the available world literature on the accumulation and bioconcentration of selected toxic trace metals in human hair and nails and other mammalian hair, fur, nails, claws, and hoofs. The toxic trace metals and metalloids include antimony, arsenic, bor...

Performance of toxicity probability interval based designs in contrast to the continual reassessment method

PubMed Central

Horton, Bethany Jablonski; Wages, Nolan A.; Conaway, Mark R.

2016-01-01

Toxicity probability interval designs have received increasing attention as a dose-finding method in recent years. In this study, we compared the two-stage, likelihood-based continual reassessment method (CRM), modified toxicity probability interval (mTPI), and the Bayesian optimal interval design (BOIN) in order to evaluate each method's performance in dose selection for Phase I trials. We use several summary measures to compare the performance of these methods, including percentage of correct selection (PCS) of the true maximum tolerable dose (MTD), allocation of patients to doses at and around the true MTD, and an accuracy index. This index is an efficiency measure that describes the entire distribution of MTD selection and patient allocation by taking into account the distance between the true probability of toxicity at each dose level and the target toxicity rate. The simulation study considered a broad range of toxicity curves and various sample sizes. When considering PCS, we found that CRM outperformed the two competing methods in most scenarios, followed by BOIN, then mTPI. We observed a similar trend when considering the accuracy index for dose allocation, where CRM most often outperformed both the mTPI and BOIN. These trends were more pronounced with increasing number of dose levels. PMID:27435150

University of Texas Southwestern Medical Center: NSCLC Cell Lines with Loss of SMARCA4 Expression are Hypersensitive to Inhibitors of Aurora Kinase A | Office of Cancer Genomics

Cancer.gov

A genome-wide siRNA screen was employed to identify genes that were selectively toxic for a non-small cell lung cancer (NSCLC) cell line that lacked expression of SMARCA4, but were not toxic in non-cancerous immortalized human bronchial epithelial cells lacking SMARCA4 expression. Among the selectively toxic genes were several mapping to the molecular machinery regulating activity of Aurora kinase A on the mitotic spindle.

University of Texas Southwestern Medical Center (UTSW): NSCLC Cell Lines with Loss of SMARCA4 Expression are Hypersensitive to Inhibitors of Aurora Kinase A | Office of Cancer Genomics

Cancer.gov

A genome-wide siRNA screen was employed to identify genes that were selectively toxic for a non-small cell lung cancer (NSCLC) cell line that lacked expression of SMARCA4, but were not toxic in non-cancerous immortalized human bronchial epithelial cells lacking SMARCA4 expression. Among the selectively toxic genes were several mapping to the molecular machinery regulating activity of Aurora kinase A on the mitotic spindle.

Analysis of Insect toxicity and repellent activity of Phytochemicals from "Skimmia laureola, Nair" against "Black garden ant, Lasius niger" of Pakistan.

PubMed

Mehmood, Ferhat; Khan, Zaheer-ud-Din; Manzoor, Farkhanda; Jamil, Muhammad

2016-05-01

A study was conducted to evaluate the toxicity and repellency of essential oils from root, stem and leaves of Nazar panra, Skimmia laureola (DC.) Zucc. Ex Walp. of family (Sapindales: Rutaceae) ver. Nair of Pakistan. The oils were tested at three concentrations i.e. 1, 5 and 10%. Black garden ant, Lasius niger L. (Hymenoptera: Formicidae) of Pakistan were selected and exposed to essential oils at room temperature. All essential oils showed Insecticidal activity with LC(50)=10.15, while dose dependant effect was significant with R(2)=0.98. It can be concluded that the three Essential oils in this study have both Insecticidal as well as repellent effect.

Acute and chronic systemic chromium toxicity.

PubMed

Gad, S C

1989-10-01

Although chromium and compounds containing it have been recognized as having potential severe adverse effects on health for more than 160 years, understanding of the systemic toxicology and true hazard of these compounds is still not complete. A review of the current state of knowledge is attempted in this paper, with appropriate attention given to the complications of multiple valence states and solubility. Selected chromium compounds, particularly hexavalent ones, are carcinogens, corrosives, delayed contact sensitizers, and have the kidney as their primary target organ. But chromium is also an essential element for humans. The body clearly possesses some effective detoxification mechanisms for some degree of exposure to hexavalent chrome compounds. The significant features of acute and chronic chromium toxicity are presented in view of these considerations.

Concentrations and geographical variations of selected toxic elements in meat from semi-domesticated reindeer (Rangifer tarandus tarandus L.) in mid- and northern Norway: evaluation of risk assessment.

PubMed

Hassan, Ammar Ali; Brustad, Magritt; Sandanger, Torkjel M

2012-05-01

Meat samples (n = 100) from semi-domesticated reindeer (Rangifer tarandus tarandus L.) were randomly collected from 10 grazing districts distributed over four Norwegian counties in 2008 and 2009. The main aim was to study concentrations and geographical variations in selected toxic elements; cadmium (Cd), lead (Pb), arsenic (As), copper (Cu), nickel (Ni) and vanadium (V) in order to assess the risk associated with reindeer meat consumption. Sample solutions were analysed using an inductively coupled plasma high resolution mass spectrometer (ICP-HRMS), whereas analysis of variance (ANOVA) was used for statistical analyses. Geographical variations in element concentrations were revealed, with As and Cd demonstrating the largest geographical differences. No clear geographical gradient was observed except for the east-west downward gradient for As. The As concentrations were highest in the vicinity of the Russian border, and only Cd was shown to increase with age (p < 0.05). Sex had no significant effect on the concentration of the studied elements. The concentrations of all the studied elements in reindeer meat were generally low and considerably below the maximum levels (ML) available for toxic elements set by the European Commission (EC). Thus, reindeer meat is not likely to be a significant contributor to the human body burden of toxic elements.

Concentrations and Geographical Variations of Selected Toxic Elements in Meat from Semi-Domesticated Reindeer (Rangifer tarandus tarandus L.) in Mid- and Northern Norway: Evaluation of Risk Assessment

PubMed Central

Hassan, Ammar Ali; Brustad, Magritt; Sandanger, Torkjel M.

2012-01-01

Meat samples (n = 100) from semi-domesticated reindeer (Rangifer tarandus tarandus L.) were randomly collected from 10 grazing districts distributed over four Norwegian counties in 2008 and 2009. The main aim was to study concentrations and geographical variations in selected toxic elements; cadmium (Cd), lead (Pb), arsenic (As), copper (Cu), nickel (Ni) and vanadium (V) in order to assess the risk associated with reindeer meat consumption. Sample solutions were analysed using an inductively coupled plasma high resolution mass spectrometer (ICP-HRMS), whereas analysis of variance (ANOVA) was used for statistical analyses. Geographical variations in element concentrations were revealed, with As and Cd demonstrating the largest geographical differences. No clear geographical gradient was observed except for the east-west downward gradient for As. The As concentrations were highest in the vicinity of the Russian border, and only Cd was shown to increase with age (p < 0.05). Sex had no significant effect on the concentration of the studied elements. The concentrations of all the studied elements in reindeer meat were generally low and considerably below the maximum levels (ML) available for toxic elements set by the European Commission (EC). Thus, reindeer meat is not likely to be a significant contributor to the human body burden of toxic elements. PMID:22754467

Toxicity of contaminated sediments in dilution series with control sediments

USGS Publications Warehouse

Nelson, M.K.; Landrum, P.F.; Burton, G.A.; Klaine, S.J.; Crecelius, E.A.; Byl, T.D.; Gossiaux, Duane C.; Tsymbal, V.N.; Cleveland, L.; Ingersoll, Christopher G.; Sasson-Brickson, G.

1993-01-01

The use of dilutions has been the foundation of our approach for assessing contaminated water, and accordingly, it may be important to establish similar or parallel approaches for sediment dilutions. Test organism responses to dilution gradients can identify the degree of necessary sediment alteration to reduce the toxicity. Using whole sediment dilutions to represent the complex interactions of in situ sediments can identify the toxicity, but the selection of the appropriate diluent for the contaminated sediment may affect the results and conclusions drawn. Contaminated whole sediments were examined to evaluate the toxicity of dilutions of sediments with a diversity of test organisms. Dilutions of the contaminated sediments were prepared with differing diluents that varied in organic carbon content, particle size distribution, and volatile solids. Studies were conducted using four macroinvertebrates and a vascular, rooted plant. Responses by some test organisms followed a sigmoidal dose-response curve, but others followed a U-shaped curve. Initial dilutions reduced toxicity as expected, but further dilution resulted in an increase in toxicity. The type of diluent used was an important factor in assessing the sediment toxicity, because the control soil reduced toxicity more effectively than sand as a diluent of the same sediment. Using sediment chemical and physical characteristics as an indicator of sediment dilution may not be as useful as chemical analysis of contaminants, but warrants further investigation.

Human exposure to neonicotinoid insecticides and the evaluation of their potential toxicity: An overview.

PubMed

Han, Wenchao; Tian, Ying; Shen, Xiaoming

2018-02-01

Neonicotinoid insecticides have become the fastest growing class of insecticides over the past few decades. The insecticidal activity of neonicotinoids is attributed to their agonist action on nicotinic acetylcholine receptors (nAChRs). Because of the special selective action on nAChRs in central nervous system of insects, and versatility in application methods, neonicotinoids are used to protect crops and pets from insect attacks globally. Although neonicotinoids are considered low toxicity to mammals and humans in comparison with traditional insecticides, more and more studies show exposure to neonicotinoids pose potential risk to mammals and even humans. In recent years, neonicotinoids and their metabolites have been successfully detected in various human biological samples. Meanwhile, many studies have focused on the health effects of neonicotinoids on humans. Our aims here are to review studies on human neonicotinoid exposure levels, health effect, evaluation of potential toxicity and to suggest possible directions for future research. Copyright © 2017 Elsevier Ltd. All rights reserved.

Development of Metal-impregnated Single Walled Carbon Nanotubes for Toxic Gas Contaminant Control in Advanced Life Support Systems

NASA Technical Reports Server (NTRS)

Pisharody, Suresh A.; Fisher, John W.; Wignarajah, K.

2002-01-01

The success of physico-chemical waste processing and resource recovery technologies for life support application depends partly on the ability of gas clean-up systems to efficiently remove trace contaminants generated during the process with minimal use of expendables. Carbon nanotubes promise superior performance over conventional approaches to gas clean-up due to their ability to direct the selective uptake of gaseous species based on their controlled pore size, high surface area, ordered chemical structure that allows functionalization and their effectiveness also as catalyst support materials for toxic gas conversion. We present results and findings from a preliminary study on the effectiveness of metal impregnated single walled nanotubes as catalyst/catalyst support materials for toxic gas contaminate control. The study included the purification of single walled nanotubes, the catalyst impregnation of the purified nanotubes, the experimental characterization of the surface properties of purified single walled nanotubes and the characterization of physisorption and chemisorption of uptake molecules.

The influence of 'time since last blood meal' on the toxicity of essential oils to the poultry red mite (Dermanyssus gallinae).

PubMed

George, D R; Smith, T J; Sparagano, O A E; Guy, J H

2008-08-17

The poultry red mite, Dermanyssus gallinae (De Geer) is a serious ectoparasitic pest of layer hens that can survive for long periods in the poultry house sub-structure without taking a blood meal from its host. The research undertaken in this study found that 'time since last blood meal' had a notable effect on how toxic a selection of plant essential oils were to D. gallinae under laboratory conditions. In general, the essential oils had a greater toxic effect on D. gallinae if mites had been starved of a blood meal for around 3 weeks, than if they had been more recently fed 3-13 days prior to tests. This result was consistent across the four essential oils used (thyme, palmarosa, caraway and juniper leaf). This suggests that plant essential oils may be of use in management schemes for D. gallinae, particularly if used to sanitise houses between flocks, when mites will have been starved.

Compatibility of endoparasitoid Hyposoter didymator (Hymenoptera: Ichneumonidae) protected stages with five selected insecticides.

PubMed

Medina, P; Morales, J J; Budia, F; Adan, A; Del Estal, P; Viñuela, E

2007-12-01

Hyposoter didymator (Thunberg) (Hymenoptera: Ichneumonidae) is a koinobiont endoparasitoid that emerges from the parasitization of economically important noctuid pests. H. didymator also is considered one of the most important native biocontrol agents of noctuids in Spain. Side effects of five insecticides with very different modes of action (fipronil, imidacloprid, natural pyrethrins + piperonyl butoxide, pymetrozine, and triflumuron) at the maximum field recommended rate in Spain were evaluated on H. didymator parasitizing Spodoptera littoralis (Boisduval) larvae and pupae of the endoparasitoid. Parasitized larvae were topically treated or ingested treated artificial diet. Parasitoid cocoons were topically treated. Host mortality when parasitized larvae were treated, as well as further development of the parasitoid surviving (e.g., percentage of cocoons spun, adult emergence, hosts attacked, and numbered progeny) were determined. Toxicity after treatment of parasitized larvae differed depending on the mode of exposure and insecticide. Fipronil was always highly toxic; imidacloprid killed all host insects by ingestion, but it was less toxic to both host and parasitoids, when administered topically; natural pyrethrins + piperonyl butoxide and triflumuron showed differing degrees of toxicity, and pymetrozine was harmless. Parasitoid cocoons provided effective protection against all the insecticides, except fipronil.

Estimation of Potential Population Level Effects of Contaminants on Wildlife

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

Loar, J.M.

2001-06-11

The objective of this project is to provide DOE with improved methods to assess risks from contaminants to wildlife populations. The current approach for wildlife risk assessment consists of comparison of contaminant exposure estimates for individual animals to literature-derived toxicity test endpoints. These test endpoints are assumed to estimate thresholds for population-level effects. Moreover, species sensitivities to contaminants is one of several criteria to be considered when selecting assessment endpoints (EPA 1997 and 1998), yet data on the sensitivities of many birds and mammals are lacking. The uncertainties associated with this approach are considerable. First, because toxicity data are notmore » available for most potential wildlife endpoint species, extrapolation of toxicity data from test species to the species of interest is required. There is no consensus on the most appropriate extrapolation method. Second, toxicity data are represented as statistical measures (e.g., NOAEL s or LOAELs) that provide no information on the nature or magnitude of effects. The level of effect is an artifact of the replication and dosing regime employed, and does not indicate how effects might increase with increasing exposure. Consequently, slight exceedance of a LOAEL is not distinguished from greatly exceeding it. Third, the relationship of toxic effects on individuals to effects on populations is poorly estimated by existing methods. It is assumed that if the exposure of individuals exceeds levels associated with impaired reproduction, then population level effects are likely. Uncertainty associated with this assumption is large because depending on the reproductive strategy of a given species, comparable levels of reproductive impairment may result in dramatically different population-level responses. This project included several tasks to address these problems: (1) investigation of the validity of the current allometric scaling approach for interspecies extrapolation an d development of new scaling models; (2) development of dose-response models for toxicity data presented in the literature; and (3) development of matrix-based population models that were coupled with dose-response models to provide realistic estimation of population-level effects for individual responses.« less

Toxicant content, physical properties and biological activity of waterpipe tobacco smoke and its tobacco-free alternatives

PubMed Central

Shihadeh, Alan; Schubert, Jens; Klaiany, Joanne; El Sabban, Marwan; Luch, Andreas; Saliba, Najat A

2015-01-01

Objectives Waterpipe smoking using sweetened, flavoured tobacco products has become a widespread global phenomenon. In this paper, we review chemical, physical and biological properties of waterpipe smoke. Data sources Peer-reviewed publications indexed in major databases between 1991 and 2014. Search keywords included a combination of: waterpipe, narghile, hookah, shisha along with names of chemical compounds and classes of compounds, in addition to terms commonly used in cellular biology and aerosol sizing. Study selection The search was limited to articles published in English which reported novel data on waterpipe tobacco smoke (WTS) toxicant content, biological activity or particle size and which met various criteria for analytical rigour including: method specificity and selectivity, precision, accuracy and recovery, linearity, range, and stability. Data extraction Multiple researchers reviewed the reports and collectively agreed on which data were pertinent for inclusion. Data synthesis Waterpipe smoke contains significant concentrations of toxicants thought to cause dependence, heart disease, lung disease and cancer in cigarette smokers, and includes 27 known or suspected carcinogens. Waterpipe smoke is a respirable aerosol that induces cellular responses associated with pulmonary and arterial diseases. Except nicotine, smoke generated using tobacco-free preparations marketed for ‘health conscious’ users contains the same or greater doses of toxicants, with the same cellular effects as conventional products. Toxicant yield data from the analytical laboratory are consistent with studies of exposure biomarkers in waterpipe users. Conclusions A sufficient evidence base exists to support public health interventions that highlight the fact that WTS presents a serious inhalation hazard. PMID:25666550

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

Health effects research in direct coal liquefaction. Studies of H-coal distillates: Phase I. PDU samples - the effects of hydrotreatment

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

Epler, J.L.; Fry, R.J.M.; Larimer, F.W.

1981-11-01

A multi-divisional effort aimed at the integrated assessment of the health and environmental effects of various coal conversion and shale oil technologies is being carried out. The feasibility of using health effects bioassays to predict the potential biohazard of various H-Coal derived test materials is examined in a coupled chemical and biological approach. The primary focus of the research is the use of preliminary chemical characterizations and preparation for bioassay, followed by testing in short-term assays in order to rapidly ascertain the potential biohazard. Mammalian toxicological assays parallel the testing. Raw and hydrotreated product liquids from process development units ofmore » H-Coal and the pilot plant solvent refined coal process were examined for acute toxicity monitored as population growth impairment of Tetrahymena exposed to aqueous extracts and for mutagenic activity monitored as revertants of Salmonella exposed to metabolically activated chemical class fractions. Medium to high severity hydrotreatment appears to be an effective means of reducing biological activity, presumably by reducing the aromaticity and heteroatom content. Five basic mammalian, acute toxicity tests have been conducted with selected H-coal samples and shale oil derivatives. The data show that H-Coal samples are moderately toxic whereas the toxicity of shale oil derived products is slight and comparable to samples obtained from naturally occurring petroleums. No overt skin or eye toxicity was found. The present data reveal that coal-derived distillates generated by the H-coal process are highly carcinogenic to mouse skin. An extreme form of neurotoxicity associated with dermal exposure to one of the lighter, minimally carcinogenic, materials was noted. (DMC)« less

Aquatic toxicity of petroleum products and dispersant agents ...

EPA Pesticide Factsheets

The U.S. EPA Office of Research and Development has developed baseline data on the ecotoxicity of selected petroleum products and several chemical dispersants as part of its oil spills research program. Two diluted bitumens (dilbits) from the Alberta Tar Sands were tested for acute and chronic toxicity to standard freshwater and marine organisms given their spill potential during shipment within the United States. Separately, two reference crude oils representing a range of characteristics, and their mixtures with four representative dispersants, were tested to evaluate acute and chronic toxicity to marine organisms in support of Subpart J of the U.S. National Contingency Plan. Water accommodated fractions (WAF) of oil were prepared using traditional slow-stir methods and toxicity tests generally followed U.S. EPA standard effluent testing guidelines. WAFs were characterized for petroleum hydrocarbons including alkyl PAH homologs. The results of these studies will assist the U.S. EPA to assess toxicity data for unconventional oils (dilbits), and establish baseline toxicity data for selected crude oils and dispersant in support of planning and response activities. Abstract reporting the results of EPA's oil and dispersant toxicity testing program

Proposing Novel MAO-B Hit Inhibitors Using Multidimensional Molecular Modeling Approaches and Application of Binary QSAR Models for Prediction of Their Therapeutic Activity, Pharmacokinetic and Toxicity Properties.

PubMed

Is, Yusuf Serhat; Durdagi, Serdar; Aksoydan, Busecan; Yurtsever, Mine

2018-05-07

Monoamine oxidase (MAO) enzymes MAO-A and MAO-B play a critical role in the metabolism of monoamine neurotransmitters. Hence, MAO inhibitors are very important for the treatment of several neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). In this study, 256 750 molecules from Otava Green Chemical Collection were virtually screened for their binding activities as MAO-B inhibitors. Two hit molecules were identified after applying different filters such as high docking scores and selectivity to MAO-B, desired pharmacokinetic profile predictions with binary quantitative structure-activity relationship (QSAR) models. Therapeutic activity prediction as well as pharmacokinetic and toxicity profiles were investigated using MetaCore/MetaDrug platform which is based on a manually curated database of molecular interactions, molecular pathways, gene-disease associations, chemical metabolism, and toxicity information. Particular therapeutic activity and toxic effect predictions are based on the ChemTree ability to correlate structural descriptors to that property using recursive partitioning algorithm. Molecular dynamics (MD) simulations were also performed to make more detailed assessments beyond docking studies. All these calculations were made not only to determine if studied molecules possess the potential to be a MAO-B inhibitor but also to find out whether they carry MAO-B selectivity versus MAO-A. The evaluation of docking results and pharmacokinetic profile predictions together with the MD simulations enabled us to identify one hit molecule (ligand 1, Otava ID: 3463218) which displayed higher selectivity toward MAO-B than a positive control selegiline which is a commercially used drug for PD therapeutic purposes.

In Vitro Methods To Measure Toxicity Of Chemicals

DTIC Science & Technology

2004-12-01

industrial compounds for toxicity will require high-throughput in vitro assays with which to select candidate compounds for more intensive animal...for estimating the starting dose for the rat oral acute toxicity test, thus reducing and refining the use of animals in the toxicological

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

The studies on the toxicity mechanism of environmentally hazardous natural (IAA) and synthetic (NAA) auxin--The experiments on model Arabidopsis thaliana and rat liver plasma membranes.

PubMed

Hąc-Wydro, Katarzyna; Flasiński, Michał

2015-06-01

This paper concerns the studies towards membrane-damage effect of two auxins: indole-3-acetic acid - IAA and 1-naphthaleneacetic acid - NAA on plant (Arabidopsis thaliana) and animal (rat liver) model membranes. The foregoing auxins are plant growth regulators widely used in agriculture to control the quality of the crop. However, their accumulation in the environment makes them hazardous for the living organisms. The aim of our investigations was to compare the effect of natural (IAA) vs. synthetic (NAA) auxin on the organization of plant and animal model membranes and find a possible correlation between membrane-disturbing effect of these compounds and their toxicity. The collected data evidenced that auxins cause destabilization of membranes, decrease their condensation and weakens interactions of molecules. The alterations in the morphology of model systems were also noticed. The foregoing effects of auxins are concentration-dependent and additionally NAA was found to act on animal vs. plant membranes more selectively than IAA. Interestingly, both IAA and NAA induce the strongest disordering in model lipid system at the concentration, which is frequently reported as toxic to animal and plants. Based on the above findings it was proposed that membrane-damage effect induced by IAA and NAA may be important from the point of view of the mechanism of toxicity of these compounds and cannot be ignored in further investigations in this area. Copyright © 2015 Elsevier B.V. All rights reserved.

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

Cytotoxicity and therapeutic effect of irinotecan combined with selenium nanoparticles.

PubMed

Gao, Fuping; Yuan, Qing; Gao, Liang; Cai, Pengju; Zhu, Huarui; Liu, Ru; Wang, Yaling; Wei, Yueteng; Huang, Guodong; Liang, Jian; Gao, Xueyun

2014-10-01

Although chemotherapeutic drugs are widely applied for clinic tumor treatment, severe toxicity restricts their therapeutic efficacy. In this study, we reported a new form of selenium, selenium nanoparticles (Nano Se) which have significant lower toxicity and acceptable bioavailability. We investigated Nano Se as chemotherapy preventive agent to protect against toxicities of anticancer drug irinotecan and synergistically enhance the anti-tumor treatment effect in vitro and in vivo. The underlying mechanisms were also investigated. The combination of Nano Se and irinotecan showed increased cytotoxic effect with HCT-8 tumor cells likely by p53 mediated apoptosis. Nano Se inhibited growth of HCT-8 tumor cells partially through caspases mediated apoptosis. In vivo experiment showed Nano Se at a dose of 4 mg/kg/day significantly alleviated adverse effects induced by irinotecan (60 mg/kg) treatment. Nano Se alone treatment did not induce any toxic manifestations. The combination of Nano Se and irinotecan dramatically inhibited tumor growth and significantly induced apoptosis of tumor cells in HCT-8 cells xenografted tumor. Tumor inhibition rate was about 17.2%, 48.6% and 62.1% for Nano Se, irinotecan and the combination of Nano Se and irinotecan, respectively. The beneficial effects of Nano Se for tumor therapy were mainly ascribed to selectively regulating Nrf2-ARE (antioxidant responsive elements) pathway in tumor tissues and normal tissues. Our results suggest Nano Se is a promising selenium species with potential application in cancer treatment. Copyright © 2014 Elsevier Ltd. All rights reserved.

Evaluation of toxicity to the amphipod, Hyalella azteca, and to the midge, Chironomus dilutus; and bioaccumulation by the oligochaete, Lumbriculus variegatus, with exposure to PCB-contaminated sediments from Anniston, Alabama

USGS Publications Warehouse

Ingersoll, Christopher G.; Steevens, Jeffery A.; MacDonald, Donald D.; Brumbaugh, William G.; Coady, Matthew R.; Farrar, J. Daniel; Lotufo, Guilherme R.; Kemble, Nile E.; Kunz, James L.; Stanley, Jacob K.; Sinclair, Jesse A.; Ingersoll, Christopher G.; Steevens, Jeffery A.; MacDonald, Donald D.

2014-01-01

The U.S. Environmental Protection Agency (USEPA) requested that as part of the remedial investigation for the Anniston, Alabama Polychlorinated Biphenyl (PCB) Site (Anniston PCB Site), that Pharmacia Corporation and Solutia Inc. (P/S) perform long-term reproduction toxicity tests with the amphipod, Hyalella azteca, and the midge, Chironomus dilutus, and bioaccumulation tests with the oligochaete, Lumbriculus variegatus, using sediment samples collected from reference locations and from Operable Unit 4 of the Anniston PCB Site. The sediment toxicity testing and sediment bioaccumulation results will be used by ARCADIS U.S., Inc. (ARCADIS) as part of a weight-of-evidence assessment to evaluate risks and establish sediment remediation goals for contaminants to sediment-dwelling organisms inhabiting the Anniston PCB Site. The goal of this study was to characterize relations between sediment chemistry and sediment toxicity and relations between sediment chemistry and sediment bioaccumulation in samples of sediments collected from the Anniston PCB Site. A total of 32 samples were evaluated from six test sites and one reference site to provide a wide range in concentrations of chemicals of potential concern (COPCs) including PCBs in samples of whole sediment. The goal of this study was not to determine the extent of sediment contamination across the Anniston PCB Site. Hence, the test sites or samples collected from within a test site were not selected to represent the spatial extent of sediment contamination across the Anniston PCB Site. Sediment chemistry, pore-water chemistry, and sediment toxicity data were generated for 26 sediment samples from the Anniston PCB Site. All of the samples were evaluated to determine if they qualified as reference sediment samples. Those samples that met the chemical selection criteria and biological selection criteria were identified as reference samples and used to develop the reference envelope for each toxicity test endpoint. Physical characterization of samples of whole sediment included analyses of grain size, TOC, and nutrients. Organic chemical characterization of samples of whole sediment included PCB homologs and select (13) PCB congeners, parent and alkylated polycyclic aromatic hydrocarbons (PAHs), organochlorine pesticides, and polychlorinated dibenzo-p-dioxins; and dibenzofurans. The PCB aroclors analyzed included 1016, 1221, 1232, 1242, 1248, 1254, 1260, 1262 and 1268. Analyses of whole sediment also included total metals, simultaneously extracted metals, and acid volatile sulfide. Chemical characterization of samples of pore water isolated from samples of whole sediment at the start of the sediment toxicity exposures or at the start of the sediment bioaccumulation exposures included metals, major cations, major anions, dissolved organic carbon, and additional water-quality characteristics. Concentrations of metals or PCBs in pore water during the sediment toxicity exposures or during sediment bioaccumulation exposures also were determined using peeper samples (for metals) or solid-phase microextraction (SPME) samplers (for PCBs). The bioavailability and bioaccumulation of PCBs in 14 sediment samples were investigated using SPME passive samplers and the 28-d L. variegatus whole-sediment bioaccumulation exposures In general the accumulation of PCBs consistently was predicted through the use of organic carbon normalization and equilibrium partitioning. In these sediments, PCB homologs were accumulated differently based on bioavailability and potential to accumulate in oligochaetes. As part of this assessment homolog specific biota sediment accumulation factor values were developed that could be applied across the larger site to predict tissue levels of PCBs. The whole-sediment toxicity tests done with H. azteca and C. dilutus met the established ASTM and USEPA test acceptability criteria. The most responsive H. azteca endpoints were day 42 survival normalized young per female and day 28 biomass and that the most responsive C. dilutus endpoints were adult biomass and percent adult emergence. Overall, between the two species, the most responsive endpoint assessed for these two species was H. azteca survival-normalized young per female (67 percent of the samples classified as toxic). Concentration-response models (CRMs) and site-specific sediment toxicity thresholds (TTs) were generated with matching sediment chemistry and sediment toxicity data. Sediment chemistry, pore-water chemistry, and sediment toxicity data were evaluated for as many as 26 sediment samples from the Anniston PCB Site. The reference-envelope approach was used to identify the sediment samples that were toxic to benthic invertebrates. This procedure involved identification of reference sediment samples, normalizing the toxicity data to reflect control responses, developing a reference envelope for each toxicity test endpoint, and designating each sediment sample as toxic or not toxic for each toxicity test endpoint, for each species, and for all species combined. These results demonstrated percent emergence of adult C. dilutus, biomass of adult C. dilutus, and reproduction of H. azteca normalized to percent survival were among the most responsive endpoints that were evaluated. Therefore, these endpoints were selected for CRM development. The site-specific TTs for whole sediment provide a reliable basis for identifying toxic and not toxic sediment samples in the Anniston PCB Site (that is, for correctly classifying the sediment samples used to derive the TTs as toxic or not toxic, for the endpoint used to derive the TTs). Among the 69 TTs for sediment, the TTLRs for total PCB homologs [499 to 1,870 micrograms per kilogram dry weight (μg/kg DW)] and for lead [(9.48 to 10.3 milligrams per kilogram (mg/kg) DW] based on reproduction of H. azteca or based on emergence or biomass of adult C. dilutus, were the most reliable. Such TTs had low rates of false negative errors (that is, only 0 to 11 percent of the samples below the TT were toxic to benthic invertebrates), low rates of false positive errors (only 0 to 6 percent of the samples greater than the TT were not toxic to benthic invertebrates), and high rates of correct classification (that is, 92 to 96 percent). The site-specific TTs for PCBs and other COPCs derived in this study also were compared to empirically based sediment quality guidelines (SQGs), to equilibrium-partitioning based SQGs, and to the results of spiked-sediment toxicity tests. The results of this evaluation indicated that the site-specific sediment TTs for PCBs were comparable to the consensus-based SQGs that were derived for PCBs. In addition, the site-specific sediment TTs for PCBs are well within the range of SQGs derived using the equilibrium partitioning approach. The site-specific sediment TTs for PCBs also are consistent with the results of chronic TTs that have been estimated for benthic invertebrates using the results of spiked-sediment toxicity tests. As the site-specific sediment TTs for PCBs are consistent with empirically based SQGs, equilibrium-partitioning based SQGs, and results of sediment-spiking studies, these site- specific sediment TTs likely represent the concentrations of PCBs that are sufficient to cause toxicity to benthic invertebrates (as opposed to simply being correlated with adverse effects on the survival, weight, or reproduction of benthic invertebrates). Importantly, such site-specific sediment TTs have been demonstrated to accurately classify sediment samples as toxic or not toxic to benthic invertebrates at the Anniston PCB Site. In contrast, the TTs for metals, PAHs, and organochlorine pesticides were generally lower than consensus-based SQGs (that is, probable effect concentrations), and LC50s (median lethal effect concentrations) generated in spiked-sediment toxicity tests, indicating that these COPCs are likely not the main contributors to the observed toxicity of the site sediments evaluated in this study. The reproduction endpoint for H. azteca provided lower TTs compared to the day 28 biomass endpoint for H. azteca and the emergence or biomass endpoints for adult C. dilutus provided lower TTs compared to the day 13 biomass endpoint for C. dilutus.

[Characteristics of heritability and effect of selection on prevalence of diffuse-toxic goiter in population].

PubMed

Shtandel', S A; Gopkalova, I V; Khaziev, V V; Dubovik, V N; Svetlova-Kovalenko, E A

2009-01-01

On genealogic data about 242 Gravers disease patients, fertility parameters of 2105 healthy and 369 Grave's disease women peculiarities of genetic determination and natural selection of disease were studied. Results of the genetic analysis have revealed conformity of Grave's disease inheritance to alternative model parameters. Homozygote penetrance within the framework of this model was 78.8%, heterozygote--17.3%. For one generation in the Kharkov area population frequency of a gene to Grave's disease predisposition increases 0.8%.

Materials safety data sheets the basis for control of toxic chemicals. Volume II

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

Bolton, N. E.; Ketchen, E. E.; Porter, W. E.

For large industrial and research operations, maintaining reasonable control of all toxic materials used in their operations can be a formidable task. A system utilizing cards has been developed that serves a dual purpose, informing the user regarding hazards of a particular material and also facilitating appropriate workplace surveillance during its use. Selected data, including threshold limit values, routes of absorption, symptoms of exposure, chronic effects, and emergency first-aid procedures, are printed on the card. A portion of the card contains the label that the user detaches and affixes to the container. This label classifies the material according to flammability,more » toxicity, reactivity, and special properties on a 0 through 4 hazard rating system. This report describes the development and use of such cards, contains the associated Toxic Material Data Sheets that provide full backup data for the labels, and furnishes a glossary of biomedical terms used in the Data Sheets.« less

myo-Inositol and Phytate Are Toxic to Formosan Subterranean Termites (Isoptera: Rhinotermitidae).

PubMed

Veillon, Lucas; Bourgeois, Jared; Leblanc, Amanda; Henderson, Gregg; Marx, Brian D; Muniruzzaman, Syed; Laine, Roger A

2014-10-01

Several rare and common monosaccharides were screened for toxic effects on the Formosan subterranean termite, Coptotermes formosanus Shiraki, with the aim of identifying environmentally friendly termiticides. myo-Inositol and phytic acid, which are nontoxic to mammals, were identified as potential termite control compounds. Feeding bioassays with termite workers, where both compounds were supplied on filter paper in concentrations from 160.2 to 1,281.7 μg/mm(3), showed concentration-dependent toxicity within 2 wk. Interestingly myo-inositol was nontoxic when administered to termites in agar (40 mg/ml) in the absence of a cellulosic food source, an unexplained phenomenon. In addition, decreased populations of termite hindgut protozoa were observed upon feeding on myo-inositol but not phytate-spiked filter paper. Radiotracer feeding studies using myo-inositol-[2-(3)H] with worker termites showed no metabolism after ingestion over a 2-d feeding period, ruling out metabolites responsible for the selective toxicity. © 2014 Entomological Society of America.

Difference of toxicity and accumulation of methylated and inorganic arsenic in arsenic-hyperaccumulating and -hypertolerant plants.

PubMed

Huang, Ze-Chun; Chen, Tong-Bin; Lei, Mei; Liu, Ying-Ru; Hu, Tian-Dou

2008-07-15

The arsenic (As) hyperaccumulators, Pteris vittata and Pteris cretica and an As-tolerant plant Boehmeria nivea, were selected to compare the toxicity, uptake, and transportation of inorganic arsenate (As(V)) and its methylated counterpart dimethylarsinic acid (DMA). The XANES method was used to elucidate the effect of As species transformation on As toxicity and accumulation characteristics. Significantly higher toxicity and lower accumulation of DMAthan inorganic As(V) was shown in the As hyperaccumulators and the As-tolerant plant. Reduction of As(V) was commonly found in the plants. Arsenic complexation with thiols, which have less mobility in plants and usually occur in As-tolerant plants, was also found in rhizoids of P. cretica. Plants with greater ability to form As-thiolate have lower ability for upward transport of As. Demethylation of DMA occurred in the three plants. The DMA component decreased from the rhizoids to the fronds in both hyperaccumulators, while this tendency is reverse in B. nivea.

Preclinical evaluation of anti-HIV microbicide products: New models and biomarkers.

PubMed

Doncel, Gustavo F; Clark, Meredith R

2010-12-01

A safe and effective microbicide product designed to prevent sexual transmission of HIV-1 rests on a solid foundation provided by the proper selection and preclinical characterization of both its active pharmaceutical ingredient (API) and formulation. The evaluation of API and formulation physicochemical properties, drug release, specific antiviral activity, cell and tissue toxicity, organ toxicity, pharmacokinetics, and pharmacodynamics and efficacy provides information to understand the product, make go/no go decisions in the critical path of product development and complete a regulatory dossier to file an investigational new drug (IND) with the US Food and Drug Administration. Incorporation of new models, assays and biomarkers has expanded our ability to understand the mechanisms of action underlying microbicide toxicity and efficacy, enabling a more rational selection of drug and formulation candidates. This review presents an overview of the models and endpoints used to comprehensively evaluate an anti-HIV microbicide in preclinical development. This article forms part of a special supplement on presentations covering HIV transmission and microbicides, based on the symposium "Trends in Microbicide Formulations", held on 25 and 26 January 2010, Arlington, VA. Copyright © 2010 Elsevier B.V. All rights reserved.

Integrating in silico models to enhance predictivity for developmental toxicity.

PubMed

Marzo, Marco; Kulkarni, Sunil; Manganaro, Alberto; Roncaglioni, Alessandra; Wu, Shengde; Barton-Maclaren, Tara S; Lester, Cathy; Benfenati, Emilio

2016-08-31

Application of in silico models to predict developmental toxicity has demonstrated limited success particularly when employed as a single source of information. It is acknowledged that modelling the complex outcomes related to this endpoint is a challenge; however, such models have been developed and reported in the literature. The current study explored the possibility of integrating the selected public domain models (CAESAR, SARpy and P&G model) with the selected commercial modelling suites (Multicase, Leadscope and Derek Nexus) to assess if there is an increase in overall predictive performance. The results varied according to the data sets used to assess performance which improved upon model integration relative to individual models. Moreover, because different models are based on different specific developmental toxicity effects, integration of these models increased the applicable chemical and biological spaces. It is suggested that this approach reduces uncertainty associated with in silico predictions by achieving a consensus among a battery of models. The use of tools to assess the applicability domain also improves the interpretation of the predictions. This has been verified in the case of the software VEGA, which makes freely available QSAR models with a measurement of the applicability domain. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Biotic interactions govern genetic adaptation to toxicants

PubMed Central

Becker, Jeremias Martin; Liess, Matthias

2015-01-01

The genetic recovery of resistant populations released from pesticide exposure is accelerated by the presence of environmental stressors. By contrast, the relevance of environmental stressors for the spread of resistance during pesticide exposure has not been studied. Moreover, the consequences of interactions between different stressors have not been considered. Here we show that stress through intraspecific competition accelerates microevolution, because it enhances fitness differences between adapted and non-adapted individuals. By contrast, stress through interspecific competition or predation reduces intraspecific competition and thereby delays microevolution. This was demonstrated in mosquito populations (Culex quinquefasciatus) that were exposed to the pesticide chlorpyrifos. Non-selective predation through harvesting and interspecific competition with Daphnia magna delayed the selection for individuals carrying the ace-1R resistance allele. Under non-toxic conditions, susceptible individuals without ace-1R prevailed. Likewise, predation delayed the reverse adaptation of the populations to a non-toxic environment, while the effect of interspecific competition was not significant. Applying a simulation model, we further identified how microevolution is generally determined by the type and degree of competition and predation. We infer that interactions with other species—especially strong in ecosystems with high biodiversity—can delay the development of pesticide resistance. PMID:25833856

Divalent Naphthalene Diimide Ligands Display High Selectivity for the Human Telomeric G‐quadruplex in K+ Buffer

PubMed Central

Street, Steven T. G.; Chin, Donovan N.; Hollingworth, Gregory J.; Berry, Monica

2017-01-01

Abstract Selective G‐quadruplex ligands offer great promise for the development of anti‐cancer therapies. A novel series of divalent cationic naphthalene diimide ligands that selectively bind to the hybrid form of the human telomeric G‐quadruplex in K+ buffer are described herein. We demonstrate that an imidazolium‐bearing mannoside‐conjugate is the most selective ligand to date for this quadruplex against several other quadruplex and duplex structures. We also show that a similarly selective methylpiperazine‐bearing ligand was more toxic to HeLa cancer cells than doxorubicin, whilst exhibiting three times less toxicity towards fetal lung fibroblasts WI‐38. PMID:28257554

Alleviating Cancer Drug Toxicity by Inhibiting a Bacterial Enzyme

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

Wallace, Bret D.; Wang, Hongwei; Lane, Kimberly T.

2011-08-12

The dose-limiting side effect of the common colon cancer chemotherapeutic CPT-11 is severe diarrhea caused by symbiotic bacterial {beta}-glucuronidases that reactivate the drug in the gut. We sought to target these enzymes without killing the commensal bacteria essential for human health. Potent bacterial {beta}-glucuronidase inhibitors were identified by high-throughput screening and shown to have no effect on the orthologous mammalian enzyme. Crystal structures established that selectivity was based on a loop unique to bacterial {beta}-glucuronidases. Inhibitors were highly effective against the enzyme target in living aerobic and anaerobic bacteria, but did not kill the bacteria or harm mammalian cells. Finally,more » oral administration of an inhibitor protected mice from CPT-11-induced toxicity. Thus, drugs may be designed to inhibit undesirable enzyme activities in essential microbial symbiotes to enhance chemotherapeutic efficacy.« less

Alleviating Cancer Drug Toxicity by Inhibiting a Bacterial Enzyme

PubMed Central

Wallace, Bret D.; Wang, Hongwei; Lane, Kimberly T.; Scott, John E.; Orans, Jillian; Koo, Ja Seol; Venkatesh, Madhukumar; Jobin, Christian; Yeh, Li-An; Mani, Sridhar; Redinbo, Matthew R.

2011-01-01

The dose-limiting side effect of the common colon cancer chemotherapeutic CPT-11 is severe diarrhea caused by symbiotic bacterial β-glucuronidases that reactivate the drug in the gut. We sought to target these enzymes without killing the commensal bacteria essential for human health. Potent bacterial β-glucuronidase inhibitors were identified by high-throughput screening and shown to have no effect on the orthologous mammalian enzyme. Crystal structures established that selectivity was based on a loop unique to bacterial β-glucuronidases. Inhibitors were highly effective against the enzyme target in living aerobic and anaerobic bacteria, but did not kill the bacteria or harm mammalian cells. Finally, oral administration of an inhibitor protected mice from CPT-11–induced toxicity. Thus, drugs may be designed to inhibit undesirable enzyme activities in essential microbial symbiotes to enhance chemotherapeutic efficacy. PMID:21051639

Alleviating cancer drug toxicity by inhibiting a bacterial enzyme.

PubMed

Wallace, Bret D; Wang, Hongwei; Lane, Kimberly T; Scott, John E; Orans, Jillian; Koo, Ja Seol; Venkatesh, Madhukumar; Jobin, Christian; Yeh, Li-An; Mani, Sridhar; Redinbo, Matthew R

2010-11-05

The dose-limiting side effect of the common colon cancer chemotherapeutic CPT-11 is severe diarrhea caused by symbiotic bacterial β-glucuronidases that reactivate the drug in the gut. We sought to target these enzymes without killing the commensal bacteria essential for human health. Potent bacterial β-glucuronidase inhibitors were identified by high-throughput screening and shown to have no effect on the orthologous mammalian enzyme. Crystal structures established that selectivity was based on a loop unique to bacterial β-glucuronidases. Inhibitors were highly effective against the enzyme target in living aerobic and anaerobic bacteria, but did not kill the bacteria or harm mammalian cells. Finally, oral administration of an inhibitor protected mice from CPT-11-induced toxicity. Thus, drugs may be designed to inhibit undesirable enzyme activities in essential microbial symbiotes to enhance chemotherapeutic efficacy.

JEM spotlight: Monitoring the treatment efficiency of a full scale ozonation on a sewage treatment plant with a mode-of-action based test battery.

PubMed

Escher, Beate I; Bramaz, Nadine; Ort, Christoph

2009-10-01

Tertiary treatment of wastewater with ozone is a promising technique for removing residual micropollutants that remain after secondary biological treatment. We monitored the performance of a full-scale ozonation reactor on a sewage treatment plant in Switzerland with a screening battery of bioassays. Six toxicity endpoints were selected that covered non-specific toxicity, as well as selected receptor-mediated modes of action and reactive toxicity. Non-specific toxicity was assessed with two bioassays, the bioluminescence inhibition of the marine luminescent bacterium Vibrio Fischeri and the growth inhibition of the green algae Pseudokirchneriella subcapitata. Treatment efficiency was around 90% for the secondary treatment, but only 65% and 76% for the ozonation step in the two non-specific endpoints, respectively. This finding is consistent with this type of oxidation reaction because ozone only modifies the organic molecules but does not mineralize them fully leaving residual toxicity of the transformation products. In contrast, the specific receptor-mediated endpoints of inhibition of photosystem II in algae and estrogenicity were largely reduced by ozonation. While compounds inhibiting photosynthesis proved to be rather recalcitrant toward biological treatment with only 47% removal, an additional 86% removal by ozonation yielded an overall treatment efficiency in the entire treatment chain of 89%. The effect on estrogenicity, quantified with the yeast estrogen screen, was even more significant: A treatment efficiency of 95% in the secondary treatment, 86% during ozonation plus a small effect by biological sand filtration yielded an overall treatment efficiency of 99.5%. Insecticides that inhibit acetylcholinesterase were fairly resistant to degradation, but an overall treatment efficiency of 91% was achieved in two steps: 72% in biological treatment and 60% during ozonation. Finally, no significant genotoxicity was observed with the umuC test after ozonation, while the influent showed a genotoxic response when it was enriched by a factor of 15 to 60. Treatment efficiency increased with the ozone dose and remained virtually unchanged over ozone doses above 500 g ozone per kg dissolved organic carbon. The reduction of toxicity can be rationalized by the chemical oxidation processes likely to occur for each group of chemicals that are typical for a given mode of toxic action. For comparison, tertiary treatment with powdered activated carbon was also evaluated, which poses a viable alternative to ozonation with respect to removal of micropollutants.

Physical linkage of metabolic genes in fungi is an adaptation against the accumulation of toxic intermediate compounds.

PubMed

McGary, Kriston L; Slot, Jason C; Rokas, Antonis

2013-07-09

Genomic analyses have proliferated without being tied to tangible phenotypes. For example, although coordination of both gene expression and genetic linkage have been offered as genetic mechanisms for the frequently observed clustering of genes participating in fungal metabolic pathways, elucidation of the phenotype(s) favored by selection, resulting in cluster formation and maintenance, has not been forthcoming. We noted that the cause of certain well-studied human metabolic disorders is the accumulation of toxic intermediate compounds (ICs), which occurs when the product of an enzyme is not used as a substrate by a downstream neighbor in the metabolic network. This raises the hypothesis that the phenotype favored by selection to drive gene clustering is the mitigation of IC toxicity. To test this, we examined 100 diverse fungal genomes for the simplest type of cluster, gene pairs that are both metabolic neighbors and chromosomal neighbors immediately adjacent to each other, which we refer to as "double neighbor gene pairs" (DNGPs). Examination of the toxicity of their corresponding ICs shows that, compared with chromosomally nonadjacent metabolic neighbors, DNGPs are enriched for ICs that have acutely toxic LD50 doses or reactive functional groups. Furthermore, DNGPs are significantly more likely to be divergently oriented on the chromosome; remarkably, ∼40% of these DNGPs have ICs known to be toxic. We submit that the structure of synteny in metabolic pathways of fungi is a signature of selection for protection against the accumulation of toxic metabolic intermediates.

Physical linkage of metabolic genes in fungi is an adaptation against the accumulation of toxic intermediate compounds

PubMed Central

McGary, Kriston L.; Slot, Jason C.; Rokas, Antonis

2013-01-01

Genomic analyses have proliferated without being tied to tangible phenotypes. For example, although coordination of both gene expression and genetic linkage have been offered as genetic mechanisms for the frequently observed clustering of genes participating in fungal metabolic pathways, elucidation of the phenotype(s) favored by selection, resulting in cluster formation and maintenance, has not been forthcoming. We noted that the cause of certain well-studied human metabolic disorders is the accumulation of toxic intermediate compounds (ICs), which occurs when the product of an enzyme is not used as a substrate by a downstream neighbor in the metabolic network. This raises the hypothesis that the phenotype favored by selection to drive gene clustering is the mitigation of IC toxicity. To test this, we examined 100 diverse fungal genomes for the simplest type of cluster, gene pairs that are both metabolic neighbors and chromosomal neighbors immediately adjacent to each other, which we refer to as “double neighbor gene pairs” (DNGPs). Examination of the toxicity of their corresponding ICs shows that, compared with chromosomally nonadjacent metabolic neighbors, DNGPs are enriched for ICs that have acutely toxic LD50 doses or reactive functional groups. Furthermore, DNGPs are significantly more likely to be divergently oriented on the chromosome; remarkably, ∼40% of these DNGPs have ICs known to be toxic. We submit that the structure of synteny in metabolic pathways of fungi is a signature of selection for protection against the accumulation of toxic metabolic intermediates. PMID:23798424

Equilibrium Partitioning Approach for Assessing Toxicity of Contaminants in Sediments: Linking Measured Concentrations to Effects

EPA Science Inventory

A variety of approaches exist for assessing the degree, extent and/or risk of metals contamination in sediments. Selection of the “correct” approach depends on the nature of the question being asked (e.g., the degree of metals contamination in marine sediments may be estimated by...

DEVELOPMENT OF PATHWAY SELECTIVE CELLS AND ASSAYS FOR SENSITIVE DETECTION OF ENVIRONMENTAL TOXICANTS VIA HIGH THROUGHPUT LABEL-FREE CELL-BASED SCREENING - PHASE I

EPA Science Inventory

Anesthetic effect of 4-styrylpyridine on lamprey and fish

USGS Publications Warehouse

Howell, John H.; Thomas, Paul M.

1964-01-01

The anestheticp roperty of 4-styrylpyridine (4-SP) on fish and lamprey was first noticed during chemical screening search of a selective toxicant for larval lamprey (Applegate, Howell, Hall, and Smith, 1957). To assess the possible value of the compound as an anesthetic, we later conducted the experiments reviewed in this report.

Improvement in Therapeutic Efficacy and Reduction in Cellular Toxicity: Introduction of a Novel Anti-PSMA-Conjugated Hybrid Antiandrogen Nanoparticle.

PubMed

Thangavel, Chellappagounder; Perepelyuk, Maryna; Boopathi, Ettickan; Liu, Yi; Polischak, Steven; Deshpande, Deepak A; Rafiq, Khadija; Dicker, Adam P; Knudsen, Karen E; Shoyele, Sunday A; Den, Robert B

2018-05-07

Second generation antiandrogens have improved overall survival for men with metastatic castrate resistant prostate cancer; however, the antiandrogens result in suppression of androgen receptor (AR) activity in all tissues resulting in dose limiting toxicity. We sought to overcome this limitation through encapsulation in a prostate specific membrane antigen (PSMA)-conjugated nanoparticle. We designed and characterized a novel nanoparticle containing an antiandrogen, enzalutamide. Selectivity and enhanced efficacy was achieved through coating the particle with PSMA. The PSMA-conjugated nanoparticle was internalized selectively in AR expressing prostate cancer cells. It did not elicit an inflammatory effect. The efficacy of enzalutamide was not compromised through insertion into the nanoparticle; in fact, lower systemic drug concentrations of enzalutamide resulted in comparable clinical activity. Normal muscle cells were not impacted by the PSMA-conjugated containing antiandrogen. This approach represents a novel strategy to increase the specificity and effectiveness of antiandrogen treatment for men with castrate resistant prostate cancer. The ability to deliver higher drug concentrations in prostate cancer cells may translate into improved clinical end points including overall survival.

Validation of the proteasome as a therapeutic target in Plasmodium using an epoxyketone inhibitor with parasite-specific toxicity

PubMed Central

Li, Hao; Ponder, Elizabeth L.; Verdoes, Martijn; Asbjornsdottir, Kristijana H.; Deu, Edgar; Edgington, Laura E.; Lee, Jeong Tae; Kirk, Christopher J.; Demo, Susan D.; Williamson, Kim C.; Bogyo, Matthew

2012-01-01

Summary The Plasmodium proteasome has been suggested to be a potential anti-malarial drug target, however toxicity of inhibitors has prevented validation of this enzyme in vivo. We report here a screen of a library of 670 analogs of the recently FDA approved inhibitor, carfilzomib, to identify compounds that selectively kill parasites. We identified one compound, PR3, that has significant parasite killing activity in vitro but dramatically reduced toxicity in host cells. We found that this parasite-specific toxicity is not due to selective targeting of the Plasmodium proteasome over the host proteasome, but instead is due to a lack of activity against one of the human proteasome subunits. Subsequently, we used PR3 to significantly reduce parasite load in P. berghei infected mice without host toxicity, thus validating the proteasome as a viable anti-malarial drug target. PMID:23142757

Toxicity of 2,4-diacetylphloroglucinol (DAPG) to plant-parasitic and bacterial-feeding nematodes.

PubMed

Meyer, Susan L F; Halbrendt, John M; Carta, Lynn K; Skantar, Andrea M; Liu, Ting; Abdelnabby, Hazem M E; Vinyard, Bryan T

2009-12-01

The antibiotic 2,4-diacetylphloroglucinol (DAPG) is produced by some isolates of the beneficial bacterium Pseudomonas fluorescens. DAPG is toxic to many organisms, and crop yield increases have been reported after application of DAPG-producing P. fluorescens. This study was conducted to determine whether DAPG is toxic to selected nematodes. The plant-parasitic nematodes Heterodera glycines, Meloidogyne incognita, Pratylenchus scribneri and Xiphinema americanum, and the bacterial-feeding nematodes Caenorhabditis elegans, Pristionchus pacificus, and Rhabditis rainai, were immersed in concentrations ranging from 0 to 100 μg/ml DAPG. Egg hatch and viability of juveniles and adults were determined. DAPG was toxic to X. americanum adults, with an LD₅₀ of 8.3 μg/ml DAPG. DAPG decreased M. incognita egg hatch, but stimulated C. elegans hatch during the first hours of incubation. Viability of M. incognita J2 and of C. elegans J1 and adults was not affected. There were no observed effects on the other nematodes. The study indicated that DAPG is not toxic to all nematodes, and did not affect the tested species of beneficial bacterial-feeding nematodes. Augmentation of DAPG-producing P. fluorescens populations for nematode biocontrol could be targeted to specific nematode species known to be affected by this compound and by other antibiotics produced by the bacteria, or these bacteria could be used for other possible effects, such as induced plant resistance.

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.

Fluorescent kapakahines serve as non-toxic probes for live cell Golgi imaging.

PubMed

Rocha, Danilo D; Espejo, Vinson R; Rainier, Jon D; La Clair, James J; Costa-Lotufo, Letícia V

2015-09-01

There is an ongoing need for fluorescent probes that specifically-target select organelles within mammalian cells. This study describes the development of probes for the selective labeling of the Golgi apparatus and offers applications for live cell and fixed cell imaging. The kapakahines, characterized by a common C(3)-N(1') dimeric tryptophan linkage, comprise a unique family of bioactive marine depsipeptide natural products. We describe the uptake and subcellular localization of fluorescently-labeled analogs of kapakahine E. Using confocal microscopy, we identify a rapid and selective localization within the Golgi apparatus. Comparison with commercial Golgi stains indicates a unique localization pattern, which differs from currently available materials, therein offering a new tool to monitor the Golgi in live cells without toxic side effects. This study identifies a fluorescent analog of kapakahine E that is rapidly uptaken in cells and localizes within the Golgi apparatus. The advance of microscopic methods is reliant on the parallel discovery of next generation molecular probes. This study describes the advance of stable and viable probe for staining the Golgi apparatus. Copyright © 2015 Elsevier Inc. All rights reserved.

A single-blinded, single-centre, controlled study in healthy adult smokers to identify the effects of a reduced toxicant prototype cigarette on biomarkers of exposure and of biological effect versus commercial cigarettes

PubMed Central

2013-01-01

Background Despite universal acceptance that smoking is harmful, a substantial number of adults continue to smoke. The development of potential reduced exposure products (more recently termed modified risk tobacco products) has been suggested as a way to reduce the risks of tobacco smoking. This trial is designed to investigate whether changes in toxicant exposure after switching from a commercial to reduced toxicant prototype (RTP) cigarette (7 mg International Organisation for Standardisation (ISO) tar yield) can be assessed by measurement of biomarkers and other factors. The primary objective is to descriptively assess changes in selected biomarkers of exposure (BoE) and biomarkers of biological effect (BoBE) within participants and within and between groups after switching. Secondary objectives are to assess similarly changes in other biomarkers, quality of life, smoking behaviours, physiological measures, mouth-level exposure to toxicants and sensory perception. Methods/design This trial will assess current smokers, ex-smokers and never-smokers in a single-centre single-blind, controlled clinical trial with a forced-switching design and in-clinic (residential) and ambulatory (non-residential) periods. Smokers will be aged 23–55 years (minimum legal smoking age plus 5 years) and non-smokers 28–55 years (minimum legal smoking age plus 5 years, plus minimum 5 years since last smoked). Smokers will be allowed to smoke freely at all times. We will assess changes in selected BoE and BoBE and effective dose in urine and blood after switching. Creatinine concentrations in serum, creatinine clearance in urine, cotinine concentration in saliva, diaries and collection of spent cigarette filters will be used to assess compliance with the study protocol. Mouth-level exposure to toxins will be assessed by filter analysis. Discussion Data from this study are expected to improve scientific understanding of the effects of RTP cigarettes on BoE and BoBE, and give insights into study design for clinical assessment of potential MRTPs. Trial registration The study was registered in the Current Controlled Trials database under the reference ISRCTN81286286. PMID:23895296

A single-blinded, single-centre, controlled study in healthy adult smokers to identify the effects of a reduced toxicant prototype cigarette on biomarkers of exposure and of biological effect versus commercial cigarettes.

PubMed

Shepperd, Christopher J; Newland, Nik; Eldridge, Alison; Graff, Don; Meyer, Ingo

2013-07-29

Despite universal acceptance that smoking is harmful, a substantial number of adults continue to smoke. The development of potential reduced exposure products (more recently termed modified risk tobacco products) has been suggested as a way to reduce the risks of tobacco smoking. This trial is designed to investigate whether changes in toxicant exposure after switching from a commercial to reduced toxicant prototype (RTP) cigarette (7 mg International Organisation for Standardisation (ISO) tar yield) can be assessed by measurement of biomarkers and other factors. The primary objective is to descriptively assess changes in selected biomarkers of exposure (BoE) and biomarkers of biological effect (BoBE) within participants and within and between groups after switching. Secondary objectives are to assess similarly changes in other biomarkers, quality of life, smoking behaviours, physiological measures, mouth-level exposure to toxicants and sensory perception. This trial will assess current smokers, ex-smokers and never-smokers in a single-centre single-blind, controlled clinical trial with a forced-switching design and in-clinic (residential) and ambulatory (non-residential) periods. Smokers will be aged 23-55 years (minimum legal smoking age plus 5 years) and non-smokers 28-55 years (minimum legal smoking age plus 5 years, plus minimum 5 years since last smoked). Smokers will be allowed to smoke freely at all times. We will assess changes in selected BoE and BoBE and effective dose in urine and blood after switching. Creatinine concentrations in serum, creatinine clearance in urine, cotinine concentration in saliva, diaries and collection of spent cigarette filters will be used to assess compliance with the study protocol. Mouth-level exposure to toxins will be assessed by filter analysis. Data from this study are expected to improve scientific understanding of the effects of RTP cigarettes on BoE and BoBE, and give insights into study design for clinical assessment of potential MRTPs. The study was registered in the Current Controlled Trials database under the reference ISRCTN81286286.

Preclinical safety assessments of nano-sized constructs on cardiovascular system toxicity: A case for telemetry.

PubMed

Cheah, Hoay Yan; Kiew, Lik Voon; Lee, Hong Boon; Japundžić-Žigon, Nina; Vicent, Marίa J; Hoe, See Ziau; Chung, Lip Yong

2017-11-01

While nano-sized construct (NSC) use in medicine has grown significantly in recent years, reported unwanted side effects have raised safety concerns. However, the toxicity of NSCs to the cardiovascular system (CVS) and the relative merits of the associated evaluation methods have not been thoroughly studied. This review discusses the toxicological profiles of selected NSCs and provides an overview of the assessment methods, including in silico, in vitro, ex vivo and in vivo models and how they are related to CVS toxicity. We conclude the review by outlining the merits of telemetry coupled with spectral analysis, baroreceptor reflex sensitivity analysis and echocardiography as an appropriate integrated strategy for the assessment of the acute and chronic impact of NSCs on the CVS. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Synergistic target combination prediction from curated signaling networks: Machine learning meets systems biology and pharmacology.

PubMed

Chua, Huey Eng; Bhowmick, Sourav S; Tucker-Kellogg, Lisa

2017-10-01

Given a signaling network, the target combination prediction problem aims to predict efficacious and safe target combinations for combination therapy. State-of-the-art in silico methods use Monte Carlo simulated annealing (mcsa) to modify a candidate solution stochastically, and use the Metropolis criterion to accept or reject the proposed modifications. However, such stochastic modifications ignore the impact of the choice of targets and their activities on the combination's therapeutic effect and off-target effects, which directly affect the solution quality. In this paper, we present mascot, a method that addresses this limitation by leveraging two additional heuristic criteria to minimize off-target effects and achieve synergy for candidate modification. Specifically, off-target effects measure the unintended response of a signaling network to the target combination and is often associated with toxicity. Synergy occurs when a pair of targets exerts effects that are greater than the sum of their individual effects, and is generally a beneficial strategy for maximizing effect while minimizing toxicity. mascot leverages on a machine learning-based target prioritization method which prioritizes potential targets in a given disease-associated network to select more effective targets (better therapeutic effect and/or lower off-target effects); and on Loewe additivity theory from pharmacology which assesses the non-additive effects in a combination drug treatment to select synergistic target activities. Our experimental study on two disease-related signaling networks demonstrates the superiority of mascot in comparison to existing approaches. Copyright © 2017 Elsevier Inc. All rights reserved.

Modeling adverse event counts in phase I clinical trials of a cytotoxic agent.

PubMed

Muenz, Daniel G; Braun, Thomas M; Taylor, Jeremy Mg

2018-05-01

Background/Aims The goal of phase I clinical trials for cytotoxic agents is to find the maximum dose with an acceptable risk of severe toxicity. The most common designs for these dose-finding trials use a binary outcome indicating whether a patient had a dose-limiting toxicity. However, a patient may experience multiple toxicities, with each toxicity assigned an ordinal severity score. The binary response is then obtained by dichotomizing a patient's richer set of data. We contribute to the growing literature on new models to exploit this richer toxicity data, with the goal of improving the efficiency in estimating the maximum tolerated dose. Methods We develop three new, related models that make use of the total number of dose-limiting and low-level toxicities a patient experiences. We use these models to estimate the probability of having at least one dose-limiting toxicity as a function of dose. In a simulation study, we evaluate how often our models select the true maximum tolerated dose, and we compare our models with the continual reassessment method, which uses binary data. Results Across a variety of simulation settings, we find that our models compare well against the continual reassessment method in terms of selecting the true optimal dose. In particular, one of our models which uses dose-limiting and low-level toxicity counts beats or ties the other models, including the continual reassessment method, in all scenarios except the one in which the true optimal dose is the highest dose available. We also find that our models, when not selecting the true optimal dose, tend to err by picking lower, safer doses, while the continual reassessment method errs more toward toxic doses. Conclusion Using dose-limiting and low-level toxicity counts, which are easily obtained from data already routinely collected, is a promising way to improve the efficiency in finding the true maximum tolerated dose in phase I trials.

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.

Effect of Toxic Metals on Indigenous Soil β-Subgroup Proteobacterium Ammonia Oxidizer Community Structure and Protection against Toxicity by Inoculated Metal-Resistant Bacteria

PubMed Central

Stephen, John R.; Chang, Yun-Juan; Macnaughton, Sarah J.; Kowalchuk, George A.; Leung, Kam T.; Flemming, Cissy A.; White, David C.

1999-01-01

Contamination of soils with toxic metals is a major problem on military, industrial, and mining sites worldwide. Of particular interest to the field of bioremediation is the selection of biological markers for the end point of remediation. In this microcosm study, we focus on the effect of addition of a mixture of toxic metals (cadmium, cobalt, cesium, and strontium as chlorides) to soil on the population structure and size of the ammonia oxidizers that are members of the beta subgroup of the Proteobacteria (β-subgroup ammonia oxidizers). In a parallel experiment, the soils were also treated by the addition of five strains of metal-resistant heterotrophic bacteria. Effects on nitrogen cycling were measured by monitoring the NH3 and NH4+ levels in soil samples. The gene encoding the α-subunit of ammonia monooxygenase (amoA) was selected as a functional molecular marker for the β-subgroup ammonia oxidizing bacteria. Community structure comparisons were performed with clone libraries of PCR-amplified fragments of amoA recovered from contaminated and control microcosms for 8 weeks. Analysis was performed by restriction digestion and sequence comparison. The abundance of ammonia oxidizers in these microcosms was also monitored by competitive PCR. All amoA gene fragments recovered grouped with sequences derived from cultured Nitrosospira. These comprised four novel sequence clusters and a single unique clone. Specific changes in the community structure of β-subgroup ammonia oxidizers were associated with the addition of metals. These changes were not seen in the presence of the inoculated metal-resistant bacteria. Neither treatment significantly altered the total number of β-subgroup ammonia-oxidizing cells per gram of soil compared to untreated controls. Following an initial decrease in concentration, ammonia began to accumulate in metal-treated soils toward the end of the experiment. PMID:9872765

Diallyl Polysulfides from Allium sativum as Immunomodulators, Hepatoprotectors, and Antimycobacterial Agents.

PubMed

Oosthuizen, Carel; Arbach, Miriam; Meyer, Debra; Hamilton, Chris; Lall, Namrita

2017-07-01

Mycobacterium tuberculosis remains one of the world's deadliest killers, with an annual death rate of ∼1.5 million. The medicinal effects of garlic have been well documented, and natural products have been shown to have antimycobacterial activity. The current study evaluated the efficacy of six Allium sativum L. polysulfide mixtures as antimycobacterial agents together with their cytotoxic, immunomodulatory, and hepatoprotective activities. The microtitre PrestoBlue assay was used to determine the minimum inhibitory concentrations (MIC). Cytotoxicity was evaluated by using peripheral blood mononuclear cells (PBMC). Excreted cytokine levels were determined by utilizing an enzyme-linked immunosorbent assay (ELISA), by exposing isolated PBMCs to varying concentrations of polysulfide mixtures. Human C3A liver cells were utilized in the hepatoprotective study, to assess the protective effect against the toxicity induced by acetaminophen. Samples with higher amounts of diallyl trisulfide (Sample G4) showed the highest antimycobacterial activity, exhibiting an MIC of 2.5 μg/mL against M. tuberculosis H37Rv. Five samples showed moderate toxicity in PBMC, with G1 showing no toxicity. The selective index of G4 was the highest, with a selectivity index close to one. Two samples, G3 and G6 containing higher amounts of diallyl tetrasulfide and lower amounts of diallyl trisulfide, showed >50% hepatoprotection. This is comparable to a hepatoprotective agent, Silymarin, which showed a hepatoprotective effect of 30% at the tested concentration. Diallyl tetrasulfide showed significant antimycobacterial activity. A combination of higher diallyl tetrasulfide and lower diallyl trisulfide was indicative of hepatoprotective activity.

Environmental and health effects of the herbicide glyphosate.

PubMed

Van Bruggen, A H C; He, M M; Shin, K; Mai, V; Jeong, K C; Finckh, M R; Morris, J G

2018-03-01

The herbicide glyphosate, N-(phosphonomethyl) glycine, has been used extensively in the past 40years, under the assumption that side effects were minimal. However, in recent years, concerns have increased worldwide about the potential wide ranging direct and indirect health effects of the large scale use of glyphosate. In 2015, the World Health Organization reclassified glyphosate as probably carcinogenic to humans. A detailed overview is given of the scientific literature on the movement and residues of glyphosate and its breakdown product aminomethyl phosphonic acid (AMPA) in soil and water, their toxicity to macro- and microorganisms, their effects on microbial compositions and potential indirect effects on plant, animal and human health. Although the acute toxic effects of glyphosate and AMPA on mammals are low, there are animal data raising the possibility of health effects associated with chronic, ultra-low doses related to accumulation of these compounds in the environment. Intensive glyphosate use has led to the selection of glyphosate-resistant weeds and microorganisms. Shifts in microbial compositions due to selective pressure by glyphosate may have contributed to the proliferation of plant and animal pathogens. Research on a link between glyphosate and antibiotic resistance is still scarce but we hypothesize that the selection pressure for glyphosate-resistance in bacteria could lead to shifts in microbiome composition and increases in antibiotic resistance to clinically important antimicrobial agents. We recommend interdisciplinary research on the associations between low level chronic glyphosate exposure, distortions in microbial communities, expansion of antibiotic resistance and the emergence of animal, human and plant diseases. Independent research is needed to revisit the tolerance thresholds for glyphosate residues in water, food and animal feed taking all possible health risks into account. Copyright © 2017 Elsevier B.V. All rights reserved.

Toxicity of selected insecticides applied to western spruce budworm

Treesearch

Jacqueline E. Robertson; Nancy L. Gillette; Barbara A. Lucas; Robert L. Lyon

1976-01-01

The contact toxlaty of 100 insecticides to last stage larvae of Choristoneura occidentalis Freeman was tested by topical application in a 10-yr series of screening experiments. Pyrethroids were generally the most toxic group of chemicals tested. Compounds more toxic than the standard, mexacarbate, at LD90 were:...

Molluscicidal properties and selective toxicity of surface-active agents

PubMed Central

Visser, S. A.

1965-01-01

Of over 100 commercially produced surface-active agents tested against the bilharziasis vector snail Biomphalaria sudanica, 13 were found to possess considerable and highly selective molluscicidal properties at concentrations of less than 1 ppm for exposures of 48 hours. Against crustacea, fish, water plants, mosquito larvae, mice, and the eggs of B. sudanica, the toxicities of the 13 surfactants were slight. The chemicals did not appear to be absorbed by organic matter to any appreciable extent. It is thought that the toxicity to B. sudanica is of both a chemical and a physical nature. PMID:5294185

Selective internal radiation therapy (SIRT) for liver metastases secondary to colorectal adenocarcinoma

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

Welsh, James S.; Kennedy, Andrew S.; Thomadsen, Bruce

2006-10-01

Introduction: Selective internal radiation therapy (SIRT) is a relatively new commercially available microbrachytherapy technique for treatment of malignant hepatic lesions using {sup 9}Y embedded in resin microspheres, which are infused directly into the hepatic arterial circulation. It is FDA approved for liver metastases secondary to colorectal carcinoma and is under investigation for treatment of other liver malignancies, such as hepatocellular carcinoma and neuroendocrine malignancies. Materials/Methods: A modest number of clinical trials, preclinical animal studies, and dosimetric studies have been reported. Here we review several of the more important results. Results: High doses of beta radiation can be selectively delivered tomore » tumors, resulting in impressive local control and survival rates. Ex vivo analyses have shown that microspheres preferentially cluster around the periphery of tumor nodules with a high tumor:normal tissue ratio of up to 200:1. Toxicity is usually mild, featuring fatigue, anorexia, nausea, abdominal discomfort, and slight elevations of liver function tests. Conclusions: Selective internal radiation therapy represents an effective means of controlling liver metastases from colorectal adenocarcinoma. Clinical trials have demonstrated improved local control of disease and survival with relatively low toxicity. Investigations of SIRT for other hepatic malignancies and in combination with newer chemotherapy agents and targeted biologic therapies are under way or in planning. A well-integrated team involving interventional radiology, nuclear medicine, medical oncology, surgical oncology, medical physics, and radiation oncology is essential for a successful program. Careful selection of patients through the combined expertise of the team can maximize therapeutic efficacy and reduce the potential for adverse effects.« less

Selected flavonoids potentiate the toxicity of cisplatin in human lung adenocarcinoma cells: A role for glutathione depletion

PubMed Central

KACHADOURIAN, REMY; LEITNER, VHEATHER M.; DAY, BRIAN J.

2014-01-01

Adjuvant therapies that enhance the anti-tumor effects of cisplatin are actively being pursued. Growing evidence supports the involvement of mitochondrial dysfunction in the anti-cancer effect of cis-diammineplatinum(II) dichloride (cisplatin, CDDP). We examined the potential of using selective flavonoids that are effective in depleting tumor cells of glu-tathione (GSH) to potentiate cisplatin-mediated cytotoxicity in human lung adenocarcinoma (A549) cells. We found that cisplatin (40 μM, 48-h treatment) disrupts the steady-state levels of mitochondrial respiratory complex I, which correlates with elevated mitochondrial reactive oxygen species (ROS) production and cytochrome c release. The flavonoids, 2′,5′-dihydroxychalcone (2′,5′-DHC, 20 μM) and chrysin (20 μM) potentiated the cytotoxicity of cisplatin (20 μM), which could be blocked by supplementation of the media with exogenous GSH (500 μM). Both 2′,5′-DHC and chrysin were more effective than the specific inhibitor of GSH synthesis, L-buthionine sulfoximine (BSO, 20 μM), in inducing GSH depletion and potentiating the cytotoxic effect of cisplatin. These data suggest that the flavonoid-induced potentiation of cisplatin’s toxicity is due, in part, to synergetic pro-oxidant effects of cisplatin by inducing mitochondrial dysfunction, and the flavonoids by depleting cellular GSH, an important antioxidant defense. PMID:17549417

Estuarine sediment toxicity tests on diatoms: Sensitivity comparison for three species

NASA Astrophysics Data System (ADS)

Moreno-Garrido, Ignacio; Lubián, Luis M.; Jiménez, Begoña; Soares, Amadeu M. V. M.; Blasco, Julián

2007-01-01

Experimental populations of three marine and estuarine diatoms were exposed to sediments with different levels of pollutants, collected from the Aveiro Lagoon (NW of Portugal). The species selected were Cylindrotheca closterium, Phaeodactylum tricornutum and Navicula sp. Previous experiments were designed to determine the influence of the sediment particle size distribution on growth of the species assayed. Percentage of silt-sized sediment affect to growth of the selected species in the experimental conditions: the higher percentage of silt-sized sediment, the lower growth. In any case, percentages of silt-sized sediment less than 10% did not affect growth. In general, C. closterium seems to be slightly more sensitive to the selected sediments than the other two species. Two groups of sediment samples were determined as a function of the general response of the exposed microalgal populations: three of the six samples used were more toxic than the other three. Chemical analysis of the samples was carried out in order to determine the specific cause of differences in toxicity. After a statistical analysis, concentrations of Sn, Zn, Hg, Cu and Cr (among all physico-chemical analyzed parameters), in order of importance, were the most important factors that divided the two groups of samples (more and less toxic samples). Benthic diatoms seem to be sensitive organisms in sediment toxicity tests. Toxicity data from bioassays involving microphytobentos should be taken into account when environmental risks are calculated.

Comparative acute toxicity of leachates from plastic products made of polypropylene, polyethylene, PVC, acrylonitrile-butadiene-styrene, and epoxy to Daphnia magna.

PubMed

Lithner, Delilah; Nordensvan, Ildikó; Dave, Göran

2012-06-01

The large global production of plastics and their presence everywhere in the society and the environment create a need for assessing chemical hazards and risks associated with plastic products. The aims of this study were to determine and compare the toxicity of leachates from plastic products made of five plastics types and to identify the class of compounds that is causing the toxicity. Selected plastic types were those with the largest global annual production, that is, polypropylene, polyethylene, and polyvinyl chloride (PVC), or those composed of hazardous monomers (e.g., PVC, acrylonitrile-butadiene-styrene [ABS], and epoxy). Altogether 26 plastic products were leached in deionized water (3 days at 50°C), and the water phases were tested for acute toxicity to Daphnia magna. Initial Toxicity Identification Evaluations (C18 filtration and EDTA addition) were performed on six leachates. For eleven leachates (42%) 48-h EC50s (i.e the concentration that causes effect in 50 percent of the test organisms) were below the highest test concentration, 250 g plastic/L. All leachates from plasticized PVC (5/5) and epoxy (5/5) products were toxic (48-h EC50s ranging from 2 to 235 g plastic/L). None of the leachates from polypropylene (5/5), ABS (5/5), and rigid PVC (1/1) products showed toxicity, but one of the five tested HDPE leachates was toxic (48-h EC50 17-24 g plastic/L). Toxicity Identification Evaluations indicated that mainly hydrophobic organics were causing the toxicity and that metals were the main cause for one leachate (metal release was also confirmed by chemical analysis). Toxic chemicals leached even during the short-term leaching in water, mainly from plasticized PVC and epoxy products.

Implication of global environmental changes on chemical toxicity-effect of water temperature, pH, and ultraviolet B irradiation on acute toxicity of several pharmaceuticals in Daphnia magna.

PubMed

Kim, Jungkon; Park, Jeongim; Kim, Pan-Gyi; Lee, Chulwoo; Choi, Kyunghee; Choi, Kyungho

2010-04-01

Global environmental change poses emerging environmental health challenges throughout the world. One of such threats could be found in chemical safety in aquatic ecosystem. In the present study, we evaluated the effect of several environmental factors, such as water pH, temperature and ultraviolet light on the toxicity of pharmaceutical compounds in water, using freshwater invertebrate Daphnia magna. Seven pharmaceuticals including ibuprofen, acetaminophen, lincomycin, ciprofloxacin, enrofloxacin, chlortetracycline and sulfathiazole were chosen as test compounds based on their frequent detection in water. The experimental conditions of environmental parameters were selected within the ranges that could be encountered in temperate environment, i.e., water temperature (15, 21, and 25 degrees C), pH (7.4, 8.3, and 9.2), and UV-B light intensity (continuous irradiation of 15.0 microW/cm(2)). For acetaminophen, enrofloxacin and sulfathiazole, decrease in water pH generally led to increase of acute lethal toxicity, which could be explained by the unionized fraction of pharmaceuticals. Increase of water temperature enhanced the acute toxicity of the acetaminophen, enrofloxacin and chlortetracycline, potentially due to alteration in toxicokinetics of chemicals as well as impact on physiological mechanisms of the test organism. The presence of UV-B light significantly increased the toxicity of sulfathiazole, which could be explained by photo-modification of this chemical that lead to oxidative stress. Under the UV light, however, acute toxicity of enrofloxacin decreased, which might be due to photo-degradation. Since changing environmental conditions could affect exposure and concentration-response profile of environmental contaminants, such conditions should be identified and evaluated in order to better manage ecosystem health under changing global environment.

Effect of capping agents on the cytotoxicity of silver nanoparticles in human normal and cancer skin cell lines

NASA Astrophysics Data System (ADS)

Netchareonsirisuk, Ponsawan; Puthong, Songchan; Dubas, Stephan; Palaga, Tanapat; Komolpis, Kittinan

2016-11-01

Silver nanoparticles (AgNPs) are among the most widely used nanomaterials in medical and consumer products. However, safety in the uses of AgNPs is still controversial. The toxicity of AgNPs toward various cell types has been reported to depend on the surface properties of the nanoparticles. In this study, the effect of AgNPs with the average size of 5-15 nm on the viability of the CCD-986SK human normal skin fibroblast cell line and A375 human malignant melanoma cell line was evaluated. Comparative toxicity studies, based on MTT assay, were performed by using either sodium alginate or poly (4-styrenesulfonic acid-co-maleic acid) sodium salt (PSSMA) as capping agent in the nanoparticle preparation. The cytotoxicity tests revealed that AgNO3 alone was highly toxic to both cell types while both alginate and PSSMA alone were not toxic. AgNPs capped with alginate were selectively toxic to the cancer cell line but not to the normal cell line while AgNPs capped with PSSMA were toxic to both cancer and normal cell lines. Judging from the 50 % inhibition concentration (IC50), it was found that the cancer cell line was more sensitive to AgNPs than the normal cell line. Study on the mode of cell death by annexin V and propidium iodide staining revealed that AgNPs induced more apoptotic cell death (84-90 %) than necrosis (8-12 %) in the skin cancer cell line. These results suggest that the toxicity of AgNPs depended on the type of capping agent and the type of cell line.

Widespread genetic switches and toxicity resistance proteins for fluoride.

PubMed

Baker, Jenny L; Sudarsan, Narasimhan; Weinberg, Zasha; Roth, Adam; Stockbridge, Randy B; Breaker, Ronald R

2012-01-13

Most riboswitches are metabolite-binding RNA structures located in bacterial messenger RNAs where they control gene expression. We have discovered a riboswitch class in many bacterial and archaeal species whose members are selectively triggered by fluoride but reject other small anions, including chloride. These fluoride riboswitches activate expression of genes that encode putative fluoride transporters, enzymes that are known to be inhibited by fluoride, and additional proteins of unknown function. Our findings indicate that most organisms are naturally exposed to toxic levels of fluoride and that many species use fluoride-sensing RNAs to control the expression of proteins that alleviate the deleterious effects of this anion.

Widespread Genetic Switches and Toxicity Resistance Proteins for Fluoride

PubMed Central

Weinberg, Zasha; Roth, Adam; Stockbridge, Randy B.; Breaker, Ronald R.

2014-01-01

Most riboswitches are metabolite-binding RNA structures located in bacterial messenger RNAs where they control gene expression. We have discovered a riboswitch class in many bacterial and archaeal species whose members are selectively triggered by fluoride but reject other small anions, including chloride. These fluoride riboswitches activate expression of genes that encode putative fluoride transporters, enzymes that are known to be inhibited by fluoride, and additional proteins of unknown function. Our findings indicate that most organisms are naturally exposed to toxic levels of fluoride and that many species use fluoride-sensing RNAs to control the expression of proteins that alleviate the deleterious effects of this anion. PMID:22194412

Inhibition of growth of Zymomonas mobilis by model compounds found in lignocellulosic hydrolysates

PubMed Central

2013-01-01

Background During the pretreatment of biomass feedstocks and subsequent conditioning prior to saccharification, many toxic compounds are produced or introduced which inhibit microbial growth and in many cases, production of ethanol. An understanding of the toxic effects of compounds found in hydrolysate is critical to improving sugar utilization and ethanol yields in the fermentation process. In this study, we established a useful tool for surveying hydrolysate toxicity by measuring growth rates in the presence of toxic compounds, and examined the effects of selected model inhibitors of aldehydes, organic and inorganic acids (along with various cations), and alcohols on growth of Zymomonas mobilis 8b (a ZM4 derivative) using glucose or xylose as the carbon source. Results Toxicity strongly correlated to hydrophobicity in Z. mobilis, which has been observed in Escherichia coli and Saccharomyces cerevisiae for aldehydes and with some exceptions, organic acids. We observed Z. mobilis 8b to be more tolerant to organic acids than previously reported, although the carbon source and growth conditions play a role in tolerance. Growth in xylose was profoundly inhibited by monocarboxylic organic acids compared to growth in glucose, whereas dicarboxylic acids demonstrated little or no effects on growth rate in either substrate. Furthermore, cations can be ranked in order of their toxicity, Ca++ > > Na+ > NH4+ > K+. HMF (5-hydroxymethylfurfural), furfural and acetate, which were observed to contribute to inhibition of Z. mobilis growth in dilute acid pretreated corn stover hydrolysate, do not interact in a synergistic manner in combination. We provide further evidence that Z. mobilis 8b is capable of converting the aldehydes furfural, vanillin, 4-hydroxybenzaldehyde and to some extent syringaldehyde to their alcohol forms (furfuryl, vanillyl, 4-hydroxybenzyl and syringyl alcohol) during fermentation. Conclusions Several key findings in this report provide a mechanism for predicting toxic contributions of inhibitory components of hydrolysate and provide guidance for potential process development, along with potential future strain improvement and tolerance strategies. PMID:23837621

Synthesis and toxicity evaluation of hydrophobic ionic liquids for volatile organic compounds biodegradation in a two-phase partitioning bioreactor.

PubMed

Rodriguez Castillo, Alfredo Santiago; Guihéneuf, Solène; Le Guével, Rémy; Biard, Pierre-François; Paquin, Ludovic; Amrane, Abdeltif; Couvert, Annabelle

2016-04-15

Synthesis of several hydrophobic ionic liquids (ILs), which might be selected as good candidates for degradation of hydrophobic volatile organic compounds in a two-phase partitioning bioreactor (TPPB), were carried out. Several bioassays were also realized, such as toxicity evaluation on activated sludge and zebrafish, cytotoxicity, fluoride release in aqueous phase and biodegradability in order to verify their possible effects in case of discharge in the aquatic environment and/or human contact during industrial manipulation. The synthesized compounds consist of alkylimidazoliums, functionalized imidazoliums, isoqinoliniums, triazoliums, sulfoniums, pyrrolidiniums and morpholiniums and various counter-ions such as: PF6(-), NTf2(-) and NfO(-). Toxicity evaluation on activated sludge of each compound (5% v/v of IL) was assessed by using a glucose uptake inhibition test. Toxicity against zebrafish and cytotoxicity were evaluated by the ImPACCell platform of Rennes (France). Fluoride release in water was estimated by regular measurements using ion chromatography equipment. IL biodegradability was determined by measuring BOD28 of aqueous samples (compound concentration,1mM). All ILs tested were not biodegradable; while some of them were toxic toward activated sludge. Isoquinolinium ILs were toxic to human cancerous cell lines. Nevertheless no toxicity was found against zebrafish Danio rerio. Only one IL released fluoride after long-time agitation. Copyright © 2016 Elsevier B.V. All rights reserved.

Applicability of ambient toxicity testing to national or regional water-quality assessment

USGS Publications Warehouse

Elder, John F.

1990-01-01

Comprehensive assessment of the quality of natural waters requires a multifaceted approach. Descriptions of existing conditions may be achieved by various kinds of chemical and hydrologic analyses, whereas information about the effects of such conditions on living organisms depends on biological monitoring. Toxicity testing is one type of biological monitoring that can be used to identify possible effects of toxic contaminants. Based on experimentation designed to monitor responses of organisms to environmental stresses, toxicity testing may have diverse purposes in water-quality assessments. These purposes may include identification of areas that warrant further study because of poor water quality or unusual ecological features, verification of other types of monitoring, or assessment of contaminant effects on aquatic communities. Toxicity-test results are most effective when used as a complement to chemical analyses, hydrologic measurements, and other biological monitoring. However, all toxicity-testing procedures have certain limitations that must be considered in developing the methodology and applications of toxicity testing in any large-scale water-quality-assessment program. A wide variety of toxicity-test methods have been developed to fulfill the needs of diverse applications. The methods differ primarily in the selections made relative to four characteristics: (1) test species, (2) endpoint (acute or chronic), (3) test-enclosure type, and (4) test substance (toxicant) that functions as the environmental stress. Toxicity-test approaches vary in their capacity to meet the needs of large-scale assessments of existing water quality. Ambient testing, whereby the test organism is exposed to naturally occurring substances that contain toxicant mixtures in an organic or inorganic matrix, is more likely to meet these needs than are procedures that call for exposure of the test organisms to known concentrations of a single toxicant. However, meaningful interpretation of ambient test results depends on the existence of accompanying chemical analysis of the ambient media. The ambient test substance may be water or sediments. Sediment tests have had limited application, but they are useful because most toxicants tend to accumulate in sediments and many test species either inhabit the sediments or are in frequent contact with them. Biochemical testing methods, which have been developing rapidly in recent years, are likely to be among the most useful procedures for large-scale water-quality assessments. They are relatively rapid and simple, and more. importantly, they focus on biochemical changes that are the initial responses of virtually all organisms to environmental stimuli. Most species are sensitive to relatively few toxicants, and their sensitivities vary as conditions change. Therefore, each test method has particular uses and limitations, and no single test has universal applicability. One of the most informative approaches to toxicity testing is to combine biochemical tests with other test methods in a 'battery of tests' that is diversified enough to characterize different types of toxicants and different trophic levels. However, such an approach can be costly, and if not carefully designed, it may not yield enough additional information to warrant the additional cost. The application of toxicity tests to large-scale water-quality assessments is hampered by a number of difficulties. Toxicity tests often are not sensitive enough to enable detection of most contaminant problems in the natural environment. Furthermore, because sensitivities among different species and test conditions can be highly variable, conclusions about the toxicant problems of an ecosystem are strongly dependent on the test procedure used. In addition, the experimental systems used in toxicity tests cannot replicate the complexity or variability of natural conditions, and positive test results cannot identify the source or nature of

Methods to assess reproductive effects of environmental chemicals: studies of cadmium and boron administered orally.

PubMed Central

Dixon, R L; Lee, I P; Sherins, R J

1976-01-01

Results of a U.S.S.R.--U.S. cooperative laboratory effort to improve and validate experimental techniques used to assess subtle reproductive effects in male laboratory animals are reported. The present studies attempted to evaluate the reproductive toxicity of cadmium as cadmium chloride and boron as borax (Na2B4O7) and to investigate the mechanism of toxicity in the rat following acute and subchronic oral exposure. In vitro cell separation techniques, in vivo serial mating tests, and plasma assays for hormones were utilized. Effects on the seminal vesicle and prostate were evaluated with chemical and enzyme assays. Clinical chemistry was monitored routinely. Acute oral doses, expressed as boron were 45, 150, and 450 mg/kg while doses for cadmium equivalent were 6.25, 12.5, and 25 mg/kg. Rats were also allowed free access to drinking water containing either boron (0.3, 1.0, and 6.0 mg/l.) or cadmium (0.001, and 0.l mg/l.) for 90 days. Randomly selected animals were studied following 30, 60, and 90 days of treatment. These initial studies, utilizing a variety of methods to assess the reproductive toxicity of environmental substances in male animals, suggest that cadmium and boron at the concentrations and dose regimens tested are without significant reproductive toxicity. PMID:1269508

New drugs for the treatment of rheumatoid arthritis.

PubMed

Schuna, A A; Megeff, C

2000-02-01

New pharmacologic treatment options for rheumatoid arthritis (RA) are described. Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely prescribed for RA but are limited by the risk of adverse effects, especially gastrointestinal and renal toxicity. The therapeutic effects of these agents are mediated primarily through inhibition of cyclooxygenase (COX) and prevention of subsequent formation of prostaglandins and related inflammatory mediators. Nonspecific COX inhibition appears to be responsible for much of the toxicity of NSAIDs. Agents have been developed that can selectively inhibit the COX-2 isoform, while sparing COX-1. Celecoxib and other COX-2 inhibitors appear to be no more efficacious than conventional NSAIDs, but offer superior safety. COX-2 inhibitors should be considered for patients who are candidates for NSAID therapy but at risk for GI bleeding. Unlike disease-modifying antirheumatic drugs (DMARDs), these agents do not alter underlying disease progression. Leflunomide is a newer DMARD that reduces pyrimidine synthesis, thus decreasing rheumatoid inflammation. Leflunomide appears to be as effective as methotrexate but, unlike that drug, does not necessitate monitoring for bone marrow toxicity. Etanercept, the first biological agent with FDA-approved labeling for use in RA, has shown efficacy and minimal toxicity, except for injection-site reactions. Other biologicals that have been investigated for use in RA include infliximab and interleukin-1-receptor antagonist. COX-2 inhibitors, leflunomide, and etanercept are promising new drugs available for treating RA. Other agents are under development.

[MODERN APPROACHES TO THE DIAGNOSIS AND TREATMENT OF CHEMOTHERAPY TOXICITY IN PATIENTS WITH BREAST CANCER].

PubMed

Syvak, L A; Hubareva, H O; Filonenko, K S; Majdanevych, N M; Aleksyk, O M; Lyalkin, S A; Klimanov, M J; Askolskyi, A V; Kasap, N V

2015-01-01

The use of modern chemotherapy (CT) allowed to achieve significant progress in the treatment of many malignant tumors that were previously considered fatal. Improving the efficiency of the treatment was achieved by the intensification of chemotherapy. However, intensification of chemotherapy regimes provoked increase in the number of side effects of anticancer therapy,which often lead to a decrease in the intensity of the selected mode, the additional financial costs of treating the complications and the formation of the negative attitude of the patient to treatment. Thus, the side effects of chemotherapy are the actual problem of modern oncology. The purpose of this literature review was to investigate the frequency, symptoms and ways to prevent and treat various types of toxicity of chemotherapy.

Pyrrolizidine Alkaloids: Testing for Toxic Constituents of Comfrey.

ERIC Educational Resources Information Center

Vollmer, John J.; And Others

1987-01-01

Discusses the possibilities of toxins present in medicinal herbs. Describes an experiment in which toxic constituents can be selectively detected by thin-layer chromatography and NMR spectroscopy. (TW)

Virulence evolution in response to anti-infection resistance: toxic food plants can select for virulent parasites of monarch butterflies.

PubMed

de Roode, J C; de Castillejo, C Lopez Fernandez; Faits, T; Alizon, S

2011-04-01

Host resistance to parasites can come in two main forms: hosts may either reduce the probability of parasite infection (anti-infection resistance) or reduce parasite growth after infection has occurred (anti-growth resistance). Both resistance mechanisms are often imperfect, meaning that they do not fully prevent or clear infections. Theoretical work has suggested that imperfect anti-growth resistance can select for higher parasite virulence by favouring faster-growing and more virulent parasites that overcome this resistance. In contrast, imperfect anti-infection resistance is thought not to select for increased parasite virulence, because it is assumed that it reduces the number of hosts that become infected, but not the fitness of parasites in successfully infected hosts. Here, we develop a theoretical model to show that anti-infection resistance can in fact select for higher virulence when such resistance reduces the effective parasite dose that enters a host. Our model is based on a monarch butterfly-parasite system in which larval food plants confer resistance to the monarch host. We carried out an experiment and showed that this environmental resistance is most likely a form of anti-infection resistance, through which toxic food plants reduce the effective dose of parasites that initiates an infection. We used these results to build a mathematical model to investigate the evolutionary consequences of food plant-induced resistance. Our model shows that when the effective infectious dose is reduced, parasites can compensate by evolving a higher per-parasite growth rate, and consequently a higher intrinsic virulence. Our results are relevant to many insect host-parasite systems, in which larval food plants often confer imperfect anti-infection resistance. Our results also suggest that - for parasites where the infectious dose affects the within-host dynamics - vaccines that reduce the effective infectious dose can select for increased parasite virulence. © 2011 The Authors. Journal of Evolutionary Biology © 2011 European Society For Evolutionary Biology.

Effect of temperature on heavy metal toxicity to juvenile crayfish, Orconectes immunis (Hagen).

PubMed

Khan, M A Q; Ahmed, S A; Catalin, Bogdon; Khodadoust, A; Ajayi, Oluwaleke; Vaughn, Mark

2006-10-01

The acute toxicity of four selected heavy metals to juvenile crayfish Orconectes immunis (Hagen) (1-2 g wet body wt. each) at room temperature increased in the following order: cadmium (x3) < copper (x10) < zinc (x2) < lead. The toxicity of these metals to crayfish acclimated at 17, 20, 23/24, and 27 degrees C increased with temperature (by 7-20% between 20 and 24 degrees C and 14-26% between 20 and 27 degrees C) as judged by the lowering of LT(50) (time to kill 50% of test animals at a fixed concentration) values. A 4 degrees C rise in temperature (from 20 to 24 degrees C), which increased the toxicity of copper by about 7%, increased the rate of oxygen consumption by about 34%. Heavy metals inhibited the rate of oxygen consumption at all temperatures. In 20 degrees C-acclimated crayfish, copper caused about 17% inhibition of oxygen consumption compared to about 7-12% by other metals including the most toxic cadmium. A 3-4 degrees C rise in temperature tripled the inhibitory effect of copper (20%), cadmium and zinc (26 and 18%, respectively), but not of lead, on oxygen consumption. A 7 degrees C-rise in temperature (from 20 to 27 degrees C) increased the inhibitory effect of heavy metals, including lead, on oxygen consumption by up to 54% in the case of copper. The data indicate that rising global temperatures (currently 0.60 degrees C) associated with climate change can have the potential to increase the sensitivity of aquatic animals to heavy metals in their environment.

An evaluation of benthic community measures using laboratory-derived sediment effect concentrations

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

Dwyer, F.J.; Canfield, T.J.; Ingersoll, C.G.

1995-12-31

Sediment effect concentrations (SECs) are contaminant sediment concentrations which are frequently associated with sediment toxicity. Recently, a number of different SECs have been calculated from laboratory toxicity tests with field collected sediments using Chironomus tentans, Chironomus riparius, and Hyalella azteca. Toxicity endpoints included (depending upon species) lethality, growth and sexual maturation. The authors selected the Effect Range Median (ERM) calculated for 28-d Hyalella azteca as an SEC for evaluating six different benthic community measures as indicators of contaminated sediment. The benthic measures included: taxa richness, chironomid genera richness, percent chironomid deformity, chironomid biotic index, ratio of chironomids/oligochaetes, and oligochaete bioticmore » index. Benthic measures were obtained for 31 stations from the Great Lakes and 13 stations from Milltown Reservoir and Clark Fork River, MT. Each benthic measure was ranked from 1 to 100 and individual ranks and various combinations of ranks were plotted against the ratio of chemical concentration at the site/ERM calculated for that chemical (similar to a toxic unit approach) and the sum of the ERM ratios (sum of toxic units). Preliminary analysis indicates that, in general, benthic measures varied widely in relatively uncontaminated stations, confounding any underlying relationship that may have existed. The absence of chironomids, in areas with suitable habitat, seems to be indicative of grossly contaminated stations, but not an endpoint useful for discriminating stations with contaminant concentrations closer to the SEC. The usefulness of benthic measures as diagnostic tools for contaminated sediments and potential ways to improve these measures will be discussed.« less

Toxicity and biodegradability of selected N-substituted phenols under anaerobic conditions

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

Donlon, B.; Razo-Flores, E.; Hwu, C.S.

1995-12-31

The anaerobic toxicity and biodegradability of N-substituted aromatics were evaluated in order to obtain information on their ultimate biotreatment. The toxicity of selected N-substituted aromatic compounds toward acetoclastic methanogens in granular sludge was measured in batch assays. This toxicity was highly correlated with compound hydrophobicity, indicating that partitioning into the bacterial membranes was an important factor in the toxicity. However, other factors, such as chemical interactions with key cell components, were suggested to be playing an important role. Nitroaromatic compounds were, on the average, over 300-fold more toxic than their amino-substituted counterparts. This finding suggests that the facile reduction ofmore » nitro-groups known to occur in anaerobic environments would result in a high level of detoxification. To test this hypothesis, continuous lab-scale upward-flow anaerobic sludge bed reactors treating 2-nitrophenol and 4-nitrophenol were established. The 4-nitrophenol was readily converted to the corresponding 4-aminophenol, whereas complete mineralization of 2-nitrophenol via intermediate formation of 2-aminophenol was obtained. These conversions led to a dramatic detoxification of the nitrophenols, because it was feasible to treat the highly toxic nitrophenolics at high organic loading rates.« less

Embryonic Zebrafish Model - A Well-Established Method for Rapidly Assessing the Toxicity of Homeopathic Drugs

PubMed Central

Gupta, Himanshu R; Patil, Yogesh; Singh, Dipty

2016-01-01

Objectives: Advancements in nanotechnology have led to nanoparticle (NP) use in various fields of medicine. Although the potential of NPs is promising, the lack of documented evidence on the toxicological effects of NPs is concerning. A few studies have documented that homeopathy uses NPs. Unfortunately, very few sound scientific studies have explored the toxic effects of homeopathic drugs. Citing this lack of high-quality scientific evidence, regulatory agencies have been reluctant to endorse homeopathic treatment as an alternative or adjunct treatment. This study aimed to enhance our insight into the impact of commercially-available homeopathic drugs, to study the presence of NPs in those drugs and any deleterious effects they might have, and to determine the distribution pattern of NPs in zebrafish embryos (Danio rerio). Methods: Homeopathic dilutions were studied using high-resolution transmission electron microscopy with selected area electron diffraction (SAED). For the toxicity assessment on Zebrafish, embryos were exposed to a test solution from 4 - 6 hours post-fertilization, and embryos/larvae were assessed up to 5 days post-fertilization (dpf) for viability and morphology. Toxicity was recorded in terms of mortality, hatching delay, phenotypic defects and metal accumulation. Around 5 dpf was found to be the optimum developmental stage for evaluation. Results: The present study aimed to conclusively prove the presence of NPs in all high dilutions of homeopathic drugs. Embryonic zebrafish were exposed to three homeopathic drugs with two potencies (30CH, 200CH) during early embryogenesis. The resulting morphological and cellular responses were observed. Exposure to these potencies produced no visibly significant malformations, pericardial edema, and mortality and no necrotic and apoptotic cellular death. Conclusion: Our findings clearly demonstrate that no toxic effects were observed for these three homeopathic drugs at the potencies and exposure times used in this study. The embryonic zebrafish model is recommended as a well-established method for rapidly assessing the toxicity of homeopathic drugs. PMID:28127503

Exploring the novel heterocyclic derivatives as lead molecules for design and development of potent anticancer agents.

PubMed

Azad, Iqbal; Nasibullah, Malik; Khan, Tahmeena; Hassan, Firoj; Akhter, Yusuf

2018-05-01

This paper deals with in silico evaluation of newly proposed heterocyclic derivatives in search of potential anticancer activity. Best possible drug candidates have been proposed using a rational approach employing a pipeline of computational techniques namely MetaPrint2D prediction, molinspiration, cheminformatics, Osiris Data warrior, AutoDock and iGEMDOCK. Lazar toxicity prediction, AdmetSAR predictions, and targeted docking studies were also performed. 27 heterocyclic derivatives were selected for bioactivity prediction and drug likeness score on the basis of Lipinski's rule, Viber rule, Ghose filter, leadlikeness and Pan Assay Interference Compounds (PAINS) rule. Bufuralol, Sunitinib, and Doxorubicin were selected as reference standard drug for the comparison of molecular descriptors and docking. Bufuralol is a known non-selective adreno-receptor blocking agent. Studies showed that beta blockers are also used against different types of cancers. Sunitinib is well known Food and Drug administration (FDA) approved pyrrole containing tyrosine kinase inhibitor and our proposed molecules possess similarities with both drug and doxorubicin is another moiety having anticancer activity. All heterocyclic derivatives were found to obey the drug filters except standard drug Doxorubicin. Bioactivity score of the compounds was predicted for drug targets including enzymes, nuclear receptors, kinase inhibitors, G protein-coupled receptor (GPCR) ligands and ion channel modulators. Absorption, distribution, metabolism and toxicity (ADMET) prediction of all proposed compound showed good Blood-brain barrier (BBB) penetration, Human intestinal absorption (HIA), Caco-2 cell permeability except compound-11 and was found to have no AdmetSAR toxicity as well as carcinogenic effect. Compounds 1-9 were slightly mutagenic while compound 2, 11, 20 and 21 showed carcinogenic effect according to Lazar toxicity prediction. Rests of the compounds were predicted to have no side effect. Molecular docking was performed with vascular endothelial growth factor receptor-2(VEGFR2) and glutathione S-transferase-1 (GSTP1) because both are common cancer causing proteins. Sunitinib and Doxorubicin possess great affinity to inhibit these cancers causing protein. Self-organizing map (SOM) was used to depict data in a simple 2D presentation. Our studies justify that good oral bioavailability and therapeutic efficacy of 10, 12-19 and 22-27 compounds can be considered as potential anticancer agents. Copyright © 2018 Elsevier Inc. All rights reserved.

Macrophage-selective toxicity as a mechanism of hydroquinone-induced myelotoxicity

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

Thomas, D.J.

1989-01-01

This research has focused upon the role of the bone marrow stroma in the etiology of benzene hematotoxicity. Treatment with the metabolite hydroquinone results in a reduced capacity of the stroma to support myelopoiesis. The goal of this research was to examine stromal cell selective toxicity following hydroquinone treatment. Populations of macrophages and a fibroblastoid cell line (LTF) or primary fibroblasts were developed from mouse bone marrow. Following treatment of with hydroquinone, treated or control fibroblastoid cells were reconstituted with control or treated macrophages, respectively, and the cultures were assayed for their ability to support myelopoiesis. To examine mechanisms ofmore » selective toxicity, macrophage and LTF cultures were incubated with 14C-hydroquinone and bioactivation was examined. After 24 hours, macrophages had 16-fold higher levels of bound {sup 14}C than LTF cells. Peroxide-dependent bioactivation in cell homogenates revealed that peroxide could support formation of covalent-binding species in macrophage homogenates but not in LTF homogenates. It was determined that macrophages, but not LTF cells, contained detectable levels of peroxidase activity which was consistent with the postulate that increased binding was due to peroxidase-mediated bioactivation of hydroquinone. Accordingly, purified myeloperoxidase incubated with {sup 14}C-hydroquinone, resulted in bioactivation to a covalent-binding species. This study provided evidence supporting selective bioactivation as a mechanism of selective toxicity of hydroquinone to bone marrow stromal macrophages.« less

Discriminating toxicant classes by mode of action. 1. (Eco)toxicity profiles.

PubMed

Nendza, Monika; Wenzel, Andrea

2006-05-01

Predictive toxicology, particularly quantitative structure-activity relationships (QSARs), require classification of chemicals by mode of action (MOA). MOA is, however, not a constant property of a compound but it varies between species and may change with concentration and duration of exposure. A battery of MOA-specific in-vitro and low-complexity assays, featuring biomolecular targets for major classes of environmental pollutants, provides characteristic responses for (1.) classification of chemicals by MOA, (2.) identification of (eco)toxicity profiles of chemicals, (3.) identification of chemicals with specific MOAs, (4.) indication of most sensitive species, (5.) identification of chemicals that are outliers in QSARs and (6.) selection of appropriate QSARs for predictions. Chemicals covering nine distinct modes of toxic action (non-polar non-specific toxicants (n=14), polar non-specific toxicants (n=18), uncouplers of oxidative phosphorylation (n=25), inhibitors of photosynthesis (n=15), inhibitors of acetylcholinesterase (n=14), inhibitors of respiration (n=3), thiol-alkylating agents (n=9), reactives (irritants) (n=8), estrogen receptor agonists (n=9)) were tested for cytotoxicity in the neutralred assay, oxygen consumption in isolated mitochondria, oxygen production in algae, inhibition of AChE, reaction with GSH and activity in the yeast estrogen receptor assay. Data on in-vivo aquatic toxicity (LC50, EC50) towards fish, daphnids, algae and bacteria were collected from the literature for reasons of comparison and reference scaling. In the MOA-specific in-vitro test battery, most test chemicals are specifically active at low concentrations, though multiple effects do occur. Graphical and statistical evaluation of the individual classes versus MOA 1 (non-polar non-specific toxicants) identifies interactions related to predominant MOA. Discriminant analyses (DA) on subsets of the data revealed correct classifications between 70% (in-vivo data) and >90% (in-vitro data). Functional similarity of chemical substances is defined in terms of their (eco)toxicity profiles. Within each MOA class, the compounds share some properties related to the rate-limiting interactions, e.g., steric fit to the target site and/or reactivity with target biomolecules, revealing a specific pattern (fingerprint) of characteristic effects. The successful discrimination of toxicant classes by MOA is based on comprehensive characterization of test chemicals' properties related to interactions with target sites. The suite of aquatic in-vivo tests using fish, daphnids, algae and bacteria covers most acute effects, whilst long-term (latent) impacts are generally neglected. With the MOA-specific in-vitro test battery such distinctions are futile, because it focuses on isolated targets, i.e. it indicates the possible targets of a chemical regardless of the timescale of effects. The data analysis indicates that the in-vitro battery covers most effects in vivo and moreover provides additional aspects of the compounds' MOA. Translating in-vitro effects to in-vivo toxicity requires combining physiological and chemical knowledge about underlying processes. Comparison of the specific in-vitro effects of a compound with the respective sensitivities of aquatic organisms indicates particularly sensitive species. Classifications of toxicants by MOA based on physicochemical descriptors provides insight to interactions and directs to mechanistic QSARs.

Multidose Preservative Free Eyedrops by Selective Removal of Benzalkonium Chloride from Ocular Formulations.

PubMed

Hsu, Kuan-Hui; Gupta, Karishma; Nayaka, Harish; Donthi, Aashrit; Kaul, Siddarth; Chauhan, Anuj

2017-12-01

About 70% of eye drops contain benzalkonium chloride (BAK) to maintain sterility. BAK is an effective preservative but it can cause irritation and toxicity. We propose to mitigate ocular toxicity without compromising sterility by incorporating a filter into an eye drop bottle to selectively remove BAK during the process of drop instillation. The filter is a packed bed of particles made from poly(2-hydroxyethyl methacrylate) (pHEMA), which is a common ophthalmic material. We showed that pHEMA particle prepared by using ethoxylated trimethylolpropane triacrylate as crosslinker can be incorporated into a modified eyedrop bottle tip to selectively remove the preservative as the formulation is squeezed out of the bottle. Hydraulic permeability of the plug is measured to determine the resistance to eye drop squeezing, and % removal of BAK and drugs are determined. The modified tip has a hydraulic permeability of about 2 Darcy, which allows eyedrops formulations to flow through without excessive resistance. The tip is designed such that the patients can create an eyedrop of solution of 1-10 cP viscosity in 4 s with a nominal pressure. During this short contact time, the packed particles removed nearly 100% of benzalkonium chloride (BAK) from a 15 mL, 0.012% BAK solution but have only minimal impact on the concentration of contained active components. Our novel design can eliminate the preservative induced toxicity from eye drops thereby impacting hundreds of millions of patients with chronic ophthalmic diseases like glaucoma and dry eyes.

The logistics of broader pre-clinical evaluation of potential anti-cancer agents with reference to anti-tumour activity and toxicity of mitozolomide.

PubMed Central

Bibby, M. C.; Double, J. A.; Wahed, I. A.; Hirbawi, N.; Baker, T. G.

1988-01-01

Anti-tumour responses with CCRG81010, M & B 39565, NSC 353451, 8-carbamoyl-3-(2-chloroethyl)imidazo [5,1-d]-1,2,3,5-tetrazin-4(3H)-one (Mitozolomide) in a panel of 4 murine colon tumours of varying growth characteristics and chemosensitivity and a spontaneous murine lymphoma are similar to those seen with standard nitrosoureas. The moderately well differentiated colon adenocarcinoma MAC 16 is nonresponsive to mitozolomide and methylCCNU. Responses in the other 4 lines studied are only achieved near to maximum tolerated dose and at this level there is severe host toxicity. Haemopoietic toxicity is clearly demonstrated by analysis of peripheral blood counts and by CFU-S assays and severe testicular and ovarian toxicity was also seen at dose levels necessary to achieve anti-tumour effects. Using mitozolomide as an example, the study has demonstrated the feasibility of conducting simple but thorough toxicity evaluation for the determination of the therapeutic index. This approach would provide invaluable guidelines for the selection for clinical trial of the most appropriate members of a series of new cytotoxic compounds. Images Figure 4 PMID:3166903

The logistics of broader pre-clinical evaluation of potential anti-cancer agents with reference to anti-tumour activity and toxicity of mitozolomide.

PubMed

Bibby, M C; Double, J A; Wahed, I A; Hirbawi, N; Baker, T G

1988-08-01

Anti-tumour responses with CCRG81010, M & B 39565, NSC 353451, 8-carbamoyl-3-(2-chloroethyl)imidazo [5,1-d]-1,2,3,5-tetrazin-4(3H)-one (Mitozolomide) in a panel of 4 murine colon tumours of varying growth characteristics and chemosensitivity and a spontaneous murine lymphoma are similar to those seen with standard nitrosoureas. The moderately well differentiated colon adenocarcinoma MAC 16 is nonresponsive to mitozolomide and methylCCNU. Responses in the other 4 lines studied are only achieved near to maximum tolerated dose and at this level there is severe host toxicity. Haemopoietic toxicity is clearly demonstrated by analysis of peripheral blood counts and by CFU-S assays and severe testicular and ovarian toxicity was also seen at dose levels necessary to achieve anti-tumour effects. Using mitozolomide as an example, the study has demonstrated the feasibility of conducting simple but thorough toxicity evaluation for the determination of the therapeutic index. This approach would provide invaluable guidelines for the selection for clinical trial of the most appropriate members of a series of new cytotoxic compounds.

Comparative Biochemistry and Metabolism: Part 2. Naphthalene Lung Toxicity

DTIC Science & Technology

1984-10-14

naphthalene, produces a highly selective lesion of the pulmonary bronchiolar epithelium in mice. This lesion appears to depend upon the cytochrome P450...predominating. The rates of metabolism were lower than in rodent lung and there were marked interindividual differences. Pulmonary microsome...54 Effect of Cobalt Protoporphyrin on Naphthalene and 2-Methylnaphthalene-Induced Pulmonary Bronchiolar Necrosis

Reconnaissance of contaminants in selected wastewater-treatment-plant effluent and stormwater runoff entering the Columbia River, Columbia River Basin, Washington and Oregon, 2008-10

USGS Publications Warehouse

Morace, Jennifer L.

2012-01-01

With a better understanding of the presence of these contaminants in the environment, future work can focus on developing research to characterize the effects of these contaminants on aquatic life and prioritize toxic-reduction efforts for the Columbia River Basin.

Use of porewater extracts to identify the cause of toxicity in marine and estuarine sediments

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

Douglas, W.S.

1994-12-31

Amphipod toxicity tests in the evaluation of dredged material proposed for ocean disposal has come under increased scrutiny by the regulated community in the Port of NY/NJ. In recent large-scale assessments of sediment quality in the harbor, the vast majority of locations were deemed highly contaminated when tested with Ampelisca abdita. Toxicity tests, by themselves, do not provide data regarding the cause of toxicity of these sediments. The enormous potential costs associated with most proposed alternatives to ocean disposal of dredged sediments has prompted the investigation of the causative agents of toxicity in sediments of the NY/NJ Harbor. Sediment frommore » five locations in the harbor, selected in consultation with local regulatory agencies to represent diverse potential contamination scenarios, was collected and tested for toxicity to the amphipods Ampelisca abdita, Leptocheirus plumulosus, Eohaustorius estuadus, Rhepoxynius abronius, and the mysid shrimp, Mysidopsis bahia, using 10-day static bioassays. Porewater from each of the five sediments was extracted under centrifugation and used in water-only toxicity tests with A. abdita, L. plumulosus, R. abronius, E. estuadus, M. bahia, M. beryllina, and Microtox. A Phase 1 Toxicity Identification Evaluation of the three most toxic porewater samples was conducted using several of the species tested. Results from the preliminary investigations and the ongoing TIE`s will be presented. Species selection, porewater toxicity test procedures, and Phase 1, 2, and 3 paradigms will be discussed.« less

Molecular characterization and identification of markers for toxic and non-toxic varieties of Jatropha curcas L. using RAPD, AFLP and SSR markers.

PubMed

Sudheer Pamidimarri, D V N; Singh, Sweta; Mastan, Shaik G; Patel, Jalpa; Reddy, Muppala P

2009-07-01

Jatropha curcas L., a multipurpose shrub has acquired significant economic importance for its seed oil which can be converted to biodiesel, is emerging as an alternative to petro-diesel. The deoiled seed cake remains after oil extraction is toxic and cannot be used as a feed despite having best nutritional contents. No quantitative and qualitative differences were observed between toxic and non-toxic varieties of J. curcas except for phorbol esters content. Development of molecular marker will enable to differentiate non-toxic from toxic variety in a mixed population and also help in improvement of the species through marker assisted breeding programs. The present investigation was undertaken to characterize the toxic and non-toxic varieties at molecular level and to develop PCR based molecular markers for distinguishing non-toxic from toxic or vice versa. The polymorphic markers were successfully identified specific to non-toxic and toxic variety using RAPD and AFLP techniques. Totally 371 RAPD, 1,442 AFLP markers were analyzed and 56 (15.09%) RAPD, 238 (16.49%) AFLP markers were found specific to either of the varieties. Genetic similarity between non-toxic and toxic verity was found to be 0.92 by RAPD and 0.90 by AFLP fingerprinting. In the present study out of 12 microsatellite markers analyzed, seven markers were found polymorphic. Among these seven, jcms21 showed homozygous allele in the toxic variety. The study demonstrated that both RAPD and AFLP techniques were equally competitive in identifying polymorphic markers and differentiating both the varieties of J. curcas. Polymorphism of SSR markers prevailed between the varieties of J. curcas. These RAPD and AFLP identified markers will help in selective cultivation of specific variety and along with SSRs these markers can be exploited for further improvement of the species through breeding and Marker Assisted Selection (MAS).

Evidence-based recommendations on the use of intravenous lipid emulsion therapy in poisoning.

PubMed

Gosselin, Sophie; Hoegberg, Lotte C G; Hoffman, Robert S; Graudins, Andis; Stork, Christine M; Thomas, Simon H L; Stellpflug, Samuel J; Hayes, Bryan D; Levine, Michael; Morris, Martin; Nesbitt-Miller, Andrea; Turgeon, Alexis F; Bailey, Benoit; Calello, Diane P; Chuang, Ryan; Bania, Theodore C; Mégarbane, Bruno; Bhalla, Ashish; Lavergne, Valéry

2016-12-01

Although intravenous lipid emulsion (ILE) was first used to treat life-threatening local anesthetic (LA) toxicity, its use has expanded to include both non-local anesthetic (non-LA) poisoning and less severe manifestations of toxicity. A collaborative workgroup appraised the literature and provides evidence-based recommendations for the use of ILE in poisoning. Following a systematic review of the literature, data were summarized in four publications: LA and non-LA poisoning efficacy, adverse effects, and analytical interferences. Twenty-two toxins or toxin categories and three clinical situations were selected for voting. Voting statements were proposed using a predetermined format. A two-round modified Delphi method was used to reach consensus on the voting statements. Disagreement was quantified using RAND/UCLA Appropriateness Method. For the management of cardiac arrest, we recommend using ILE with bupivacaine toxicity, while our recommendations are neutral regarding its use for all other toxins. For the management of life-threatening toxicity, (1) as first line therapy, we suggest not to use ILE with toxicity from amitriptyline, non-lipid soluble beta receptor antagonists, bupropion, calcium channel blockers, cocaine, diphenhydramine, lamotrigine, malathion but are neutral for other toxins, (2) as part of treatment modalities, we suggest using ILE in bupivacaine toxicity if other therapies fail, but are neutral for other toxins, (3) if other therapies fail, we recommend ILE for bupivacaine toxicity and we suggest using ILE for toxicity due to other LAs, amitriptyline, and bupropion, but our recommendations are neutral for all other toxins. In the treatment of non-life-threatening toxicity, recommendations are variable according to the balance of expected risks and benefits for each toxin. For LA-toxicity we suggest the use of Intralipid ® 20% as it is the formulation the most often reported. There is no evidence to support a recommendation for the best formulation of ILE for non-LAs. The voting panel is neutral regarding ILE dosing and infusion duration due to insufficient data for non-LAs. All recommendations were based on very low quality of evidence. Clinical recommendations regarding the use of ILE in poisoning were only possible in a small number of scenarios and were based mainly on very low quality of evidence, balance of expected risks and benefits, adverse effects, laboratory interferences as well as related costs and resources. The workgroup emphasizes that dose-finding and controlled studies reflecting human poisoning scenarios are required to advance knowledge of limitations, indications, adverse effects, effectiveness, and best regimen for ILE treatment.

The effect of the lamprey larvicide, 3-trifluormethyl-4-nitrophenol, on selected aquatic invertebrates

USGS Publications Warehouse

Smith, Allen J.

1967-01-01

The chemical compound 3-trifluoromethyl-4-nitrophenol (TFM) is used to control the sea lamprey (Petromyzon marinus) in the upper Great Lakes. It is introduced into streams in which sea lampreys have spawned, to kill the larvae. These 'treatments' are carried out at intervals shorter than the larval phase of the sea lamprey's life cycle (about 4 to 7 years) to prevent movement of the metamorphosed parasitic lampreys into the lakes. Most of the streams which contain sea lamprey larvae also have valuable resident fish or serve as spawning and nursery areas for fish of the Great Lakes. These species must be protected from both the direct toxic effects of the control method and from indirect effects such as destruction of food supplies. Studies have shown that TFM is nontoxic to most species of fish when used at the concentrations that kill larval lampreys. Information on the effect of TFM on aquatic invertebrates is meager. Applegate et al. reported that TFM was not harmful to selected invertebrates which they included in simulated stream tests. They also stated that no harmful effects to invertebrates were observed during actual stream application. The variety of invertebrate species used in simulated stream tests was limited, and close observation of invertebrates under stream conditions is difficult. Therefore, the present laboratory bioassays were conducted to determine the toxicity of TFM to representatives of a number of groups of invertebrates.

Immunophototherapy for the treatment of AIDS and AIDS-related infections

NASA Astrophysics Data System (ADS)

Schlager, Kenneth J.

1992-06-01

Immunophototherapy (IPT) is an experimental method of medical treatment that seeks to provide for the selective destruction of diseased cells and microbes such as human immunodeficiency virus (HIV)-T4 cells and the rapid elimination of their toxic by-products from the human body. Photosensitive monoclonal or polyclonal antibody fragments, which are specific to the diseased cell or microbe, will be used to treat acquired immunodeficiency syndrome (AIDS) and related infections. These antibody fragments are tagged with photosensitive compounds and metal colloids and then intravenously injected into the patient. The tagged antibodies quickly and selectively bind to the diseased cells or microbes in the blood stream and affected organs. These cells or microbes are then selectively destroyed by irradiation of these complexes with light of the proper wavelength. This light activates the photosensitive material which then creates singlet oxygen that destroys the microbe or cell. Toxic products of lysis are quickly discharged from the body by activation of the reticuloendothelial system. IPT has been demonstrated by Biotronics to be very effective in the in vitro selective destruction of specified cell types. In a proposed AIDS-treatment research program, IPT will be first demonstrated in vitro for a set of infected blood samples using commercially-available antibodies labeled with appropriate photosensitizers. Efficacy will be determined by a p24 antigen immunodiagnostic test that will indicate the % inhibition in comparison to controls and samples treated with the drug AZT. Subcontracted animal efficacy studies will use a SCID-hu mouse model and PCR/DNA-RNA for endpoint analysis. Toxicity studies of animal (rat) models will be based on post-treatment investigations of lymph nodes, spleen, liver and other organs.

Cytotoxicity of Nanoparticles Contained in Food on Intestinal Cells and the Gut Microbiota

PubMed Central

Fröhlich, Esther E.; Fröhlich, Eleonore

2016-01-01

Toxicity of nanoparticles (NPs) upon oral exposure has been studied in animals using physiological changes, behavior, histology, and blood analysis for evaluation. The effects recorded include the combination of the action on cells of the exposed animal and the reaction of the microorganisms that populate the external and internal surfaces of the body. The importance of these microorganisms, collectively termed as microbiota, for the health of the host has been widely recognized. They may also influence toxicity of NPs but these effects are difficult to differentiate from toxicity on cells of the gastrointestinal tract. To estimate the likelihood of preferential damage of the microbiota by NPs the relative sensitivity of enterocytes and bacteria was compared. For this comparison NPs with antimicrobial action present in consumer products were chosen. The comparison of cytotoxicity with Escherichia coli as representative for intestinal bacteria and on gastrointestinal cells revealed that silver NPs damaged bacteria at lower concentrations than enterocytes, while the opposite was true for zinc oxide NPs. These results indicate that silver NPs may cause adverse effects by selectively affecting the gut microbiota. Fecal transplantation from NP-exposed animals to unexposed ones offers the possibility to verify this hypothesis. PMID:27058534

Metal release from contaminated leaf litter and leachate toxicity for the freshwater crustacean Gammarus fossarum.

PubMed

Maunoury-Danger, Florence; Felten, Vincent; Bojic, Clément; Fraysse, Fabrice; Cosin Ponce, Mar; Dedourge-Geffard, Odile; Geffard, Alain; Guérold, François; Danger, Michael

2018-04-01

Industrialization has left large surfaces of contaminated soils, which may act as a source of pollution for contiguous ecosystems, either terrestrial or aquatic. When polluted sites are recolonized by plants, dispersion of leaf litter might represent a non-negligible source of contaminants, especially metals. To evaluate the risks associated to contaminated leaf litter dispersion in aquatic ecosystems, we first measured the dynamics of metal loss from leaf litter during a 48-h experimental leaching. We used aspen (Populus tremula L.), a common tree species on these polluted sites, and collected leaf litter on three polluted sites (settling pond of a former steel mill) and three control sites situated in the same geographic area. Then, toxicity tests were carried out on individuals of a key detritivore species widely used in ecotoxicology tests, Gammarus fossarum (Crustacea, Amphipoda), with uncontaminated and contaminated leaf litter leachates, using a battery of biomarkers selected for their sensitivity to metallic stress. Leaf litters collected on polluted sites exhibited not only significantly higher cadmium and zinc concentrations but also lower lignin contents. All leaf litters released high amounts of chemical elements during the leaching process, especially potassium and magnesium, and, in a lesser extent, phosphorus, calcium, and trace metals (copper, cadmium, and zinc but not lead). Toxicity tests revealed that the most important toxic effects measured on G. fossarum were due to leaf litter leachates by themselves, whatever the origin of litter (from polluted or control sites), confirming the toxicity of such substances, probably due to their high content in phenolic compounds. Small additional toxic effects of leachates from contaminated leaf litters were only evidenced on gammarid lipid peroxidation, indicating that contaminated leaf litter leachates might be slightly more toxic than uncontaminated ones, but in a very reduced manner. Further studies will be required to verify if these patterns are generalizable to other species and to investigate the effects of contaminated leaf litter ingestion by consumers on aquatic food webs. Nevertheless, our results do not permit to exclude potential chronic effects of an exposure to contaminated leaf litter leachates in aquatic ecosystems.

Astaxanthin and Docosahexaenoic Acid Reverse the Toxicity of the Maxi-K (BK) Channel Antagonist Mycotoxin Penitrem A

PubMed Central

Goda, Amira A.; Naguib, Khayria M.; Mohamed, Magdy M.; Amra, Hassan A.; Nada, Somaia A.; Abdel-Ghaffar, Abdel-Rahman B.; Gissendanner, Chris R.; El Sayed, Khalid A.

2016-01-01

Penitrem A (PA) is a food mycotoxin produced by several terrestrial and few marine Penicillium species. PA is a potent tremorgen through selective antagonism of the calcium-dependent potassium BK (Maxi-K) channels. Discovery of natural products that can prevent the toxic effects of PA is important for food safety. Astaxanthin (AST) is a marine natural xanthophyll carotenoid with documented antioxidant activity. Unlike other common antioxidants, AST can cross blood brain barriers (BBBs), inducing neuroprotective effects. Docosahexaenoic acid (DHA) is polyunsaturated ω-3 fatty acid naturally occurring in fish and algae. DHA is essential for normal neurological and cellular development. This study evaluated the protective activity of AST and DHA against PA-induced toxicity, in vitro on Schwann cells CRL-2765 and in vivo in the worm Caenorhbitidis elegans and Sprague Dawley rat models. PA inhibited the viability of Schwann cells, with an IC50 of 22.6 μM. Dose-dependent treatments with 10–100 μM DHA significantly reversed the PA toxicity at its IC50 dose, and improved the survival of Schwann cells to 70.5%–98.8%. Similarly, dose-dependent treatments with 10–20 μM AST reversed the PA toxicity at its IC50 dose and raised these cells’ survival to 61.7%–70.5%. BK channel inhibition in the nematode C. elegans is associated with abnormal reversal locomotion. DHA and AST counteracted the in vivo PA BK channel antagonistic activity in the C. elegans model. Rats fed a PA-contaminated diet showed high levels of glutamate (GLU), aspartate (ASP), and gamma amino butyric acid (GABA), with observed necrosis or absence of Purkinjie neurons, typical of PA-induced neurotoxicity. Dopamine (DA), serotonin (5-HT), and norepinephrine (NE) levels were abnormal, Nitric Oxide (NO) and Malondialdehyde (MDA) levels were significantly increased, and total antioxidant capacity (TAC) level in serum and brain homogenates was significantly decreased in PA-treated rats. DHA and AST treatments effectively counteracted the toxic effects of PA and normalized most biochemical parameters in rats. DHA and AST can be useful food additives to prevent and reverse PA food-induced toxicity. PMID:27834847

Spatial-temporal and cancer risk assessment of selected hazardous air pollutants in Seattle.

PubMed

Wu, Chang-fu; Liu, L-J Sally; Cullen, Alison; Westberg, Hal; Williamson, John

2011-01-01

In the Seattle Air Toxics Monitoring Pilot Program, we measured 15 hazardous air pollutants (HAPs) at 6 sites for more than a year between 2000 and 2002. Spatial-temporal variations were evaluated with random-effects models and principal component analyses. The potential health risks were further estimated based on the monitored data, with the incorporation of the bootstrapping technique for the uncertainty analysis. It is found that the temporal variability was generally higher than the spatial variability for most air toxics. The highest temporal variability was observed for tetrachloroethylene (70% temporal vs. 34% spatial variability). Nevertheless, most air toxics still exhibited significant spatial variations, even after accounting for the temporal effects. These results suggest that it would require operating multiple air toxics monitoring sites over a significant period of time with proper monitoring frequency to better evaluate population exposure to HAPs. The median values of the estimated inhalation cancer risks ranged between 4.3 × 10⁻⁵ and 6.0 × 10⁻⁵, with the 5th and 95th percentile levels exceeding the 1 in a million level. VOCs as a whole contributed over 80% of the risk among the HAPs measured and arsenic contributed most substantially to the overall risk associated with metals. Copyright © 2010 Elsevier Ltd. All rights reserved.

Toxicity of Piper aduncum (Piperaceae) Essential Oil Against Euschistus heros (F.) (Hemiptera: Pentatomidae) and Non-Effect on Egg Parasitoids.

PubMed

Turchen, L M; Piton, L P; Dall'Oglio, E L; Butnariu, A R; Pereira, M J B

2016-10-01

Plant essential oils have been recognized as significant natural resources for insecticides. Herein, we have assessed the toxicity of the essential oil of Piper aduncum (Piperaceae) against Euschistus heros (F.) (Hemiptera: Pentatomidae), a key soybean pest in Neotropical America. In addition, we have assessed its effect on the performance of egg parasitoids. The essential oil was obtained from the leaves of P. aduncum via hydrodistillation. Subsequently, bioassays of the concentration response to eggs (contact and immersion methods), nymphs, and adults (topical application) were conducted, to assess the lethal effects on the stink bug. We also evaluated the performance of parasitism and adult emergence of egg parasitoids, when the host eggs were treated with essential oil. In the egg bioassay, both exposure methods were efficient for unviable eggs (immersion LC 50  = 15.64 mg mL -1 ; contact LC 50  = 21.29 mg mL -1 ), with the highlight on the immersion method. The bioassay with nymphs indicated a higher toxicity of essential oil, with lower concentrations (LC 50  = 11.37 mg mL -1 ) being required to cause the death of insects. For adults, a reduction in survival of insects was observed, and consequently, there was a reduction in the number of individuals in the next generation. Although the essential oil was toxic to E. heros, it exhibited lower toxicity for egg parasitoids, as there was no effect on parasitism and the emergence of wasps. We discuss likely explanations for such selectivity. In summary, we found that the essential oil was promising for the control of E. heros, because it caused deleterious effects at all development stages of the stink bug and had no effect on parasitism and emergence of the egg parasitoids, which suggested compatibility with biological control.

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

A MAA-based dosimetric study in patients with intrahepatic cholangiocarcinoma treated with a combination of chemotherapy and 90Y-loaded glass microsphere selective internal radiation therapy.

PubMed

Manceau, Vincent; Palard, Xavier; Rolland, Yan; Pracht, March; Le Sourd, Samuel; Laffont, Sophie; Boudjema, Karim; Lievre, Astride; Mesbah, Habiba; Haumont, Laure-Anne; Lenoir, Laurence; Brun, Vanessa; Uguen, Thomas; Edeline, Julien; Garin, Etienne

2018-03-20

Selective internal radiation therapy (SIRT) appears to be an interesting treatment possibility for locally-advanced intrahepatic cholangiocarcinoma (ICC), yet the appropriate dosimetry has never been evaluated in this context. We retrospectively studied data from 40 patients treated at our institution with 90 Y-loaded glass microsphere SIRT combined with chemotherapy for inoperable ICC as first-line treatment. Macroaggregated albumin (MAA)-based single-photon emission computed tomography (SPECT)/computed tomography (CT) quantitative analysis was used to calculate the tumor dose (TD), healthy-injected liver dose (HILD), and injected liver dose (ILD). Response was evaluated at 3 months using the European Association for the Study of the Liver criteria. Factors associated with response and toxicity were analyzed using univariate analysis. We assessed a total of 35 patients (five excluded) receiving 55 injections. Mean TD was 322 ± 165Gy and mean HILD was 74 ± 24Gy for a mean ILD of 128 ± 28Gy. All but two lesions responded, with a minimal TD for responding lesions of 158Gy. Six Grade 3-4 permanent liver toxicities were observed. Mean HILD was not associated with liver toxicity (73.2 ± 25.8Gy for patients with liver toxicity and 77.8 ± 16.9Gy for patients without, ns). Only underlying Child-Pugh status (p = 0.0014) and underlying cirrhosis (p = 0.0021) were associated with liver toxicity. Median progression-free survival was 12.7 months and median overall survival (OS) was 28.6 months. Median OS was 52.7 months for patients with Child-Pugh A5 status. When combined with chemotherapy, SIRT is highly effective, with a TD > 158Gy. Tolerance was good except for the few patients with cirrhosis or Child-Pugh status ≥A6, who exhibited some liver toxicity. Prospective studies are warranted to confirm.

Mode of action and variability in efficacy of plant essential oils showing toxicity against the poultry red mite, Dermanyssus gallinae.

PubMed

George, D R; Smith, T J; Shiel, R S; Sparagano, O A E; Guy, J H

2009-05-12

This paper describes a series of experiments to examine the mode of action and toxicity of three plant essential oils (thyme, manuka and pennyroyal) to the poultry red mite, Dermanyssus gallinae (De Geer), a serious ectoparasitic pest of laying hens. All three oils were found to be toxic to D. gallinae in laboratory tests with LC(50), LC(90) and LC(99) values below 0.05, 0.20 and 0.30mg/cm(3), respectively, suggesting that these products may make for effective acaricides against this pest. Further experiments demonstrated that when mites were exposed to only the vapour phase of the essential oil without contact with the oil itself, mortality was consistently higher in closed arenas than in arenas open to the surrounding environment, or in control arenas. This suggests that all three essential oils were toxic to D. gallinae by fumigant action. In addition, in an experiment where mites were allowed contact with the essential oil in either open or closed arenas, mortality was always reduced in the open arenas where this was comparable to control mortality for thyme and pennyroyal essential oil treatments. This supports the findings of the previous experiment and also suggests that, with the possible exception of manuka, the selected essential oils were not toxic to D. gallinae on contact. Statistical comparisons were made between the toxicity of the selected essential oils to D. gallinae in the current work and in a previous study conducted in the same laboratory. The results demonstrated considerable variation in LC(50), LC(90) and LC(99) values. Since both the essential oils and the mites were obtained from identical sources in the two studies, it is hypothesized that this variation resulted from the use of different 'batches' of essential oil, which could have varied in chemistry and hence acaricidal activity.

Development of QSAR models using artificial neural network analysis for risk assessment of repeated-dose, reproductive, and developmental toxicities of cosmetic ingredients.

PubMed

Hisaki, Tomoka; Aiba Née Kaneko, Maki; Yamaguchi, Masahiko; Sasa, Hitoshi; Kouzuki, Hirokazu

2015-04-01

Use of laboratory animals for systemic toxicity testing is subject to strong ethical and regulatory constraints, but few alternatives are yet available. One possible approach to predict systemic toxicity of chemicals in the absence of experimental data is quantitative structure-activity relationship (QSAR) analysis. Here, we present QSAR models for prediction of maximum "no observed effect level" (NOEL) for repeated-dose, developmental and reproductive toxicities. NOEL values of 421 chemicals for repeated-dose toxicity, 315 for reproductive toxicity, and 156 for developmental toxicity were collected from Japan Existing Chemical Data Base (JECDB). Descriptors to predict toxicity were selected based on molecular orbital (MO) calculations, and QSAR models employing multiple independent descriptors as the input layer of an artificial neural network (ANN) were constructed to predict NOEL values. Robustness of the models was indicated by the root-mean-square (RMS) errors after 10-fold cross-validation (0.529 for repeated-dose, 0.508 for reproductive, and 0.558 for developmental toxicity). Evaluation of the models in terms of the percentages of predicted NOELs falling within factors of 2, 5 and 10 of the in-vivo-determined NOELs suggested that the model is applicable to both general chemicals and the subset of chemicals listed in International Nomenclature of Cosmetic Ingredients (INCI). Our results indicate that ANN models using in silico parameters have useful predictive performance, and should contribute to integrated risk assessment of systemic toxicity using a weight-of-evidence approach. Availability of predicted NOELs will allow calculation of the margin of safety, as recommended by the Scientific Committee on Consumer Safety (SCCS).

Moderate hypofractionated radiotherapy with volumetric modulated arc therapy and simultaneous integrated boost for pelvic irradiation in prostate cancer.

PubMed

Franzese, C; Fogliata, A; D'Agostino, G R; Di Brina, L; Comito, T; Navarria, P; Cozzi, L; Scorsetti, M

2017-07-01

The optimal treatment for unfavourable intermediate/high-risk prostate cancer is still debated. In the present study, the pattern of toxicity and early clinical outcome of patients with localized prostate cancer was analyzed. A cohort of 90 patients treated on pelvic lymph nodes from 2010 to 2015 was selected. All patients were treated with Volumetric Modulated Arc Therapy (VMAT), and Simultaneous integrated boost (SIB) in 28 fractions; the prostate, the seminal vesicle and the pelvic lymph node received total doses of 74.2, 65.5, and 51.8 Gy, respectively. End points were the detection of acute and late toxicities graded according to the Common Toxicity Criteria CTCAE version 3, evaluating the rectal, genito-urinary and gastro-intestinal toxicity. Correlation of OARs dose parameters and related toxicities was explored. Preliminary overall survival and Progression-free survival (PFS) were evaluated. With a median follow-up of 25 months, no interruptions for treatment-related toxicity were recorded. Univariate analysis among dosimetric data and acute toxicities showed no correlations. Regarding late toxicity: the dose received by a rectal volume of 90 cm 3 was found to be significant for toxicity prediction (p = 0.024). PFS was 90.6% and 60.2% at 2 and 4 years, respectively. PFS correlates with age (p = 0.011) and Gleason score (p = 0.011). Stratifying the PSA nadir in quartiles, its value was significant (p = 0.016) in predicting PFS, showing a reduction of PFS of 2 months for each PSA-nadir increase of 0.1 ng/ml. HRT with VMAT and SIB on the whole pelvis in unfavourable prostate cancer patients is effective with a mild pattern of toxicity.

Preclinical animal acute toxicity studies of new developed MRI contrast agent based on gadolinium

NASA Astrophysics Data System (ADS)

Nam, I. F.; Zhuk, V. V.

2015-04-01

Acute toxicity test of new developed MRI contrast agent based on disodium salt of gadopentetic acid complex were carried out on Mus musculus and Sprague Dawley rats according to guidelines of preclinical studies [1]. Groups of six animals each were selected for experiment. Death and clinical symptoms of animals were recorded during 14 days. As a result the maximum tolerated dose (MTD) for female mice is 2.8 mM/kg of body weight, male mice - 1.4 mM/kg, female rats - 2.8 mM/kg, male rats - 5.6 mM/kg of body weight. No Observed Adverse Effect Dose (NOAEL) for female mice is 1.4 mM/kg, male mice - 0.7 mM/kg, male and female rats - 0.7 mM/kg. According to experimental data new developed MRI contrast agent based on Gd-DTPA complex is low-toxic.

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

Bolton, N. E.; Ketchen, E. E.; Porter, W. E.

For large industrial and research operations, maintaining reasonable control of all toxic materials used in their operations can be a formidable task. A system utilizing cards has been developed that serves a dual purpose, informing the user regarding hazards of a particular material and also facilitating appropriate workplace surveillance during its use. Selected data, including threshold limit values, routes of absorption, symptoms of exposure, chronic effects, and emergency first-aid procedures, are printed on the card. A portion of the card contains the label that the user detaches and affixes to the container. This label classifies the material according to flammability,more » toxicity, reactivity, and special properties on a 0 through 4 hazard rating system. This report describes the development and use of such cards, contains the associated Toxic Material Data Sheets that provide full backup data for the labels, and furnishes a glossary of biomedical terms used in the Data Sheets.« less

ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function

PubMed Central

Sharma, Aarti; Lyashchenko, Alexander K.; Lu, Lei; Nasrabady, Sara Ebrahimi; Elmaleh, Margot; Mendelsohn, Monica; Nemes, Adriana; Tapia, Juan Carlos; Mentis, George Z.; Shneider, Neil A.

2016-01-01

Mutations in FUS cause amyotrophic lateral sclerosis (ALS), including some of the most aggressive, juvenile-onset forms of the disease. FUS loss-of-function and toxic gain-of-function mechanisms have been proposed to explain how mutant FUS leads to motor neuron degeneration, but neither has been firmly established in the pathogenesis of ALS. Here we characterize a series of transgenic FUS mouse lines that manifest progressive, mutant-dependent motor neuron degeneration preceded by early, structural and functional abnormalities at the neuromuscular junction. A novel, conditional FUS knockout mutant reveals that postnatal elimination of FUS has no effect on motor neuron survival or function. Moreover, endogenous FUS does not contribute to the onset of the ALS phenotype induced by mutant FUS. These findings demonstrate that FUS-dependent motor degeneration is not due to loss of FUS function, but to the gain of toxic properties conferred by ALS mutations. PMID:26842965

Acute toxic effects of two lampricides on twenty-one freshwater invertebrates

USGS Publications Warehouse

Rye, Robert P.; King, Everett Louis

1976-01-01

We conducted laboratory static bioassays to determine acute toxicity of two lampricides -- a 70% 2-aminoethanol salt of 5,2'dichloro-4'-nitrosalicylanilide (Bayer 73) and a mixture containing 98% 3-trifluoromethyl-4-nitrophenol (TFM) and 2% Bayer 73 (TFM-2B) -- to 21 freshwater invertebrates. LC50 values were determined for 24-h exposure periods at 12.8 C. Organisms relatively sensitive to Bayer 73 were a turbellarian (Dugesia tigrina), aquatic earthworms (Tubifex tubifex and Lumbriculus inconstans), snails (Physa sp.) and (Pleurocera sp.), a clam (Eliptio dilatatus), blackflies (Simulium sp.), leeches (Erpobdellidae), and a daphnid (Daphnia pulex). The invertebrates most sensitive to TFM-2B were turbellarians, aquatic earthworms (Tubifex), snails (Physa), blackflies, leeches, and burrowing mayflies (Hexagenia sp.). Bayer 73 was generally much more toxic to the test organisms than TFM-2B. At lampricidal concentrations, TFM-2B was more highly selective than Bayer 73 against larval sea lampreys (Petromyzon marinus).

ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function.

PubMed

Sharma, Aarti; Lyashchenko, Alexander K; Lu, Lei; Nasrabady, Sara Ebrahimi; Elmaleh, Margot; Mendelsohn, Monica; Nemes, Adriana; Tapia, Juan Carlos; Mentis, George Z; Shneider, Neil A

2016-02-04

Mutations in FUS cause amyotrophic lateral sclerosis (ALS), including some of the most aggressive, juvenile-onset forms of the disease. FUS loss-of-function and toxic gain-of-function mechanisms have been proposed to explain how mutant FUS leads to motor neuron degeneration, but neither has been firmly established in the pathogenesis of ALS. Here we characterize a series of transgenic FUS mouse lines that manifest progressive, mutant-dependent motor neuron degeneration preceded by early, structural and functional abnormalities at the neuromuscular junction. A novel, conditional FUS knockout mutant reveals that postnatal elimination of FUS has no effect on motor neuron survival or function. Moreover, endogenous FUS does not contribute to the onset of the ALS phenotype induced by mutant FUS. These findings demonstrate that FUS-dependent motor degeneration is not due to loss of FUS function, but to the gain of toxic properties conferred by ALS mutations.

Toxicity of plant essential oils to different life stages of the poultry red mite, Dermanyssus gallinae, and non-target invertebrates.

PubMed

George, D R; Sparagano, O A E; Port, G; Okello, E; Shiel, R S; Guy, J H

2010-03-01

Seven essential oils with potential as acaricides for use against the poultry red mite, Dermanyssus gallinae (De Geer) (Acari: Dermanyssidae), were selected for study. These products (essential oils of manuka, cade, pennyroyal, thyme, garlic, clove bud and cinnamon bark) were deployed against different life stages of D. gallinae in laboratory tests at the (lethal concentration) LC(50) level for adult mites. For all essential oils tested, toxicity to D. gallinae juveniles was as high as toxicity to adults, if not higher. However, at the LC(50) level determined for adults, some oils were ineffective in preventing hatching of D. gallinae eggs. The essential oils were also tested under laboratory conditions at their LC(90) levels for D. gallinae adults on two model non-target species, the brine shrimp, Artemia salina (L.), and the mealworm beetle, Tenebrio molitor (L.). Results showed that not all essential oils were as toxic to A. salina and T. molitor as they were to D. gallinae, suggesting that it may be possible to select certain oils for development as acaricides against D. gallinae that would have minimal impact on non-target organisms. However, the level of toxicity to A. salina and T. molitor was not consistent across the selected essential oils.

Patient- and therapy-related factors associated with the incidence of xerostomia in nasopharyngeal carcinoma patients receiving parotid-sparing helical tomotherapy.

PubMed

Lee, Tsair-Fwu; Liou, Ming-Hsiang; Ting, Hui-Min; Chang, Liyun; Lee, Hsiao-Yi; Wan Leung, Stephen; Huang, Chih-Jen; Chao, Pei-Ju

2015-08-20

We investigated the incidence of moderate to severe patient-reported xerostomia among nasopharyngeal carcinoma (NPC) patients treated with helical tomotherapy (HT) and identified patient- and therapy-related factors associated with acute and chronic xerostomia toxicity. The least absolute shrinkage and selection operator (LASSO) normal tissue complication probability (NTCP) models were developed using quality-of-life questionnaire datasets from 67 patients with NPC. For acute toxicity, the dosimetric factors of the mean doses to the ipsilateral submandibular gland (Dis) and the contralateral submandibular gland (Dcs) were selected as the first two significant predictors. For chronic toxicity, four predictive factors were selected: age, mean dose to the oral cavity (Doc), education, and T stage. The substantial sparing data can be used to avoid xerostomia toxicity. We suggest that the tolerance values corresponded to a 20% incidence of complications (TD20) for Dis = 39.0 Gy, Dcs = 38.4 Gy, and Doc = 32.5 Gy, respectively, when mean doses to the parotid glands met the QUANTEC 25 Gy sparing guidelines. To avoid patient-reported xerostomia toxicity, the mean doses to the parotid gland, submandibular gland, and oral cavity have to meet the sparing tolerance, although there is also a need to take inherent patient characteristics into consideration.

Toxic hydrogen sulfide and dark caves: life-history adaptations in a livebearing fish (Poecilia mexicana, Poeciliidae).

PubMed

Riesch, Rüdiger; Plath, Martin; Schlupp, Ingo

2010-05-01

Life-history traits are very sensitive to extreme environmental conditions, because resources that need to be invested in somatic maintenance cannot be invested in reproduction. Here we examined female life-history traits in the Mexican livebearing fish Poecilia mexicana from a variety of benign surface habitats, a creek with naturally occurring toxic hydrogen sulfide (H2S), a sulfidic cave, and a non-sulfidic cave. Previous studies revealed pronounced genetic and morphological divergence over very small geographic scales in this system despite the absence of physical barriers, suggesting that local adaptation to different combinations of two selection factors, toxicity (H2S) and darkness, is accompanied by very low rates of gene flow. Hence, we investigated life-history divergence between these populations in response to the selective pressures of darkness and/or toxicity. Our main results show that toxicity and darkness both select for (or impose constraints on) the same female trait dynamics: reduced fecundity and increased offspring size. Since reduced fecundity in the sulfur cave population was previously shown to be heritable, we discuss how divergent life-history evolution may promote further ecological divergence: for example, reduced fecundity and increased offspring autonomy are clearly beneficial in extreme environments, but fish with these traits are outcompeted in benign habitats.

Decaleside: a new class of natural insecticide targeting tarsal gustatory sites

NASA Astrophysics Data System (ADS)

Rajashekar, Yallappa; Rao, Lingamallu J. M.; Shivanandappa, Thimmappa

2012-10-01

Natural sources for novel insecticide molecules hold promise in view of their eco-friendly nature, selectivity, and mammalian safety. Recent progress in understanding the biology of insect olfaction and taste offers new strategies for developing selective pest control agents. We have isolated two natural insecticidal molecules from edible roots of Decalepis hamiltonii named Decalesides I and II, which are novel trisaccharides, highly toxic to household insect pests and stored-product insects. We have experimentally shown that insecticidal activity requires contact with tarsi on the legs but is not toxic orally. The insecticidal activity of molecules is lost by hydrolysis, and various sugars modify toxic response, showing that the insecticidal activity is via gustatory sites on the tarsi. Selective toxicity to insects by virtue of their gustatory site of action and the mammalian safety of the new insecticides is inherent in their chemical structure with 1-4 or 1-1 α linkage that is easily hydrolyzed by digestive enzymes of mammals. Decalesides represent a new chemical class of natural insecticides with a unique mode of action targeting tarsal chemosensory/gustatory system of insects.

Toxicity of new pyrethroid in pest insects Asciamonuste and Diaphania hyalinata, predator Solenopsis saevissima and stingless bee Tetragonisca angustula.

PubMed

Moreno, Shaiene C; Silvério, Flaviano O; Lopes, Mayara C; Ramos, Rodrigo S; Alvarenga, Elson S; Picanço, Marcelo C

2017-04-03

There is increasing demand for new products for vegetable pest management. Thus, the aim of this study was to assess the toxicity of pyrethroids with acid moiety modifications to measure the insecticidal activity of these compounds on the lepidopteran vegetable pests Diaphania hyalinata (L.) (Lepidoptera: Pyralidae) and Asciamonuste (Latreille) (Lepidoptera: Pieridae) and evaluate their selectivity for the predatory ant Solenopsis saevissima (F. Smith) (Hymenoptera: Formicidae) and pollinator Tetragonisca angustula (Latreille) (Hymenoptera: Apidae: Meliponinae). Racemic mixtures of five new pyrethroids (30 µg molecule mg -1 insect body weight) resulted in high (100%) and rapid (stable LD 50 after 12 h) mortality in D. hyalinata and A. monuste. In A. monuste, the trans-pyrethroid [12] isomer showed similar toxicity to permethrin. For D. hyalinata, the trans-pyrethroid [9] isomer and cis-pyrethroid [10] isomer were as toxic as permethrin. Due to their low selectivity, these new pyrethroids should be applied on the basis of ecological selectivity principles to minimize impacts on nontarget organisms S. saevissima and T. angustula.

Using organic-certified rather than synthetic pesticides may not be safer for biological control agents: selectivity and side effects of 14 pesticides on the predator Orius laevigatus.

PubMed

Biondi, Antonio; Desneux, Nicolas; Siscaro, Gaetano; Zappalà, Lucia

2012-05-01

The generalist predator Orius laevigatus (Fieber) (Hemiptera: Anthocoridae) is a key natural enemy of various arthropods in agricultural and natural ecosystems. Releases of this predator are frequently carried out, and it is included in the Integrated Pest Management (IPM) programs of several crops. The accurate assessment of the compatibility of various pesticides with predator activity is key for the success of this strategy. We assessed acute and sublethal toxicity of 14 pesticides on O. laevigatus adults under laboratory conditions. Pesticides commonly used in either conventional or organic farming were selected for the study, including six biopesticides, three synthetic insecticides, two sulfur compounds and three adjuvants. To assess the pesticides' residual persistence, the predator was exposed for 3d to pesticide residues on tomato sprouts that had been treated 1 h, 7 d or 14 d prior to the assay. The percentage of mortality and the sublethal effects on predator reproductive capacity were summarized in a reduction coefficient (E(x)) and the pesticides were classified according to the IOBC (International Organization for Biological Control) toxicity categories. The results showed that the pesticides greatly differed in their toxicity, both in terms of lethal and sub lethal effects, as well as in their persistence. In particular, abamectin was the most noxious and persistent, and was classified as harmful up to 14 d after the treatment, causing almost 100% mortality. Spinosad, emamectin, metaflumizone were moderately harmful until 7 d after the treatment, while the other pesticides were slightly harmful or harmless. The results, based on the combination of assessment of acute mortality, predator reproductive capacity pesticides residual and pesticides residual persistence, stress the need of using complementary bioassays (e.g. assessment of lethal and sublethal effects) to carefully select the pesticides to be used in IPM programs and appropriately time the pesticides application (as function of natural enemies present in crops) and potential releases of natural enemies like O. laevigatus. Copyright © 2012 Elsevier Ltd. All rights reserved.

Therapeutic compounds for Cushing's syndrome: a patent review (2012-2016).

PubMed

Ma, Li; Yin, Lina; Hu, Qingzhong

2016-11-01

Endogenous Cushing's syndrome (CS) is a set of disorders caused by chronic exposure to excess glucocorticoids induced by neuroendocrine tumors in pituitary, adrenals, and infrequently other sites (ectopic ACTH syndrome). Due to various comorbidities, CS patients exhibit higher risks of cardiovascular diseases and thus increased mortality. Pharmaceutical therapy is an important constituent of treatment regimen. Areas covered: Patents published since 2012 are reviewed, which claim therapeutic compounds interfering with ACTH secretion and down-stream signal transduction, inhibiting cortisol biosynthesis and antagonizing glucocorticoid receptors. Advances focus on a) new analogues with improved efficacy and PK properties or less off-target toxicity; b) existing drugs (candidates) being repurposed to treat CS; and c) novel strategies such as selective inhibition of CYP11B1. Expert opinion: New compounds against established targets need to be developed because current drugs lack selectivity leading to off-target toxicity. Selective inhibition of CYP11B1 is a novel alternative strategy and is potentially versatile in controlling all types of hypercortisolism. Selective multi-targeting enzymes in steroidogenesis network is promising due to potential synergistic effects. However, doses toward each targets are not feasible to adjust because the corresponding intrinsic potencies are rigid. Targeting PRKACA mutations is promising in treating CS caused by adrenal adenomas.

Analogs of natural aminoacyl-tRNA synthetase inhibitors clear malaria in vivo

PubMed Central

Novoa, Eva Maria; Camacho, Noelia; Tor, Anna; Wilkinson, Barrie; Moss, Steven; Marín-García, Patricia; Azcárate, Isabel G.; Bautista, José M.; Mirando, Adam C.; Francklyn, Christopher S.; Varon, Sònia; Royo, Miriam; Cortés, Alfred; Ribas de Pouplana, Lluís

2014-01-01

Malaria remains a major global health problem. Emerging resistance to existing antimalarial drugs drives the search for new antimalarials, and protein translation is a promising pathway to target. Here we explore the potential of the aminoacyl-tRNA synthetase (ARS) family as a source of antimalarial drug targets. First, a battery of known and novel ARS inhibitors was tested against Plasmodium falciparum cultures, and their activities were compared. Borrelidin, a natural inhibitor of threonyl-tRNA synthetase (ThrRS), stands out for its potent antimalarial effect. However, it also inhibits human ThrRS and is highly toxic to human cells. To circumvent this problem, we tested a library of bioengineered and semisynthetic borrelidin analogs for their antimalarial activity and toxicity. We found that some analogs effectively lose their toxicity against human cells while retaining a potent antiparasitic activity both in vitro and in vivo and cleared malaria from Plasmodium yoelii-infected mice, resulting in 100% mice survival rates. Our work identifies borrelidin analogs as potent, selective, and unexplored scaffolds that efficiently clear malaria both in vitro and in vivo. PMID:25489076

On the retinal toxicity of intraocular glucocorticoids.

PubMed

Torriglia, Alicia; Valamanesh, Fatemeh; Behar-Cohen, Francine

2010-12-15

Corticosteroids are hormones involved in many physiological responses such as stress, immune modulation, protein catabolism and water homeostasis. The subfamily of glucocorticoids is used systemically in the treatment of inflammatory diseases or allergic reactions. In the eye, glucocorticoides are used to treat macular edema, inflammation and neovascularization. The most commonly used glucocorticoid is triamcinolone acetonide (TA). The pharmaceutical formulation of TA is not adapted for intravitreal administration but has been selected by ophthalmologists because its very low intraocular solubility provides sustained effect. Visual benefits of intraocular TA do not clearly correlate with morpho-anatomical improvements, suggesting potential toxicity. We therefore studied, non-common, but deleterious effects of glucocorticoids on the retina. We found that the intravitreal administration of TA is beneficial in the treatment of neovascularization because it triggers cell death of endothelial cells of neovessels by a caspase-independent mechanism. However, this treatment is toxic for the retina because it induces a non-apoptotic, caspase-independent cell death related to paraptosis, mostly in the retinal pigmented epithelium cells and the Müller cells. Copyright © 2010 Elsevier Inc. All rights reserved.

Acute toxicity and histopathological effects of naproxen in zebrafish (Danio rerio) early life stages.

PubMed

Li, Qian; Wang, Peipei; Chen, Ling; Gao, Hongwen; Wu, Lingling

2016-09-01

Zebrafish (Danio rerio) embryos and larvae were selected to investigate the potential risk and aquatic toxicity of a widely used pharmaceutical, naproxen. The acute toxicity of naproxen to embryos and larvae was measured, respectively. The histopathology was investigated in the liver of zebrafish larvae after 8-day embryo-larvae exposure to naproxen. The values of 96-h LC50 were 115.2 mg/L for embryos and 147.6 mg/L for larvae, indicating that zebrafish embryos were more sensitive than larvae to naproxen exposure. Large suites of symptoms were induced in zebrafish (D. rerio) early life stages by different dosages of naproxen, including hatching inhibition, lower heart rate, and morphological abnormalities. The most sensitive sub-lethal effect caused by naproxen was pericardial edema, the 72-h EC50 values of which for embryos and larvae were 98.3 and 149.0 mg/L, respectively. In addition, naproxen-treated zebrafish larvae exhibited histopathological liver damage, including swollen hepatocytes, vacuolar degeneration, and nuclei pycnosis. The results indicated that naproxen is a potential threat to aquatic organisms.

A model for field toxicity tests

USGS Publications Warehouse

Kaiser, Mark S.; Finger, Susan E.

1996-01-01

Toxicity tests conducted under field conditions present an interesting challenge for statistical modelling. In contrast to laboratory tests, the concentrations of potential toxicants are not held constant over the test. In addition, the number and identity of toxicants that belong in a model as explanatory factors are not known and must be determined through a model selection process. We present one model to deal with these needs. This model takes the record of mortalities to form a multinomial distribution in which parameters are modelled as products of conditional daily survival probabilities. These conditional probabilities are in turn modelled as logistic functions of the explanatory factors. The model incorporates lagged values of the explanatory factors to deal with changes in the pattern of mortalities over time. The issue of model selection and assessment is approached through the use of generalized information criteria and power divergence goodness-of-fit tests. These model selection criteria are applied in a cross-validation scheme designed to assess the ability of a model to both fit data used in estimation and predict data deleted from the estimation data set. The example presented demonstrates the need for inclusion of lagged values of the explanatory factors and suggests that penalized likelihood criteria may not provide adequate protection against overparameterized models in model selection.

alpha-Tocopheryl succinate promotes selective cell death induced by vitamin K3 in combination with ascorbate.

PubMed

Tomasetti, M; Strafella, E; Staffolani, S; Santarelli, L; Neuzil, J; Guerrieri, R

2010-04-13

A strategy to reduce the secondary effects of anti-cancer agents is to potentiate the therapeutic effect by their combination. A combination of vitamin K3 (VK3) and ascorbic acid (AA) exhibited an anti-cancer synergistic effect, associated with extracellular production of H(2)O(2) that promoted cell death. The redox-silent vitamin E analogue alpha-tocopheryl succinate (alpha-TOS) was used in combination with VK3 and AA to evaluate their effect on prostate cancer cells. Prostate cancer cells were sensitive to alpha-TOS and VK3 treatment, but resistant to AA upto 3.2 mM. When combined, a synergistic effect was found for VK3-AA, whereas alpha-TOS-VK3 and alpha-TOS-AA combination showed an antagonist and additive effect, respectively. However, sub-lethal doses of AA-VK3 combination combined with a sub-toxic dose of alpha-TOS showed to induce efficient cell death that resembles autoschizis. Associated with this cell demise, lipid peroxidation, DNA damage, cytoskeleton alteration, lysosomal-mitochondrial perturbation, and release of cytochrome c without caspase activation were observed. Inhibition of lysosomal proteases did not attenuate cell death induced by the combined agents. Furthermore, cell deaths by apoptosis and autoschizis were detected. These finding support the emerging idea that synergistic combinations of some agents can overcome toxicity and other side-effects associated with high doses of single drugs creating the opportunity for therapeutically relevant selectivity.

Biomarkers of Exposure to Toxic Substances. Volume 1. Global Experimental Design: Biomarker Discovery for Early Prediction of Organ-Selective Toxicity

DTIC Science & Technology

2009-05-30

in the polyphenols chlorogenic acid , quinic acid and caffeic acid ). It appears in variable concentrations in urine and at much lower concentrations...liver, kidney, toxicity, gene, expression, nephrotoxin, D-serine, hippuric acid , Puromycin, Amphotericin B 16. SECURITY CLASSIFICATION OF: 17...6 1.4.4. Hippuric Acid

A novel mechanism for the pyruvate protection against zinc-induced cytotoxicity: mediation by the chelating effect of citrate and isocitrate.

PubMed

Sul, Jee-Won; Kim, Tae-Youn; Yoo, Hyun Ju; Kim, Jean; Suh, Young-Ah; Hwang, Jung Jin; Koh, Jae-Young

2016-08-01

Intracellular accumulation of free zinc contributes to neuronal death in brain injuries such as ischemia and epilepsy. Pyruvate, a glucose metabolite, has been shown to block zinc neurotoxicity. However, it is largely unknown how pyruvate shows such a selective and remarkable protective effect. In this study, we sought to find a plausible mechanism of pyruvate protection against zinc toxicity. Pyruvate almost completely blocked cortical neuronal death induced by zinc, yet showed no protective effects against death induced by calcium (ionomycin, NMDA) or ferrous iron. Of the TCA cycle intermediates, citrate, isocitrate, and to a lesser extent oxaloacetate, protected against zinc toxicity. We then noted with LC-MS/MS assay that exposure to pyruvate, and to a lesser degree oxaloacetate, increased levels of citrate and isocitrate, which are known zinc chelators. While pyruvate added only during zinc exposure did not reduce zinc toxicity, citrate and isocitrate added only during zinc exposure, as did extracellular zinc chelator CaEDTA, completely blocked it. Furthermore, addition of pyruvate after zinc exposure substantially reduced intracellular zinc levels. Our results suggest that the remarkable protective effect of pyruvate against zinc cytotoxicity may be mediated indirectly by the accumulation of intracellular citrate and isocitrate, which act as intracellular zinc chelators.

Safety and efficacy of oral DMSA therapy for children with autism spectrum disorders: Part A - Medical results

PubMed Central

Adams, James B; Baral, Matthew; Geis, Elizabeth; Mitchell, Jessica; Ingram, Julie; Hensley, Andrea; Zappia, Irene; Newmark, Sanford; Gehn, Eva; Rubin, Robert A; Mitchell, Ken; Bradstreet, Jeff; El-Dahr, Jane

2009-01-01

Background This study investigated the effect of oral dimercapto succinic acid (DMSA) therapy for children with autism spectrum disorders ages 3-8 years. Methods Phase 1 involved 65 children who received one round of DMSA (3 days). Participants who had high urinary excretion of toxic metals were selected to continue on to phase 2. In phase 2, 49 participants were randomly assigned in a double-blind design to receive an additional 6 rounds of either DMSA or placebo. Results DMSA greatly increased the excretion of lead, substantially increased excretion of tin and bismuth, and somewhat increased the excretion of thallium, mercury, antimony, and tungsten. There was some increase in urinary excretion of essential minerals, especially potassium and chromium. The Phase 1 single round of DMSA led to a dramatic normalization of RBC glutathione in almost all cases, and greatly improved abnormal platelet counts, suggesting a significant decrease in inflammation. Conclusion Overall, DMSA therapy seems to be reasonably safe, effective in removing several toxic metals (especially lead), dramatically effective in normalizing RBC glutathione, and effective in normalizing platelet counts. Only 1 round (3 days) was sufficient to improve glutathione and platelets. Additional rounds increased excretion of toxic metals. PMID:19852789

Effect-directed analysis: Current status and future challenges

NASA Astrophysics Data System (ADS)

Hong, Seongjin; Giesy, John P.; Lee, Jung-Suk; Lee, Jong-Hyeon; Khim, Jong Seong

2016-09-01

Effect-directed analysis (EDA) has become useful for identification of toxicant(s) that occur in mixtures in the environment, especially those that are causative agents of specific adverse effects. Here, we summarize and review EDA methodology including preparation of samples, biological analyses, fractionations, and instrumental analyses, highlighting key scientific advancements. A total of 63 documents since 1999 (Scopus search) including 46 research articles, 13 review papers, and 4 project descriptions, have been collected and reviewed in this study. At the early stage (1999-2010), most studies that applied EDA focused on organic extracts of freshwater and coastal contaminated sediments and wastewater. Toxic effects were often measured using cell-based bioassays ( in vitro) and the causative chemicals were identified by use of low resolution gas chromatography with mass selective detector (GCMSD). More recently (2010-present), EDA has been extended to various matrices such as biota, soil, crude oil, and suspended solids and techniques have been improved to include determination of bioavailability in vivo. In particular, methods for non-target screenings of organic chemicals in environmental samples using cutting-edge instrumentation such as time of flight-mass spectrometry (ToF-MS), Fourier transform-ion cyclotron resonance (FT-ICR), and Orbitrap mass spectrometer have been developed. This overview provides descriptions of recent improvements of EDA and suggests future research directions based on current understandings and limitations.

FTIR gas analysis with improved sensitivity and selectivity for CWA and TIC detection

NASA Astrophysics Data System (ADS)

Phillips, Charles M.; Tan, Huwei

2010-04-01

This presentation describes the use of an FTIR (Fourier Transform Infrared)-based spectrometer designed to continuously monitor ambient air for the presence of chemical warfare agents (CWAs) and toxic industrial chemicals (TICs). The necessity of a reliable system capable of quickly and accurately detecting very low levels of CWAs and TICs while simultaneously retaining a negligible false alarm rate will be explored. Technological advancements in FTIR sensing have reduced noise while increasing selectivity and speed of detection. These novel analyzer design characteristics are discussed in detail and descriptions are provided which show how optical throughput, gas cell form factor, and detector response are optimized. The hardware and algorithms described here will explain why this FTIR system is very effective for the simultaneous detection and speciation of a wide variety of toxic compounds at ppb concentrations. Analytical test data will be reviewed demonstrating the system's sensitivity to and selectivity for specific CWAs and TICs; this will include recent data acquired as part of the DHS ARFCAM (Autonomous Rapid Facility Chemical Agent Monitor) project. These results include analyses of the data from live agent testing for the determination of CWA detection limits, immunity to interferences, detection times, residual noise analysis and false alarm rates. Sensing systems such as this are critical for effective chemical hazard identification which is directly relevant to the CBRNE community.

Design of selective nuclear receptor modulators: RAR and RXR as a case study.

PubMed

de Lera, Angel R; Bourguet, William; Altucci, Lucia; Gronemeyer, Hinrich

2007-10-01

Retinoic acid receptors (RARs) and retinoid X receptors (RXRs) are members of the nuclear receptor superfamily whose effects on cell growth and survival can be modulated therapeutically by small-molecule ligands. Although compounds that target these receptors are powerful anticancer drugs, their use is limited by toxicity. An improved understanding of the structural biology of RXRs and RARs and recent advances in the chemical synthesis of modified retinoid and rexinoid ligands should enable the rational design of more selective agents that might overcome such problems. Here, we review structural data for RXRs and RARs, discuss strategies in the design of selective RXR and RAR modulators, and consider lessons that can be learned for the design of selective nuclear-receptor modulators in general.

Second Generation Amphiphilic Poly-Lysine Dendrons Inhibit Glioblastoma Cell Proliferation without Toxicity for Neurons or Astrocytes

PubMed Central

Janiszewska, Jolanta; Posadas, Inmaculada; Játiva, Pablo; Bugaj-Zarebska, Marta; Urbanczyk-Lipkowska, Zofia; Ceña, Valentín

2016-01-01

Glioblastomas are the most common malignant primary brain tumours in adults and one of the most aggressive and difficult-to-treat cancers. No effective treatment exits actually for this tumour and new therapeutic approaches are needed for this disease. One possible innovative approach involves the nanoparticle-mediated specific delivery of drugs and/or genetic material to glioblastoma cells where they can provide therapeutic benefits. In the present work, we have synthesised and characterised several second generation amphiphilic polylysine dendrons to be used as siRNA carriers. We have found that, in addition to their siRNA binding properties, these new compounds inhibit the proliferation of two glioblastoma cell lines while being nontoxic for non-tumoural central nervous system cells like neurons and glia, cell types that share the anatomical space with glioblastoma cells during the course of the disease. The selective toxicity of these nanoparticles to glioblastoma cells, as compared to neurons and glial cells, involves mitochondrial depolarisation and reactive oxygen species production. This selective toxicity, together with the ability to complex and release siRNA, suggests that these new polylysine dendrons might offer a scaffold in the development of future nanoparticles designed to restrict the proliferation of glioblastoma cells. PMID:27832093

Iron Promotes the Toxicity of Amyloid β Peptide by Impeding Its Ordered Aggregation*

PubMed Central

Liu, Beinan; Moloney, Aileen; Meehan, Sarah; Morris, Kyle; Thomas, Sally E.; Serpell, Louise C.; Hider, Robert; Marciniak, Stefan J.; Lomas, David A.; Crowther, Damian C.

2011-01-01

We have previously shown that overexpressing subunits of the iron-binding protein ferritin can rescue the toxicity of the amyloid β (Aβ) peptide in our Drosophila model system. These data point to an important pathogenic role for iron in Alzheimer disease. In this study, we have used an iron-selective chelating compound and RNAi-mediated knockdown of endogenous ferritin to further manipulate iron in the brain. We confirm that chelation of iron protects the fly from the harmful effects of Aβ. To understand the pathogenic mechanisms, we have used biophysical techniques to see how iron affects Aβ aggregation. We find that iron slows the progression of the Aβ peptide from an unstructured conformation to the ordered cross-β fibrils that are characteristic of amyloid. Finally, using mammalian cell culture systems, we have shown that iron specifically enhances Aβ toxicity but only if the metal is present throughout the aggregation process. These data support the hypothesis that iron delays the formation of well ordered aggregates of Aβ and so promotes its toxicity in Alzheimer disease. PMID:21147772

Iron promotes the toxicity of amyloid beta peptide by impeding its ordered aggregation.

PubMed

Liu, Beinan; Moloney, Aileen; Meehan, Sarah; Morris, Kyle; Thomas, Sally E; Serpell, Louise C; Hider, Robert; Marciniak, Stefan J; Lomas, David A; Crowther, Damian C

2011-02-11

We have previously shown that overexpressing subunits of the iron-binding protein ferritin can rescue the toxicity of the amyloid β (Aβ) peptide in our Drosophila model system. These data point to an important pathogenic role for iron in Alzheimer disease. In this study, we have used an iron-selective chelating compound and RNAi-mediated knockdown of endogenous ferritin to further manipulate iron in the brain. We confirm that chelation of iron protects the fly from the harmful effects of Aβ. To understand the pathogenic mechanisms, we have used biophysical techniques to see how iron affects Aβ aggregation. We find that iron slows the progression of the Aβ peptide from an unstructured conformation to the ordered cross-β fibrils that are characteristic of amyloid. Finally, using mammalian cell culture systems, we have shown that iron specifically enhances Aβ toxicity but only if the metal is present throughout the aggregation process. These data support the hypothesis that iron delays the formation of well ordered aggregates of Aβ and so promotes its toxicity in Alzheimer disease.

Mixture toxicity of water contaminants-effect analysis using the zebrafish embryo assay (Danio rerio).

PubMed

Schmidt, Susanne; Busch, Wibke; Altenburger, Rolf; Küster, Eberhard

2016-06-01

Three water contaminants were selected to be tested in the zebrafish embryo toxicity test (DarT) in order to investigate the sensitivity of the zebrafish embryo toxicity test with respect to mixture effect detection. The concentration-response curves for the observed effects lethality and hypo-pigmentation were calculated after an exposure of the embryos for 96 h with a fungicide (carbendazim), a plasticizer or propellent precursor (2,4-DNT: 2,4- dinitrotoluene) and an aromatic compound (AαC: 2-amino-9H-pyrido[2,3-b]indol), respectively. Follow-up mixture tests were based on the calculated LC50 or EC50 of the single compounds and combined effects were predicted according to the mixture concepts of concentration addition (CA) and independent action (IA). The order of toxicity for the single substances was carbendazim (LC50 = 1.25 μM) < AαC (LC50 = 8.16 μM) < 2,4-DNT (LC50 = 177.05 μM). For AαC and 2,4 DNT hypo-pigmentation was observed in addition (AαC EC50 = 1.81 μM; 2,4-DNT EC50 = 8.81 μM). Two binary and one ternary mixture were studied on lethality and one on hypo-pigmentation: 2,4-DNT/AαC (LC50 = 119.21 μM, EC50 = 5.37 μM), carbendazim/AαC (LC50 = 4.49 μM) and AαC/Carbendazim/2,4 DNT (LC50 = 108.62 μM). Results showed that the effects were in agreement with the CA model when substances were tested in mixtures. Therefore, in a reasonable worst case scenario substance combination effects in fish embryos were at maximum only prone to overestimation when using CA as the mixture concept. Copyright © 2016 Elsevier Ltd. All rights reserved.

Trophic transfer of soil arsenate and associated toxic effects in a plant-aphid-parasitoid system

NASA Astrophysics Data System (ADS)

Lee, Y. S.; Wee, J.; Lee, M.; Hong, J.; Cho, K.

2017-12-01

Terrestrial toxic effects of soil arsenic were studied using a model system consisting of soil which artificially treated with arsenic, Capsicum annum,Myzus persicae and Aphidus colemani. We investigated the transfer of arsenic in a soil-plant-aphid system and toxic effect of elevated arsenic through a plant-aphid-parasitoid system. To remove the effect of poor plant growth on aphid performance, test concentrations which have a no effect on health plant growth were selected. Arsenic concentration of growth medium, plant tissues (root, stem, leaf) aphids were measured to observe the arsenic transfer. Correlation matrix was made with arsenic in growth medium which extracted with three extractants (aquaregia, 0.01 M CaCl2 and deionized water), arsenic in plant tissues and plant performance. Toxic effects of elevated arsenic concentrations on each species were investigated at population level. Studied plant performances were dry weight of each tissue, elongation of roots and stems, area of leaves, chlorophyll content of leaves, protein content of leaves and sugar content of leaves. Mean development time, fecundity and honeydew excretion of the aphids and host choice capacity and parasitism success of the parasitoids were examined. In addition, enzyme activities of the plants and the aphids against reactive oxygen species (ROS) induced by arsenic stress were also investigated. The results suggest that arsenic concentration in plant tissues and aphids were elevated with increased concentration of arsenic in soil. Decreased fecundity and honeydew excretion of aphids were observed and decreased eclosion rate of parasitoids were observed with increased arsenic treatment in growth medium. The results showed low concentration of arsenic in soil can transfer through food chain and can impact on higher trophic level species.

PPTOX III: environmental stressors in the developmental origins of disease--evidence and mechanisms.

PubMed

Schug, Thaddeus T; Barouki, Robert; Gluckman, Peter D; Grandjean, Philippe; Hanson, Mark; Heindel, Jerold J

2013-02-01

Fetal and early postnatal development constitutes the most vulnerable time period of human life in regard to adverse effects of environmental hazards. Subtle effects during development can lead to functional deficits and increased disease risk later in life. The hypothesis stating that environmental exposures leads to altered programming and, thereby, to increased susceptibility to disease or dysfunction later in life has garnered much support from both experimental and epidemiological studies. Similar observations have been made on the long-term impact of nutritional unbalance during early development. In an effort to bridge the fields of nutritional and environmental developmental toxicity, the Society of Toxicology sponsored this work. This report summarizes novel findings in developmental toxicity as reported by select invited experts and meeting attendees. Recommendations for the application and improvement of current and future research efforts are also presented.

Understanding the Effects of Genotype, Growing Year, and Breeding on Tunisian Durum Wheat Allergenicity. 2. The Celiac Disease Case.

PubMed

Boukid, Fatma; Prandi, Barbara; Sforza, Stefano; Sayar, Rhouma; Seo, Yong Weon; Mejri, Mondher; Yacoubi, Ines

2017-07-19

The aim of this study was to compare immunogenic and toxic gluten peptides related to celiac disease (CD). 100 accessions of genotypes selected during the 20th century in Tunisia were in vitro digested and then analyzed by UPLC/ESI-MS technique using an isotopically labeled internal standard. The first MANOVA confirmed a high variability in the content of immunogenic and toxic peptides reflecting high genetic diversity in the germplasm released during the past century in Tunisia, consistently with PCA and clustering analysis results. Our finding showed also important variability in CD epitopes due to growing season's climate scenarios. Moreover, the second MANOVA revealed significant differences between abandoned and modern cultivars' CD-related peptide amounts. Although we could not conclude that there was an augment of allergens in newly selected durum wheat lines compared to abandoned ones, we demonstrated that modern genotype peptides were less sensitive to climate variation, which is a useful indicator for wheat breeders.

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.

Relative toxicity testing of spacecraft materials. 1: Spacecraft materials. [lethality of pyrolysates

NASA Technical Reports Server (NTRS)

Lawrence, W. H.

1980-01-01

In chamber thermodegradation procedures were used to access the lethality to rats of the pyrolysis/combustion products of three foams, an adhesive backed metallic tape and RTV silicone rubber adhesive sealant used in spacecraft construction. The role of carbon monoxide in the overall pyrolysate toxicity was also investigated. Post exposure observation of the rats, histological evaluation of selected organs, carbon monoxide concentration in the chamber atmosphere during exposure and the percent carboxyhemoglobin in the animals expiring in the chamber are discussed. Thermogravimetric analysis and dosage response results are given. The lethal effect of the RTV silicon appears to be due to physical obstruction of the respiratory system by particulate matter from pyrolysis.

Risk of Severe Toxicity According to Site of Recurrence in Patients Treated With Stereotactic Body Radiation Therapy for Recurrent Head and Neck Cancer

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

Ling, Diane C.; Vargo, John A.; Ferris, Robert L.

Purpose: To report a 10-year update of our institutional experience with stereotactic body radiation therapy (SBRT) for reirradiation of locally recurrent head and neck cancer, focusing on predictors of toxicity. Methods and Materials: A retrospective review was performed on 291 patients treated with SBRT for recurrent, previously irradiated head and neck cancer between April 2002 and March 2013. Logistic regression analysis was performed to identify predictors of severe acute and late toxicity. Patients with <3 months of follow-up (n=43) or who died within 3 months of treatment (n=21) were excluded from late toxicity analysis. Results: Median time to death or last clinicalmore » follow-up was 9.8 months among the entire cohort and 53.1 months among surviving patients. Overall, 33 patients (11.3%) experienced grade ≥3 acute toxicity and 43 (18.9%) experienced grade ≥3 late toxicity. Compared with larynx/hypopharynx, treatment of nodal recurrence was associated with a lower risk of severe acute toxicity (P=.03), with no significant differences in severe acute toxicity among other sites. Patients treated for a recurrence in the larynx/hypopharynx experienced significantly more severe late toxicity compared with those with oropharyngeal, oral cavity, base of skull/paranasal sinus, salivary gland, or nodal site of recurrence (P<.05 for all). Sixteen patients (50%) with laryngeal/hypopharyngeal recurrence experienced severe late toxicity, compared with 6-20% for other sites. Conclusions: Salvage SBRT is a safe and effective option for most patients with previously irradiated head and neck cancer. However, patients treated to the larynx or hypopharynx experience significantly more late toxicity compared with others and should be carefully selected for treatment, with consideration given to patient performance status, pre-existing organ dysfunction, and goals of care. Treatment toxicity in these patients may be mitigated with more conformal plans to allow for increased sparing of adjacent normal tissues.« less

Toxicity of selected essential oils, silicone oils, and paraffino oil against the common bed bug, cimex lectularius L. (Hemiptera: Cimicidae)

USDA-ARS?s Scientific Manuscript database

The common bed bug (Cimex lectularius L.) resurged in the U.S. and many other countries over the past decade. The need for safe and effective bed bug control products propelled the development of numerous “green pesticides”, mostly with essential oils listed as active ingredients. Various inorganic ...

Newly Engineered Magnetic Erythrocytes for Sustained and Targeted Delivery of Anti-Cancer Therapeutic Compounds

PubMed Central

Taranta, Monia; Naldi, Ilaria

2011-01-01

Cytotoxic chemotherapy of cancer is limited by serious, sometimes life-threatening, side effects that arise from toxicities to sensitive normal cells because the therapies are not selective for malignant cells. So how can they be selectively improved? Alternative pharmaceutical formulations of anti-cancer agents have been investigated in order to improve conventional chemotherapy treatment. These formulations are associated with problems like severe toxic side effects on healthy organs, drug resistance and limited access of the drug to the tumor sites suggested the need to focus on site-specific controlled drug delivery systems. In response to these concerns, we have developed a new drug delivery system based on magnetic erythrocytes engineered with a viral spike fusion protein. This new erythrocyte-based drug delivery system has the potential for magnetic-controlled site-specific localization and highly efficient fusion capability with the targeted cells. Here we show that the erythro-magneto-HA virosomes drug delivery system is able to attach and fuse with the target cells and to efficiently release therapeutic compounds inside the cells. The efficacy of the anti-cancer drug employed is increased and the dose required is 10 time less than that needed with conventional therapy. PMID:21373641

The neurotoxicology and pathology of organomercury, organolead, and organotin.

PubMed

Chang, L W

1990-12-01

The toxicities of many metals, such as mercury and lead, are known to man since the dawn of civilization. Organic compounds of some heavy metals are known to have a particular toxic impact on the central nervous system. Organomercury, particularly alkyl-mercuric compounds (e.g. methylmercury), has a selective effect on the granule cells of the cerebellum, the nerve cells of the calcarine cortex, and the sensory neurons in the dorsal root ganglia. The well known Minamata Bay disease is the result of a massive epidemic episode of human exposure to alkylmercury contaminated food sources. Mental retardation and other developmental defects are also known to be a consequence of exposure to this toxic metal. Organic lead compounds have been employed as gasoline additives and in other industrial purposes. Unlike its inorganic counterpart, organolead compounds have a more prominent impact on the central nervous system. Pathological changes of the brain stem neurons have been described. Organotin compounds have been used in plastic industries and as agricultural chemicals. Both trimethyl and triethyl tin compounds are found to be extremely neurotoxic. Despite the similarity of their chemical structures, trimethyl and triethyl tins have a diversely different toxic property and effects. While triethyl tin is myelinotoxic, producing edematous and vacuolar changes in the central myelin, trimethyl tin is neurotoxic, producing prominent toxic changes in the neurons of the limbic system (hippocampus, entorhinal cortex, etc.). The factors which determine the specificity and selectivity of the neurotoxic impacts by various organometals are still unknown. In view that most of the organometals are still widely employed by many countries for industrial and for agricultural purposes, caution must be made for their proper handling and disposure to avoid undesirable exposures to workers and environmental contamination of water sources and food-chain for the common public. Since organometals are difficult to eliminate from the central nervous system, injuries usually lead to permanent neurological deficits, such tragedies are frequently long lasting and create not only a medical problem, but also a social economical problem for the society.

Evaluation of scopadulciol-related molecules for their stimulatory effect on the cytotoxicity of acyclovir and ganciclovir against Herpes simplex virus type 1 thymidine kinase gene-transfected HeLa cells.

PubMed

Hayashi, Kyoko; Rahman, S M Abdur; Ohno, Hiroaki; Tanaka, Tetsuaki; Toyooka, Naoki; Nemoto, Hideo; Hayashi, Toshimitsu

2004-08-01

Herpes simplex virus type 1 thymidine kinase (HSV TK) is involved in both antiherpetic therapy and cancer gene therapy with acyclovir (ACV) and ganciclovir (GCV). Enhanced sensitivity to these drugs is advantageous in their clinical use. In the present study, scopadulciol (SDC) and its related compounds were evaluated for their stimulatory effect on the cytotoxicity of ACV and GCV by determination of selective toxicities against HSV TK-expressing HeLa cells. Although SDC remarkably potenciated the cytotoxicity of ACV and GCV, the other tested compounds showed only weak selectivity, except for compound 34.

Biofumigation for control of pale potato cyst nematodes: activity of brassica leaf extracts and green manures on Globodera pallida in vitro and in soil.

PubMed

Lord, James S; Lazzeri, Luca; Atkinson, Howard J; Urwin, Peter E

2011-07-27

The effects of brassica green manures on Globodera pallida were assessed in vitro and in soil microcosms. Twelve of 22 brassica accessions significantly inhibited the motility of G. pallida infective juveniles in vitro. Green manures of selected brassicas were then incorporated into soil containing encysted eggs of G. pallida. Their effect on egg viability was estimated by quantifying nematode actin 1 mRNA by RT-qPCR. The leaf glucosinolate profiles of the plants were determined by high-performance liquid chromatography. Three Brassica juncea lines (Nemfix, Fumus, and ISCI99) containing high concentrations of 2-propenyl glucosinolate were the most effective, causing over 95% mortality of encysted eggs of G. pallida in polyethylene-covered soil. The toxic effects of green manures were greater in polyethylene-covered than in open soil. Toxicity in soil correlated with the concentration of isothiocyanate-producing glucosinolate but not total glucosinolate in green manures.

Sublethal Toxicity Endpoints of Heavy Metals to the Nematode Caenorhabditis elegans

PubMed Central

Wu, Yue; Wang, Qiang; Li, Huixin

2016-01-01

Caenorhabditis elegans, a free-living nematode, is commonly used as a model organism in ecotoxicological studies. The current literatures have provided useful insight into the relative sensitivity of several endpoints, but few direct comparisons of multiple endpoints under a common set of experimental conditions. The objective of this study was to determine appropriate sublethal endpoints to develop an ecotoxicity screening and monitoring system. C. elegans was applied to explore the sublethal toxicity of four heavy metals (copper, zinc, cadmium and chromium). Two physiological endpoints (growth and reproduction), three behavioral endpoints (head thrash frequency, body bend frequency and feeding) and two enzymatic endpoints (acetylcholine esterase [AChE] and superoxide dismutase [SOD]) were selected for the assessment of heavy metal toxicity. The squared correlation coefficients (R2) between the responses observed and fitted by Logit function were higher than 0.90 and the RMSE were lower than 0.10, indicating a good significance statistically. There was no significant difference among the half effect concentration (EC50) endpoints in physiological and behavioral effects of the four heavy metals, indicating similar sensitivity of physiological and behavioral effects. AChE enzyme was more sensitive to copper, zinc, and cadmium than to other physiological and behavioral effects, and SOD enzyme was most sensitive to chromium. The EC50 of copper, zinc, and cadmium, to the AChE enzyme in the nematodes were 0.68 mg/L, 2.76 mg/L, and 0.92 mg/L respectively and the EC50 of chromium to the SOD enzyme in the nematode was 1.58 mg/L. The results of this study showed that there was a good concentration-response relationship between all four heavy metals and the sublethal toxicity effects to C. elegans. Considering these sublethal endpoints in terms of simplicity, accuracy, repeatability and costs of the experiments, feeding is the relatively ideal sublethal toxicity endpoint of heavy metals to C. elegans. PMID:26824831

Mixture toxicity revisited from a toxicogenomic perspective.

PubMed

Altenburger, Rolf; Scholz, Stefan; Schmitt-Jansen, Mechthild; Busch, Wibke; Escher, Beate I

2012-03-06

The advent of new genomic techniques has raised expectations that central questions of mixture toxicology such as for mechanisms of low dose interactions can now be answered. This review provides an overview on experimental studies from the past decade that address diagnostic and/or mechanistic questions regarding the combined effects of chemical mixtures using toxicogenomic techniques. From 2002 to 2011, 41 studies were published with a focus on mixture toxicity assessment. Primarily multiplexed quantification of gene transcripts was performed, though metabolomic and proteomic analysis of joint exposures have also been undertaken. It is now standard to explicitly state criteria for selecting concentrations and provide insight into data transformation and statistical treatment with respect to minimizing sources of undue variability. Bioinformatic analysis of toxicogenomic data, by contrast, is still a field with diverse and rapidly evolving tools. The reported combined effect assessments are discussed in the light of established toxicological dose-response and mixture toxicity models. Receptor-based assays seem to be the most advanced toward establishing quantitative relationships between exposure and biological responses. Often transcriptomic responses are discussed based on the presence or absence of signals, where the interpretation may remain ambiguous due to methodological problems. The majority of mixture studies design their studies to compare the recorded mixture outcome against responses for individual components only. This stands in stark contrast to our existing understanding of joint biological activity at the levels of chemical target interactions and apical combined effects. By joining established mixture effect models with toxicokinetic and -dynamic thinking, we suggest a conceptual framework that may help to overcome the current limitation of providing mainly anecdotal evidence on mixture effects. To achieve this we suggest (i) to design studies to establish quantitative relationships between dose and time dependency of responses and (ii) to adopt mixture toxicity models. Moreover, (iii) utilization of novel bioinformatic tools and (iv) stress response concepts could be productive to translate multiple responses into hypotheses on the relationships between general stress and specific toxicity reactions of organisms.

Development of Medical Technology for Contingency Response to Marrow Toxic Agents

DTIC Science & Technology

2014-05-06

Development of Medical Technology for Contingency Response to Marrow Toxic Agents - Final Performance/Technical Report for January 01, 2011 to...Enhancing HLA Data for Selected Donors 44 IIB.1.6 Maintain a Quality Control Program 44 IIB.2.1 Collection of Primary Data 45 IIB.2.2 Validation of...Receptor Donor Selection KORI Korean LD Linkage Disequilibrium LTA Lymphotoxin Alpha MALDI-TOF Matrix-Assisted Laser Desorption/Ionization – Time Of

The role of tramadol in current treatment strategies for musculoskeletal pain

PubMed Central

Schug, Stephan A

2007-01-01

Non-selective and cyclooxygenase-2 (COX-2) selective non-steroidal anti-inflammatory drugs (NSAIDs) have been the mainstay of treatment for musculoskeletal pain of moderate intensity. However, in addition to gastrointestinal and renal toxicity, an increased cardiovascular risk may be a class effect for all NSAIDs. Despite these safety risks and the acknowledged ceiling effect of NSAIDs, many doctors still use them to treat moderate, mostly musculoskeletal pain. Recent guidelines for treating osteoarthritis and low back pain, issued by numerous professional medical societies, recommend NSAIDs and COX-2 inhibitors only in strictly defined circumstances, at the lowest effective dose and for the shortest possible period of time. These recent guidelines bring more focus to the usage of paracetamol and opioids. But opioids still remain under-utilized, although they are effective with minimal organ toxicity. In this setting, the atypical, centrally acting analgesic tramadol offers important benefits. Its multi-modal effect results from a dual mode of action, ie, opioid and monoaminergic mechanisms, with efficacy in both nociceptive and neuropathic pain. Moreover, fewer instances of side effects such as constipation, respiratory depression, and sedation occur than with traditional opioids, and tramadol has been prescribed for 30 years for a broad range of indications. Tramadol is now regarded as the first-line analgesic for many musculoskeletal indications. In conclusion, it is recommended to better implement the more recent guidelines focusing on pain management and consider the role of tramadol in musculoskeletal pain treatment strategies. PMID:18472996

Toward a magic or imaginary bullet? Ligands for drug targeting to cancer cells: principles, hopes, and challenges

PubMed Central

Toporkiewicz, Monika; Meissner, Justyna; Matusewicz, Lucyna; Czogalla, Aleksander; Sikorski, Aleksander F

2015-01-01

There are many problems directly correlated with the systemic administration of drugs and how they reach their target site. Targeting promises to be a hopeful strategy as an improved means of drug delivery, with reduced toxicity and minimal adverse side effects. Targeting exploits the high affinity of cell-surface-targeted ligands, either directly or as carriers for a drug, for specific retention and uptake by the targeted diseased cells. One of the most important parameters which should be taken into consideration in the selection of an appropriate ligand for targeting is the binding affinity (KD). In this review we focus on the importance of binding affinities of monoclonal antibodies, antibody derivatives, peptides, aptamers, DARPins, and small targeting molecules in the process of selection of the most suitable ligand for targeting of nanoparticles. In order to provide a critical comparison between these various options, we have also assessed each technology format across a range of parameters such as molecular size, immunogenicity, costs of production, clinical profiles, and examples of the level of selectivity and toxicity of each. Wherever possible, we have also assessed how incorporating such a targeted approach compares with, or is superior to, original treatments. PMID:25733832

Synergistic action of octopamine receptor agonists on the activity of selected novel insecticides for control of dengue vector Aedes aegypti (Diptera: Culicidae) mosquito.

PubMed

Ahmed, Mohamed Ahmed Ibrahim; Vogel, Christoph Franz Adam

2015-05-01

Studying insecticide resistance in mosquitoes has attracted the attention of many scientists to elucidate the pathways of resistance development and to design novel strategies in order to prevent or minimize the spread and evolution of resistance. Here, we tested the synergistic action of piperonyl butoxide (PBO) and two octopamine receptor (OR) agonists, amitraz (AMZ) and chlordimeform (CDM) on selected novel insecticides to increase their lethal action on the fourth instar larvae of Aedes aegypti L. However, chlorfenapyr was the most toxic insecticide (LC50 = 193, 102, and 48 ng/ml, after 24, 48, and 72 h exposure, respectively) tested. Further, PBO synergized all insecticides and the most toxic combinatorial insecticide was nitenpyram even after 48 and 72 h exposure. In addition, OR agonists significantly synergized most of the selected insecticides especially after 48 and 72 h exposure. The results imply that the synergistic effects of amitraz are a promising approach in increasing the potency of certain insecticides in controlling the dengue vector Ae. aegypti mosquito. Copyright © 2015 Elsevier Inc. All rights reserved.

Effect of Antimicrobial Peptide KSL-W on Human Gingival Tissue and C. albicans Growth, Transition and Secreted Aspartyl Proteinase (SAPS) 2, 4, 5 and 6 Expressions

DTIC Science & Technology

2013-04-01

1 AWARD NUMBER: W81XWH-12-2-0025 TITLE: Effect of Antimicrobial Peptide KSL-W on Human Gingival Tissue and C. albicans Growth, Transition...drugs using various synthetic and naturally occurring antimicrobial molecules. Natural antimicrobial peptides , such as defensins produced by...These antimicrobial peptides generally exhibit selective toxicity for microorganisms and show fewer propensities to induce microbial resistance

[Advance in studies on TRPV1 and analgesic effect of traditional Chinese medicines].

PubMed

Liu, Xiao-Li; Lv, Cui; Zhang, Wen-Sheng

2014-05-01

Transient receptor potential vanilloid 1 (TRPV1) is a non-selective positive ion channel that is mainly expressed in sensory neurons and a member of transient receptor potential (TRP) family. The receptor could be activated by mechanical irritation, chemical irritation or endogenous ligand to mediate pains and cause injury to body functions. Traditional Chinese medicine believes that the mechanism of pain is that "stagnation leads to pain". Specifically, both of the contracture and tautness caused by cold and the blood stasis could result in blood impassability and pain. Most of traditional Chinese medicines for clearing heat and removing toxicity have the anti-inflammatory effect, while those for warming interior, and promoting blood circulation to remove blood stasis have the effect in smoothening blood vessels. Therefore, either with the anti-inflammatory effect or the effect in smoothening blood vessels, traditional Chinese medicines for clearing heat and removing toxicity, warming interior, and promoting blood circulation have the analgesic effect In this paper, the authors summarize the analgesic effect of the above three traditional Chinese medicines, with TRPV1 as the target.

Lethal Dietary Toxicities of Environmental Contaminants and Pesticides to Coturnix

USGS Publications Warehouse

Hill, E.F.; Camardese, M.B.

1986-01-01

Five-day subacute dietary toxicity tests of 193 potential environmental contaminants, pesticides, organic solvents, and various adjuvants are presented for young coturnix (Japanese quail, Coturnix japonica Temminck and Schlegel). The report provides the most comprehensive data base available for avian subacute dietary toxicity tests and is primarily intended for use in ranking toxicities by a standard method that has a reasonable degree of environmental relevance. Findings are presented in two parts: Part I is a critique of selected drugs that includes discussion of subacute toxicity in relation to chemical class and structure, pesticide formulation, and age of animals; Part II is a summary of toxicologic findings for each test substance and provides a statistically basis for comparing toxicities. Data presented include the median lethal concentration (LC50), slope of the probit regression curve (dose-response curve), response chronology, and food consumption. We observed that: 1) fewer than 15% of the compounds were classed 'very' or 'highly' toxic (i.e, LC50 < 200 ppm) and all of these were either chlorinated hydrocarbons, organophosphates, or organometallics; 2) subacute toxicity may vary widely among structurally similar chemicals and between different formulations of the same chemical; therefore, conclusions about lethal hazard must be made cautiously until the actual formulation of inset has been tested: 3) inclusion of a general standard in each battery of tests is useful for detection of atypical trials and monitoring population changes but should not be used indiscriminantly for adjusting LC50's for intertest differences unless the chemicals of concern and the standard elicit their toxicities through the same action; 4) although other species have been tested effectively under the subacute protocol, coturnix were ideal for the stated purpose of this research because they are inexpensive, well-adapted to the laboratory environment, and yield good intertest reproducibility of response.

Organic carbon content effects on bioavailability of pyrethroid insecticides and validation of solid phase extraction with Poly (2,6-diphenyl-p-phenylene oxide) Polymer by Daphnia magna toxicity tests.

PubMed

Feo, M L; Corcellas, C; Barata, C; Ginebreda, A; Eljarrat, E; Barceló, D

2013-01-01

Solid phase extraction with Poly (2,6-diphenyl-p-phenylene oxide) Polymer (Tenax) was used for determining the bioavailability of eleven pyrethroids in field collected sediments with different organic carbon content (OC). The bioavailable fraction of pyrethroids decreased with increasing OC in sediments; the percentages of desorption ranged from 10 to 20% for sediment with higher OC content (5.8%) and 15-40% for that with lower OC (2%). Generally pyrethroids showed low bioavailability and cyfluthrin resulted to be the most bioavailable among the studied pyrethroids. Acute toxicity tests with Daphnia magna were carried out on sediment spiked with three selected pyrethroids (λ-cyhalothrin, cypermethrin and deltamethrin) and served to validate the efficiency of Tenax as a method for assessing the bioavailability of pyrethroids. Toxicity test demonstrated that Tenax was able to remove the toxic bio-available fraction of pyrethroids in sediment. Extracts from Tenax beads after the desorption experiments and spiked sediment before desorption had an equivalent toxicity (LC50) to D. magna neonates at 48 and 72 h of exposure. These results indicate that Tenax beds can be used to predict bio-available and toxic fractions of pyrethroids sorbed to sediments to aquatic organisms like D. magna. Copyright © 2012 Elsevier B.V. All rights reserved.

Distinct C9orf72-Associated Dipeptide Repeat Structures Correlate with Neuronal Toxicity

PubMed Central

Krans, Amy; Sawaya, Michael R.; Paulson, Henry L.; Todd, Peter K.; Barmada, Sami J.; Ivanova, Magdalena I.

2016-01-01

Hexanucleotide repeat expansions in C9orf72 are the most common inherited cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The expansions elicit toxicity in part through repeat-associated non-AUG (RAN) translation of the intronic (GGGGCC)n sequence into dipeptide repeat-containing proteins (DPRs). Little is known, however, about the structural characteristics and aggregation propensities of the dipeptide units comprising DPRs. To address this question, we synthesized dipeptide units corresponding to the three sense-strand RAN translation products, analyzed their structures by circular dichroism, electron microscopy and dye binding assays, and assessed their relative toxicity when applied to primary cortical neurons. Short, glycine-arginine (GR)3 dipeptides formed spherical aggregates and selectively reduced neuronal survival compared to glycine-alanine (GA)3 and glycine-proline (GP)3 dipeptides. Doubling peptide length had little effect on the structure of GR or GP peptides, but (GA)6 peptides formed β-sheet rich aggregates that bound thioflavin T and Congo red yet lacked the typical fibrillar morphology of amyloids. Aging of (GA)6 dipeptides increased their β-sheet content and enhanced their toxicity when applied to neurons. We also observed that the relative toxicity of each tested dipeptide was proportional to peptide internalization. Our results demonstrate that different C9orf72-related dipeptides exhibit distinct structural properties that correlate with their relative toxicity. PMID:27776165

Promising Diabetes Therapy Based on the Molecular Mechanism for Glucose Toxicity: Usefulness of SGLT2 Inhibitors as well as Incretin-Related Drugs.

PubMed

Kaneto, Hideaki; Obata, Atsushi; Shimoda, Masashi; Kimura, Tomohiko; Hirukawa, Hidenori; Okauchi, Seizo; Matsuoka, Taka-Aki; Kaku, Kohei

2016-01-01

Pancreatic β-cell dysfunction and insulin resistance are the main characteristics of type 2 diabetes. Chronic exposure of β-cells to hyperglycemia leads to the deterioration of β-cell function. Such phenomena are well known as pancreatic β-cell glucose toxicity. MafA, a strong transactivator of insulin gene, is particularly important for the maintenance of mature β-cell function, but its expression level is significantly reduced under diabetic conditions which is likely associated with β-cell failure. Reduction of incretin receptor expression level in β-cells in diabetes is also likely associated with β-cell failure. On the other hand, incretin-related drugs and sodium-glucose co-transporter 2 (SGLT2) inhibitors are promising diabetes therapy based on the mechanism for pancreatic β-cell glucose toxicity. Indeed, it was shown that incretin-related drugs exerted protective effects on β-cells through the augmentation of IRS-2 expression especially in the presence of pioglitazone. It was also shown that incretin-related drug and/or pioglitazone exerted more protective effects on β-cells at the early stage of diabetes compared to the advanced stage. SGLT2 inhibitors, new hypoglycemic agents, also exert beneficial effects for the protection of pancreatic β-cells as well as for the reduction of insulin resistance in various insulin target tissues. Taken together, it is important to select appropriate therapy based on the molecular mechanism for glucose toxicity.

Influence of salinity and dissolved organic carbon on acute Cu toxicity to the rotifer Brachionus plicatilis.

PubMed

Cooper, Christopher A; Tait, Tara; Gray, Holly; Cimprich, Giselle; Santore, Robert C; McGeer, James C; Wood, Christopher M; Smith, D Scott

2014-01-21

Acute copper (Cu) toxicity tests (48-h LC50) using the euryhaline rotifer Brachionus plicatilis were performed to assess the effects of salinity (3, 16, 30 ppt) and dissolved organic carbon (DOC, ∼ 1.1, ∼ 3.1, ∼ 4.9, ∼ 13.6 mg C L(-1)) on Cu bioavailability. Total Cu was measured using anodic stripping voltammetry, and free Cu(2+) was measured using ion-selective electrodes. There was a protective effect of salinity observed in all but the highest DOC concentrations; at all other DOC concentrations the LC50 value was significantly higher at 30 ppt than at 3 ppt. At all salinities, DOC complexation significantly reduced Cu toxicity. At higher concentrations of DOC the protective effect increased, but the increase was less than expected from a linear extrapolation of the trend observed at lower concentrations, and the deviation from linearity was greatest at the highest salinity. Light-scattering data indicated that salt induced colloid formation of DOC could be occurring under these conditions, thereby decreasing the number of available reactive sites to complex Cu. When measurements of free Cu across DOC concentrations at each individual salinity were compared, values were very similar, even though the total Cu LC50 values and DOC concentrations varied considerably. Furthermore, measured free Cu values and predicted model values were comparable, highlighting the important link between the concentration of bioavailable free Cu and Cu toxicity.

Assessment of Chemical Impact of Invasive Bryozoan Pectinatella magnifica on the Environment: Cytotoxicity and Antimicrobial Activity of P. magnifica Extracts.

PubMed

Kollar, Peter; Šmejkal, Karel; Salmonová, Hana; Vlková, Eva; Lepšová-Skácelová, Olga; Balounová, Zuzana; Rajchard, Josef; Cvačka, Josef; Jaša, Libor; Babica, Pavel; Pazourek, Jiří

2016-11-04

Pectinatella magnifica , an invasive bryozoan, might significantly affect ecosystem balance due to its massive occurrence in many areas in Europe and other parts of the world. Biological and chemical analyses are needed to get complete information about the impact of the animal on the environment. In this paper, we aimed to evaluate in vitro cytotoxic effects of five extracts prepared from P. magnifica using LDH assay on THP-1 cell line. Antimicrobial activities of extracts against 22 different bacterial strains were tested by microdilution method. Our study showed that all extracts tested, except aqueous portion, demonstrated LD 50 values below 100 μg/mL, which indicates potential toxicity. The water extract of P. magnifica with LD 50 value of 250 μg/mL also shows potentially harmful effects. Also, an environmental risk resulting from the presence and increasing biomass of potentially toxic benthic cyanobacteria in old colonies should not be underestimated. Toxicity of Pectinatella extracts could be partially caused by presence of Aeromonas species in material, since we found members of these genera as most abundant bacteria associated with P. magnifica . Furthermore, P. magnifica seems to be a promising source of certain antimicrobial agents. Its methanolic extract, hexane, and chloroform fractions possessed selective inhibitory effect on some potential pathogens and food spoiling bacteria in the range of MIC 0.5-10 mg/mL. Future effort should be made to isolate and characterize the content compounds derived from P. magnifica , which could help to identify the substance(s) responsible for the toxic effects of P. magnifica extracts.

Toxicities of Selected Essential Oils, Silicone Oils, and Paraffin Oil against the Common Bed Bug (Hemiptera: Cimicidae).

PubMed

Zha, Chen; Wang, Changlu; Li, Andrew

2018-02-09

The common bed bug [Cimex lectularius L. (Hemiptera: Cimicidae)] and tropical bed bug [Cimex hemipterus F. (Hemiptera: Cimicidae)] resurged in the United States and many other countries over the past decades. The need for safe and effective bed bug control products propelled the development of numerous 'green insecticides', mostly with essential oils listed as active ingredients. Various inorganic and organic oils also were used for bed bug management. However, there are no published studies on their toxicities against bed bugs. In this study, we screened 18 essential oils, three silicone oils, and paraffin oil (C5-20 paraffins) for their toxicities against bed bugs. All the oils exhibited insecticidal activity in topical assays. Their toxicities varied significantly; all of the evaluated essential oils were less effective than silicone oils and paraffin oil. The LD50 values of the most effective essential oil (blood orange), paraffin oil, and the most effective silicone oil (dodecamethylpentasiloxane) are 0.184 ± 0.018, 0.069 ± 0.012, and 0.036 ± 0.005 mg per bug, respectively. Direct spray of 1% water solution of 3-[hydroxy (polyethyleneoxy) propyl] heptamethyltrisiloxane, the only silicone oil that mixes well with water, resulted in 92% bed bug mortality after 1 d. Results of this study indicate silicone oils and paraffin oil have the potential to be used as safer alternative bed bug control materials. © The Author(s) 2017. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Ecotoxicological evaluation of propranolol hydrochloride and losartan potassium to Lemna minor L. (1753) individually and in binary mixtures.

PubMed

Godoy, Aline A; Kummrow, Fábio; Pamplin, Paulo Augusto Z

2015-07-01

Antihypertensive pharmaceuticals, including the beta-blockers, are one of the most detected therapeutic classes in the environment. The ecotoxicity of propranolol hydrochloride and losartan potassium was evaluated, both individually and combined in a binary mixture, by using the Lemna minor growth inhibition test. The endpoints evaluated in the single-pharmaceutical tests were frond number, total frond area and fresh weight. For the evaluation of the mixture toxicity, the selected endpoint was frond number. Water quality criteria values (WQC) were derived for the protection of freshwater and saltwater pelagic communities regarding the effects induced by propranolol and losartan using ecotoxicological data from the literature, including our data. The risks associated with both pharmaceutical effects on non-target organisms were quantified through the measured environmental concentration (MEC)/predicted-no-effect concentration (PNEC) ratios. For propranolol, the total frond area was the most sensitive endpoint (EC50 = 77.3 mg L(-1)), while for losartan there was no statistically significant difference between the endpoints. Losartan is only slightly more toxic than propranolol. Both concentration addition and independent action models overestimated the mixture toxicity of the pharmaceuticals at all the effect concentration levels evaluated. The joint action of both pharmaceuticals showed an antagonistic interaction to L. minor. Derived WQC assumed lower values for propranolol than for losartan. The MEC/PNEC ratios showed that propranolol may pose a risk for the most sensitive aquatic species, while acceptable risks posed by losartan were estimated for most of aquatic matrices. To the authors knowledge these are the first data about losartan toxicity for L. minor.

Effects of triclosan on aquatic invertebrates in tropics and the influence of pH on its toxicity on microalgae.

PubMed

Khatikarn, Jidapa; Satapornvanit, Kriengkrai; Price, Oliver R; Van den Brink, Paul J

2018-05-01

The antimicrobial triclosan (TCS) has been detected in household wastewaters (untreated and treated) and receiving environments across the globe. The toxic effects of TCS on temperate standard aquatic test organisms have been widely reported with microalgae being the most sensitive. However, environmental differences between tropical and temperate regions may have selected different trait compositions between these two regions, which in turn may lead to a difference in species sensitivity. Therefore, additional information is required to better characterize risks to organisms in tropics and ensure biodiversity in these regions is not adversely impacted. This study aims to supplement existing TCS toxicity data with five aquatic invertebrates found in tropics and to compare the sensitivity between aquatic invertebrate species from tropical and temperate regions. In addition, the effect of pH on the toxicity of neutral and ionized forms of TCS to microalgae (Chlorella ellipsoidea) was investigated. The reported 96-h LC50 values for the studied invertebrate species ranged from 72 to 962 μg/L. There was no significant difference between the sensitivity of aquatic invertebrate species from tropical and temperate regions. EC50 values for C. ellipsoidea, with and without pH buffer, were significantly different. The findings of this study can be used to support site-specific water quality criteria and environmental risk assessment for TCS in tropical regions. However, further chronic and semi-field experiments with TCS could potentially enable a refined assessment of direct and indirect effects on tropical aquatic communities and further explore functional endpoints of tropical ecosystems.

Characterization of the Maize Stalk Rot Pathogens Fusarium subglutinans and F. temperatum and the Effect of Fungicides on Their Mycelial Growth and Colony Formation

PubMed Central

Shin, Jong-Hwan; Han, Joon-Hee; Lee, Ju Kyong; Kim, Kyoung Su

2014-01-01

Maize is a socioeconomically important crop in many countries. Recently, a high incidence of stalk rot disease has been reported in several maize fields in Gangwon province. In this report, we show that maize stalk rot is associated with the fungal pathogens Fusarium subglutinans and F. temperatum. Since no fungicides are available to control these pathogens on maize plants, we selected six fungicides (tebuconazole, difenoconazole, fluquinconazole, azoxystrobin, prochloraz and kresoxim-methyl) and examined their effectiveness against the two pathogens. The in vitro antifungal effects of the six fungicides on mycelial growth and colony formation were investigated. Based on the inhibition of mycelial growth, the most toxic fungicide was tebuconazole with 50% effective concentrations (EC50) of <0.1 μg/ml and EC90 values of 0.9 μg/ml for both pathogens, while the least toxic fungicide was azoxystrobin with EC50 values of 0.7 and 0.5 μg/ml for F. subglutinans and F. temperatum, respectively, and EC90 values of >3,000 μg/ml for both pathogens. Based on the inhibition of colony formation by the two pathogens, kresoxim-methyl was the most toxic fungicide with complete inhibition of colony formation at concentrations of 0.1 and 0.01 μg/ml for F. subglutinans and F. temperatum, respectively, whereas azoxystrobin was the least toxic fungicide with complete inhibition of colony formation at concentrations >3,000 μg/ml for both pathogens. PMID:25506304

Development and application of the adverse outcome pathway framework for understanding and predicting chronic toxicity: II. A focus on growth impairment in fish.

PubMed

Groh, Ksenia J; Carvalho, Raquel N; Chipman, James K; Denslow, Nancy D; Halder, Marlies; Murphy, Cheryl A; Roelofs, Dick; Rolaki, Alexandra; Schirmer, Kristin; Watanabe, Karen H

2015-02-01

Adverse outcome pathways (AOPs) organize knowledge on the progression of toxicity through levels of biological organization. By determining the linkages between toxicity events at different levels, AOPs lay the foundation for mechanism-based alternative testing approaches to hazard assessment. Here, we focus on growth impairment in fish to illustrate the initial stages in the process of AOP development for chronic toxicity outcomes. Growth is an apical endpoint commonly assessed in chronic toxicity tests for which a replacement is desirable. Based on several criteria, we identified reduction in food intake to be a suitable key event for initiation of middle-out AOP development. To start exploring the upstream and downstream links of this key event, we developed three AOP case studies, for pyrethroids, selective serotonin reuptake inhibitors (SSRIs) and cadmium. Our analysis showed that the effect of pyrethroids and SSRIs on food intake is strongly linked to growth impairment, while cadmium causes a reduction in growth due to increased metabolic demands rather than changes in food intake. Locomotion impairment by pyrethroids is strongly linked to their effects on food intake and growth, while for SSRIs their direct influence on appetite may play a more important role. We further discuss which alternative tests could be used to inform on the predictive key events identified in the case studies. In conclusion, our work demonstrates how the AOP concept can be used in practice to assess critically the knowledge available for specific chronic toxicity cases and to identify existing knowledge gaps and potential alternative tests. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Toxicity of chlorine to zebrafish embryos

PubMed Central

Kent, Michael L.; Buchner, Cari; Barton, Carrie; Tanguay, Robert L.

2014-01-01

Surface disinfection of fertilized fish eggs is widely used in aquaculture to reduce extraovum pathogens that may be released from brood fish during spawning, and this is routinely used in zebrafish (Danio rerio) research laboratories. Most laboratories use approximately 25 – 50 ppm unbuffered chlorine solution for 5 – 10 min. Treatment of embryos with chlorine has significant germicidal effects for many Gram-negative bacteria, viruses, and trophozoite stages of protozoa, it has reduced efficacy against cyst or spore stages of protozoa and certain Mycobacterium spp. Therefore, we evaluated the toxicity of unbufferred and buffered chlorine solution to embryos exposed at 6 or 24 hours post-fertilization (hpf) to determine if higher concentrations can be used for treating zebrafish embryos. Most of our experiments entailed using an outbred line (5D), with both mortality and malformations as endpoints. We found that 6 hpf embryos consistently were more resistant than 24 hpf embryos to the toxic effects of chlorine. Chlorine is more toxic and germicidal at lower pHs, and chlorine causes elevated pH. Consistent with this, we found that unbufferred chlorine solutions (pH ca 8–9) were less toxic at corresponding concentrations than solutions buffered to pH 7. Based on our findings here, we recommend treating 6 hpf embryos for 10 min and 24 hpf for 5 min with unbuffered chlorine solution at 100 ppm. One trial indicated that AB fish, a popular outbred line, are more susceptible to toxicity than 5Ds. This suggests that variability between zebrafish lines occurs, and researchers should evaluate each line or strain under their particular laboratory conditions for selection of the optimum chlorine treatment procedure. PMID:24429474

Robust EM Continual Reassessment Method in Oncology Dose Finding

PubMed Central

Yuan, Ying; Yin, Guosheng

2012-01-01

The continual reassessment method (CRM) is a commonly used dose-finding design for phase I clinical trials. Practical applications of this method have been restricted by two limitations: (1) the requirement that the toxicity outcome needs to be observed shortly after the initiation of the treatment; and (2) the potential sensitivity to the prespecified toxicity probability at each dose. To overcome these limitations, we naturally treat the unobserved toxicity outcomes as missing data, and use the expectation-maximization (EM) algorithm to estimate the dose toxicity probabilities based on the incomplete data to direct dose assignment. To enhance the robustness of the design, we propose prespecifying multiple sets of toxicity probabilities, each set corresponding to an individual CRM model. We carry out these multiple CRMs in parallel, across which model selection and model averaging procedures are used to make more robust inference. We evaluate the operating characteristics of the proposed robust EM-CRM designs through simulation studies and show that the proposed methods satisfactorily resolve both limitations of the CRM. Besides improving the MTD selection percentage, the new designs dramatically shorten the duration of the trial, and are robust to the prespecification of the toxicity probabilities. PMID:22375092

Serotonin toxicity caused by moclobemide too soon after paroxetine-selegiline.

PubMed

Wu, Ming-Ling; Deng, Jou-Fang

2009-08-01

Serotonin toxicity is an iatrogenic complication of serotonergic drug therapy. It is due to an overstimulation of central and peripheral serotonin receptors that lead to neuromuscular, mental and autonomic changes. Moclobemide is a reversible inhibitor of monoamine oxidase (MAO)-A, selegiline is an irreversible selective inhibitor of MAO-B, and paroxetine is a selective serotonin reuptake inhibitor. Combined use of these agents is known to cause serotonin toxicity. A 53-year-old woman had been treated with paroxetine and selegiline. After moclobemide was prescribed in place of paroxetine without a washout period, she quickly developed confusion, agitation, ataxia, diaphoresis, tremor, mydriasis, ocular clonus, hyperreflexia, tachycardia, moderately elevated blood pressure and high fever, symptoms that were consistent with serotonin toxicity. Discontinuation of the drugs, hydration and supportive care were followed by remarkable improvement of baseline status within 3 days. This case demonstrates that serotonin toxicity may occur even with small doses of paroxetine, selegiline and moclobemide in combination. Physicians managing patients with depression must be aware of the potential for serotonin toxicity and should be able to recognize and treat or, ideally, anticipate and avoid this pharmacodynamically-mediated interaction that may occur between prescribed drugs.

Safety and feasibility of targeted agent combinations in solid tumours.

PubMed

Park, Sook Ryun; Davis, Myrtle; Doroshow, James H; Kummar, Shivaani

2013-03-01

The plethora of novel molecular-targeted agents (MTAs) has provided an opportunity to selectively target pathways involved in carcinogenesis and tumour progression. Combination strategies of MTAs are being used to inhibit multiple aberrant pathways in the hope of optimizing antitumour efficacy and to prevent development of resistance. While the selection of specific agents in a given combination has been based on biological considerations (including the role of the putative targets in cancer) and the interactions of the agents used in combination, there has been little exploration of the possible enhanced toxicity of combinations resulting from alterations in multiple signalling pathways in normal cell biology. Owing to the complex networks and crosstalk that govern normal and tumour cell proliferation, inhibiting multiple pathways with MTA combinations can result in unpredictable disturbances in normal physiology. This Review focuses on the main toxicities and the lack of tolerability of some common MTA combinations, particularly where evidence of enhanced toxicity compared to either agent alone is documented or there is development of unexpected toxicity. Toxicities caused by MTA combinations highlight the need to introduce new preclinical testing paradigms early in the drug development process for the assessment of chronic toxicities resulting from such combinations.

Electrical Insulation Fire Characteristics : Volume 2. Toxicity.

DOT National Transportation Integrated Search

1978-12-01

The purpose of this research was to determine the relative inhalation toxicity of the thermal degradation products or gaseous pyrolysis of selected types of electrical wiring insulations. The specific materials to be evaluated were supplied by the Bo...

In vitro microbial inhibition and cellular response to novel biodegradable composite wound dressings with controlled release of antibiotics.

PubMed

Elsner, J J; Berdicevsky, I; Zilberman, M

2011-01-01

About 70% of all people with severe burns die from related infections, despite advances in treatment regimens and the best efforts of nurses and doctors. Although silver-eluting wound dressings are available for addressing this problem, there is growing evidence of the deleterious effects of such dressings in delaying the healing process owing to cellular toxicity. A new concept of antibiotic-eluting composite wound dressings is described here. These dressings are based on a polyglyconate mesh coated with a porous poly-(dl-lactic-co-glycolic acid) matrix loaded with antibiotic drugs. The effect of antibiotic release on bacterial inhibition was studied, and cell cytotoxicity was examined. The dressings resulted in a 99.99% decrease in the viable counts of Pseudomonas aeruginosa and Staphylococcus albus at very high initial inoculations of 10⁷-10⁸ CFU ml⁻¹ after only 1 day, while such a decrease in Staphylococcus aureus was obtained within 3 days. Bacterial inhibition zones around the dressing material were found to persist for 2 weeks, indicating a long-lasting antimicrobial effect. Despite severe toxicity to bacteria, the dressing material was found to have no toxic effect on cultured fibroblasts, indicating that the new antibiotic-eluting wound dressings represent an effective option for selective treatment of bacterial infections. Copyright © 2010 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Comparative toxicities of selected rare earth elements: Sea urchin embryogenesis and fertilization damage with redox and cytogenetic effects

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

Pagano, Giovanni, E-mail: gbpagano@tin.it; Guida, Marco; Siciliano, Antonietta

Background: Broad-ranging adverse effects are known for rare earth elements (REE), yet only a few studies tested the toxicity of several REE, prompting studies focusing on multi-parameter REE toxicity. Methods: Trichloride salts of Y, La, Ce, Nd, Sm, Eu and Gd were tested in Paracentrotus lividus sea urchin embryos and sperm for: (1) developmental defects in either REE-exposed larvae or in the offspring of REE-exposed sperm; (2) fertilization success; (3) mitotic anomalies in REE-exposed embryos and in the offspring of REE-exposed sperm, and (4) reactive oxygen species (ROS) formation, and malondialdehyde (MDA) and nitric oxide (NO) levels. Results: REEs affectedmore » P. lividus larvae with concentration-related increase in developmental defects, 10{sup −6} to 10{sup −4} M, ranking as: Gd(III)>Y(III)>La(III)>Nd(III)≅Eu(III)>Ce(III)≅Sm(III). Nominal concentrations of REE salts were confirmed by inductively coupled plasma mass spectrometry (ICP-MS). Significant increases in MDA levels, ROS formation, and NO levels were found in REE-exposed embryos. Sperm exposure to REEs (10{sup −5} to 10{sup −4} M) resulted in concentration-related decrease in fertilization success along with increase in offspring damage. Decreased mitotic activity and increased aberration rates were detected in REE-exposed embryos and in the offspring of REE-exposed sperm. Conclusion: REE-associated toxicity affecting embryogenesis, fertilization, cytogenetic and redox endpoints showed different activities of tested REEs. Damage to early life stages, along with redox and cytogenetic anomalies should be the focus of future REE toxicity studies. - Highlights: • Seven rare earth elements exerted different effects on sea urchin early life stages. • Embryo-, spermio- and mitotoxicity, and oxidative/ nitrosative stress were found. • Nominal vs. analytical REE concentrations were checked. • Comparative toxicities were evaluated for the different REE.« less

Molecular insights into microbial β-glucuronidase inhibition to abrogate CPT-11 toxicity.

PubMed

Roberts, Adam B; Wallace, Bret D; Venkatesh, Madhu Kumar; Mani, Sridhar; Redinbo, Matthew R

2013-08-01

Bacterial β-glucuronidases expressed by the symbiotic intestinal microbiota appear to play important roles in drug-induced epithelial cell toxicity in the gastrointestinal (GI) tract. For the anticancer drug CPT-11 (irinotecan) and the nonsteroidal anti-inflammatory drug diclofenac, it has been shown that removal of the glucuronide moieties from drug metabolites by bacterial β-glucuronidases in the GI lumen can significantly damage the intestinal epithelium. Furthermore, selective disruption of bacterial β-glucuronidases by small molecule inhibitors alleviates these side effects, which, for CPT-11 {7-ethyl-10-[4-(1-piperidino)-1-piperidino]}, can be dose limiting. Here we characterize novel microbial β-glucuronidase inhibitors that inhibit Escherichia coli β-glucuronidase in vitro with Ki values between 180 nM and 2 μM, and disrupt the enzyme in E. coli cells, with EC50 values as low as 300 nM. All compounds are selective for E. coli β-glucuronidase without inhibiting purified mammalian β-glucuronidase, and they do not impact the survival of either bacterial or mammalian cells. The 2.8 Å resolution crystal structure of one inhibitor bound to E. coli β-glucuronidase demonstrates that it contacts and orders only a portion of the "bacterial loop" present in microbial, but not mammalian, β-glucuronidases. The most potent compound examined in this group was found to protect mice against CPT-11-induced diarrhea. Taken together, these data advance our understanding of the chemical and structural basis of selective microbial β-glucuronidase inhibition, which may improve human drug efficacy and toxicity.

Molecular Insights into Microbial β-Glucuronidase Inhibition to Abrogate CPT-11 Toxicity

PubMed Central

Roberts, Adam B.; Wallace, Bret D.; Venkatesh, Madhu Kumar; Mani, Sridhar

2013-01-01

Bacterial β-glucuronidases expressed by the symbiotic intestinal microbiota appear to play important roles in drug-induced epithelial cell toxicity in the gastrointestinal (GI) tract. For the anticancer drug CPT-11 (irinotecan) and the nonsteroidal anti-inflammatory drug diclofenac, it has been shown that removal of the glucuronide moieties from drug metabolites by bacterial β-glucuronidases in the GI lumen can significantly damage the intestinal epithelium. Furthermore, selective disruption of bacterial β-glucuronidases by small molecule inhibitors alleviates these side effects, which, for CPT-11 {7-ethyl-10-[4-(1-piperidino)-1-piperidino]}, can be dose limiting. Here we characterize novel microbial β-glucuronidase inhibitors that inhibit Escherichia coli β-glucuronidase in vitro with Ki values between 180 nM and 2 μM, and disrupt the enzyme in E. coli cells, with EC50 values as low as 300 nM. All compounds are selective for E. coli β-glucuronidase without inhibiting purified mammalian β-glucuronidase, and they do not impact the survival of either bacterial or mammalian cells. The 2.8 Å resolution crystal structure of one inhibitor bound to E. coli β-glucuronidase demonstrates that it contacts and orders only a portion of the “bacterial loop” present in microbial, but not mammalian, β-glucuronidases. The most potent compound examined in this group was found to protect mice against CPT-11–induced diarrhea. Taken together, these data advance our understanding of the chemical and structural basis of selective microbial β-glucuronidase inhibition, which may improve human drug efficacy and toxicity. PMID:23690068

Plasmonic Nanobubbles Rapidly Detect and Destroy Drug-Resistant Tumors

PubMed Central

Lukianova-Hleb, Ekaterina Y.; Ren, Xiaoyang; Townley, Debra; Wu, Xiangwei; Kupferman, Michael E.; Lapotko, Dmitri O.

2012-01-01

The resistance of residual cancer cells after oncological resection to adjuvant chemoradiotherapies results in both high recurrence rates and high non-specific tissue toxicity, thus preventing the successful treatment of such cancers as head and neck squamous cell carcinoma (HNSCC). The patients' survival rate and quality of life therefore depend upon the efficacy, selectivity and low non-specific toxicity of the adjuvant treatment. We report a novel, theranostic in vivo technology that unites both the acoustic diagnostics and guided intracellular delivery of anti-tumor drug (liposome-encapsulated doxorubicin, Doxil) in one rapid process, namely a pulsed laser-activated plasmonic nanobubble (PNB). HNSCC-bearing mice were treated with gold nanoparticle conjugates, Doxil, and single near-infrared laser pulses of low energy. Tumor-specific clusters of gold nanoparticles (solid gold spheres) converted the optical pulses into localized PNBs. The acoustic signals of the PNB detected the tumor with high specificity and sensitivity. The mechanical impact of the PNB, co-localized with Doxil liposomes, selectively ejected the drug into the cytoplasm of cancer cells. Cancer cell-specific generation of PNBs and their intracellular co-localization with Doxil improved the in vivo therapeutic efficacy from 5-7% for administration of only Doxil or PNBs alone to 90% thus demonstrating the synergistic therapeutic effect of the PNB-based intracellular drug release. This mechanism also reduced the non-specific toxicity of Doxil below a detectable level and the treatment time to less than one minute. Thus PNBs combine highly sensitive diagnosis, overcome drug resistance and minimize non-specific toxicity in a single rapid theranostic procedure for intra-operative treatment. PMID:23139725

Baseline susceptibility of Planococcus ficus (Hemiptera: Pseudococcidae) from California to select insecticides.

PubMed

Prabhaker, Nilima; Gispert, Carmen; Castle, Steven J

2012-08-01

Between 2006 and 2008, 20 populations of Planococcus ficus (Signoret), from Coachella and San Joaquin Valleys of California were measured in the laboratory for susceptibility to buprofezin, chlorpyrifos, dimethoate, methomyl, and imidacloprid. Toxicity was assessed using a petri dish bioassay technique for contact insecticides and by a systemic uptake technique for imidacloprid. Mixed life stages were tested for susceptibility to all insecticides except for buprofezin, which was measured against early and late instars (first, second, and third). Dose-response regression lines from the mortality data established LC50 and LC99 values by both techniques. Responses of populations from the two geographical locations to all five insecticides varied, in some cases significantly. Variations in susceptibility to each insecticide among sample sites showed a sevenfold difference for buprofezin, 11-fold to chlorpyrifos, ninefold to dimethoate, 24-fold to methomyl, and 8.5-fold to imidacloprid. In spite of susceptibility differences between populations, baseline toxicity data revealed that all five insecticides were quite effective based on low LC50s. Chlorpyrifos was the most toxic compound to Planococcus ficus populations as shown by lowest LC50s. Buprofezin was toxic to all immature stages but was more potent to first instars. The highest LC99 estimated by probit analysis of the bioassay data of all 20 populations for each compound was selected as a candidate discriminating dose for use in future resistance monitoring efforts. Establishment of baseline data and development of resistance monitoring tools such as bioassay methods and discriminating doses are essential elements of a sustainable management program for Planococcus ficus.

Patient- and therapy-related factors associated with the incidence of xerostomia in nasopharyngeal carcinoma patients receiving parotid-sparing helical tomotherapy

PubMed Central

Lee, Tsair-Fwu; Liou, Ming-Hsiang; Ting, Hui-Min; Chang, Liyun; Lee, Hsiao-Yi; Wan Leung, Stephen; Huang, Chih-Jen; Chao, Pei-Ju

2015-01-01

We investigated the incidence of moderate to severe patient-reported xerostomia among nasopharyngeal carcinoma (NPC) patients treated with helical tomotherapy (HT) and identified patient- and therapy-related factors associated with acute and chronic xerostomia toxicity. The least absolute shrinkage and selection operator (LASSO) normal tissue complication probability (NTCP) models were developed using quality-of-life questionnaire datasets from 67 patients with NPC. For acute toxicity, the dosimetric factors of the mean doses to the ipsilateral submandibular gland (Dis) and the contralateral submandibular gland (Dcs) were selected as the first two significant predictors. For chronic toxicity, four predictive factors were selected: age, mean dose to the oral cavity (Doc), education, and T stage. The substantial sparing data can be used to avoid xerostomia toxicity. We suggest that the tolerance values corresponded to a 20% incidence of complications (TD20) for Dis = 39.0 Gy, Dcs = 38.4 Gy, and Doc = 32.5 Gy, respectively, when mean doses to the parotid glands met the QUANTEC 25 Gy sparing guidelines. To avoid patient-reported xerostomia toxicity, the mean doses to the parotid gland, submandibular gland, and oral cavity have to meet the sparing tolerance, although there is also a need to take inherent patient characteristics into consideration. PMID:26289304

The interactive effects of microcystin-LR and cylindrospermopsin on the growth rate of the freshwater algae Chlorella vulgaris.

PubMed

Pinheiro, Carlos; Azevedo, Joana; Campos, Alexandre; Vasconcelos, Vítor; Loureiro, Susana

2016-05-01

Microcystin-LR (MC-LR) and cylindrospermopsin (CYN) are the most representative cyanobacterial cyanotoxins. They have been simultaneously detected in aquatic systems, but their combined ecotoxicological effects to aquatic organisms, especially microalgae, is unknown. In this study, we examined the effects of these cyanotoxins individually and as a binary mixture on the growth rate of the freshwater algae Chlorella vulgaris. Using the MIXTOX tool, the reference model concentration addition (CA) was selected to evaluate the combined effects of MC-LR and CYN on the growth of the freshwater green algae due to its conservative prediction of mixture effect for putative similar or dissimilar acting chemicals. Deviations from the CA model such as synergism/antagonism, dose-ratio and dose-level dependency were also assessed. In single exposures, our results demonstrated that MC-LR and CYN had different impacts on the growth rates of C. vulgaris at the highest tested concentrations, being CYN the most toxic. In the mixture exposure trial, MC-LR and CYN showed a synergistic deviation from the conceptual model CA as the best descriptive model. MC-LR individually was not toxic even at high concentrations (37 mg L(-1)); however, the presence of MC-LR at much lower concentrations (0.4-16.7 mg L(-1)) increased the CYN toxicity. From these results, the combined exposure of MC-LR and CYN should be considered for risk assessment of mixtures as the toxicity may be underestimated when looking only at the single cyanotoxins and not their combination. This study also represents an important step to understand the interactions among MC-LR and CYN detected previously in aquatic systems.

Oxidized/misfolded superoxide dismutase-1: the cause of all amyotrophic lateral sclerosis?

PubMed

Kabashi, Edor; Valdmanis, Paul N; Dion, Patrick; Rouleau, Guy A

2007-12-01

The identification in 1993 of superoxide dismutase-1 (SOD1) mutations as the cause of 10 to 20% of familial amyotrophic lateral sclerosis cases, which represents 1 to 2% of all amyotrophic lateral sclerosis (ALS) cases, prompted a substantial amount of research into the mechanisms of SOD1-mediated toxicity. Recent experiments have demonstrated that oxidation of wild-type SOD1 leads to its misfolding, causing it to gain many of the same toxic properties as mutant SOD1. In vitro studies of oxidized/misfolded SOD1 and in vivo studies of misfolded SOD1 have indicated that these protein species are selectively toxic to motor neurons, suggesting that oxidized/misfolded SOD1 could lead to ALS even in individuals who do not carry an SOD1 mutation. It has also been reported that glial cells secrete oxidized/misfolded mutant SOD1 to the extracellular environment, where it can trigger the selective death of motor neurons, offering a possible explanation for the noncell autonomous nature of mutant SOD1 toxicity and the rapid progression of disease once the first symptoms develop. Therefore, considering that sporadic (SALS) and familial ALS (FALS) cases are clinically indistinguishable, the toxic properties of mutated SOD1 are similar to that of oxidized/misfolded wild-type SOD1 (wtSOD1), and secreted/extracellular misfolded SOD1 is selectively toxic to motor neurons, we propose that oxidized/misfolded SOD1 is the cause of most forms of classic ALS and should be a prime target for the design of ALS treatments.

Attractiveness of food and avoidance from contamination as conflicting stimuli to habitat selection by fish.

PubMed

Araújo, Cristiano V M; Rodríguez, Elizabeth N V; Salvatierra, David; Cedeño-Macias, Luis A; Vera-Vera, Victoria C; Moreira-Santos, Matilde; Ribeiro, Rui

2016-11-01

Habitat selection by fish is the outcome of a choice between different stimuli. Typically, the presence of food tends to attract organisms, while contamination triggers an avoidance response to prevent toxic effects. Given that both food and contaminants are not homogeneously distributed in the environment and that food can be available in contaminated zones, a key question has been put forward in the present study: does a higher availability of food in contaminated areas interfere in the avoidance response to contaminants regardless of the contamination level? Tilapia fry (Oreochromis sp.; 2.5-3.0 cm and 0.5-0.8 g) were exposed to two different effluent samples, diluted along a free-choice, non-forced exposure system simulating a contamination gradient. Initially, avoidance to the effluents was checked during a one hour exposure. Afterwards, food was added to the system so that the availability of food increased with the increase in the level of contamination, and the avoidance response to contamination was checked during another hour. Results clearly showed a concentration-dependent avoidance response for both effluents during the first hour (i.e., with no food). However, in presence of the food, the avoidance pattern was altered: organisms were propelled to intermittently move towards contaminated areas where food availability was higher. The incursions were taken regardless of the potential risk linked to the toxic effects. In conclusion, even when the risk of toxicity was imminent, tilapia fry were more intensively stimulated by the attractiveness of the food than by repulsion to the contamination. Copyright © 2016 Elsevier Ltd. All rights reserved.

Selective Thinning of the Perifoveal Inner Retina as an Early Sign of Hydroxychloroquine Retinal Toxicity

PubMed Central

Pasadhika, Sirichai; Fishman, Gerald A; Choi, Dongseok; Shahidi, Mahnaz

2013-01-01

Purpose To evaluate macular thickness profiles using spectral-domain optical coherence tomography (SDOCT) and image segmentation in patients with chronic exposure to hydroxychloroquine. Methods This study included 8 patients with chronic exposure to hydroxychloroquine (Group 1) and 8 controls (Group 2). Group 1 patients had no clinically-evident retinal toxicity. All subjects underwent SDOCT imaging of the macula. An image segmentation technique was used to measure thickness of 6 retinal layers at 200 µm intervals. A mixed-effects model was used for multivariate analysis. Results By measuring total retinal thickness either at the central macular (2800 µm in diameter), the perifoveal region 1200-µm-width ring surrounding the central macula), or the overall macular area (5200 µm in diameter), there were no significant differences in the thickness between Groups 1 and 2. On an image segmentation analysis, selective thinning of the inner plexiform + ganglion cell layers (p=0.021) was observed only in the perifoveal area of the patients in Group 1 compared to that of Group 2 by using the mixed-effects model analysis. Conclusions Our results suggest that chronic exposure to hydroxychloroquine is associated with thinning of the perifoveal inner retinal layers, especially in the ganglion cell and inner plexiform layers, even in the absence of functional or structural clinical changes involving the photoreceptor or retinal pigment epithelial cell layers. This may be a contributing factor as the reason most patients who have early detectable signs of drug toxicity present with paracentral or pericentral scotomas. PMID:20395978

A subchronic toxicity study in rats and genotoxicity tests with an aqueous ethylcellulose dispersion.

PubMed

DeMerlis, C C; Schoneker, D R; Borzelleca, J F

2005-09-01

Surelease Aqueous Ethylcellulose Dispersion is an excipient used as a modified release coating for beads, granules, non-pariels, drug crystals and tablets and for taste masking applications for drug products and dietary supplement products. A study was conducted to assess the toxicity of spray-dried Surelease when administered orally, via dietary admixture, to Sprague-Dawley CD rats (20/sex/group) at dose levels of 0, 2000, 3500, and 5000 mg/kg/day for a period of at least 3 months. After 3 months of treatment, all rats scheduled for terminal sacrifice were killed and selected organs were weighed. Complete macroscopic examinations and histopathological evaluation of selected tissues were conducted on all animals. Neuropathological evaluations were performed on 5 animals/sex/group. No mortality occurred during the study. Clinical observations, ophthalmology, body weight and food consumption, hematology, coagulation, clinical chemistry, urinalysis, functional observational assessments, motor activity, organ weights and ratios and macroscopic and microscopic observations did not reveal any significant, consistent, dose-dependent test article-related adverse effects. The NOAEL (no-observed-adverse-effect-level) is 5000 mg/kg/day, the highest dose tested. A series of genotoxicity tests were conducted with Surelease. Surelease showed no evidence of mutagenic activity in the bacterial reverse mutation test with and without metabolic activation and in the in vitro cell mutation assay under the experimental conditions employed. Surelease did not show any evidence of causing chromosome damage or bone marrow cell toxicity when administered by gavage in the mouse micronucleus in vivo test procedure. These findings support the safety of Surelease for use as an excipient.

Silibinin preferentially radiosensitizes prostate cancer by inhibiting DNA repair signaling

PubMed Central

Nambiar, Dhanya K.; Rajamani, Paulraj; Deep, Gagan; Jain, Anil K.; Agarwal, Rajesh; Singh, Rana P.

2015-01-01

Radiotherapy, a frequent mode of cancer treatment, is often restricted by dose-related toxicity and development of therapeutic resistance. To develop a novel and selective radiosensitizer, we studied the radiosensitizing effects and associated mechanisms of silibinin in prostate cancer (PCa). The radiosensitizing effect of silibinin with ionizing radiation (IR) was assessed on radioresistant PCa cell lines by clonogenic, cell cycle, cell death and DNA repair assays. Tumor xenograft growth, immunohistochemical (IHC) analysis of tumor tissues, and toxicity-related parameters were measured in vivo. Silibinin (25 μM) enhanced IR (2.5-10 Gy)-caused inhibition (up to 96%, P<0.001) of colony formation selectively in PCa cells, and prolonged and enhanced IR-caused G2/M arrest, apoptosis and ROS production. Mechanistically, silibinin inhibited IR-induced DNA repair (ATM and Chk1/2) and EGFR signaling and attenuated the levels of anti-apoptotic proteins. Specifically, silibinin suppressed IR-induced nuclear translocation of EGFR and DNA-PK, an important mediator of DSB repair, leading to an increased number of γ-H2AX (ser139) foci suggesting lesser DNA repair. In vivo, silibinin strongly radiosensitized DU145 tumor xenograft inhibition (84%, P<0.01) with higher apoptotic response (10-fold, P<0.01) and reduced repair of DNA damage, and rescued the mice from IR-induced toxicity and hematopoietic injury. Overall, silibinin enhanced the radiotherapeutic response via suppressing IR-induced pro-survival signaling and DSB repair by inhibiting nuclear translocation of EGFR and DNA-PK. Since silibinin is already in phase II clinical trial for PCa patients, the present finding has translational relevance for radioresistant PCa. PMID:26516160

Mefloquine use, psychosis, and violence: a retinoid toxicity hypothesis.

PubMed

Mawson, Anthony

2013-07-15

Mefloquine use has been linked to severe gastrointestinal and neuropsychiatric adverse effects, including cognitive disturbances, anxiety, depression, psychosis, and violence. The adverse effects of the drug are thought to result from the secondary consequences of hepatocellular injury; in fact, mefloquine is known to cause a transient, anicteric chemical hepatitis. However, the mechanism of mefloquine-associated liver damage and the associated neuropsychiatric and behavioral effects of the drug are not well understood. Mefloquine and other 8-amino-quinolines are the only antimalarial drugs that target the liver-stage malaria parasites, which selectively absorb vitamin A from the host. Vitamin A is also stored mainly in the liver, in potentially poisonous concentrations. These observations suggest that both the therapeutic effectiveness of mefloquine and its adverse effects are related to the ability of the 8-aminoquinolines to alter the metabolism of retinoids (vitamin A and its congeners). Several lines of evidence support the hypothesis that mefloquine neurotoxicity and other adverse effects reflect an endogenous form of hypervitaminosis A due to a process involving: mefloquine-induced dehydrogenase inhibition; the accumulation of retinoids in the liver; retinoid-induced hepatocellular damage; the spillage of stored retinoids into the circulation; and the transport of these compounds to the gut and brain in toxic concentrations. The retinoid hypothesis could be tested clinically by comparing cases of mefloquine toxicity and untreated controls in terms of retinoid profiles (retinol, retinyl esters, percent retinyl esters, and retinoic acid). Subject to such tests, retinoid profiling could provide an indicator for assessing mefloquine-associated adverse effects.

Investigations of chemical warfare agents and toxic industrial compounds with proton-transfer-reaction mass spectrometry for a real-time threat monitoring scenario.

PubMed

Kassebacher, Thomas; Sulzer, Philipp; Jürschik, Simone; Hartungen, Eugen; Jordan, Alfons; Edtbauer, Achim; Feil, Stefan; Hanel, Gernot; Jaksch, Stefan; Märk, Lukas; Mayhew, Chris A; Märk, Tilmann D

2013-01-30

Security and protection against terrorist attacks are major issues in modern society. One especially challenging task is the monitoring and protection of air conditioning and heating systems of buildings against terrorist attacks with toxic chemicals. As existing technologies have low selectivity, long response times or insufficient sensitivity, there is a need for a novel approach such as we present here. We have analyzed various chemical warfare agents (CWAs) and/or toxic industrial compounds (TICs) and related compounds, namely phosgene, diphosgene, chloroacetone, chloroacetophenone, diisopropylaminoethanol, and triethyl phosphate, utilizing a high-resolution proton-transfer-reaction time-of-flight mass spectrometry (PTR-TOFMS) instrument with the objective of finding key product ions and their intensities, which will allow a low-resolution quadrupole mass spectrometry based PTR-MS system to be used with high confidence in the assignment of threat agents in the atmosphere. We obtained high accuracy PTR-TOFMS mass spectra of the six compounds under study at two different values for the reduced electric field in the drift tube (E/N). From these data we have compiled a table containing product ions, and isotopic and E/N ratios for highly selective threat compound detection with a compact and cost-effective quadrupole-based PTR-MS instrument. Furthermore, using chloroacetophenone (tear gas), we demonstrated that this instrument's response is highly linear in the concentration range of typical Acute Exposure Guideline Levels (AEGLs). On the basis of the presented results it is possible to develop a compact and cost-effective PTR-QMS instrument that monitors air supply systems and triggers an alarm as soon as the presence of a threat agent is detected. We hope that this real-time surveillance device will help to seriously improve safety and security in environments vulnerable to terrorist attacks with toxic chemicals. Copyright © 2012 John Wiley & Sons, Ltd.

Ecotoxic effect of photocatalytic active nanoparticles (TiO2) on algae and daphnids.

PubMed

Hund-Rinke, Kerstin; Simon, Markus

2006-07-01

Due to their large potential for manifold applications, the use of nanoparticles is of increasing importance. As large amounts of nanoparticles may reach the environment voluntarily or by accident, attention should be paid on the potential impacts on the environment. First studies on potential environmental effects of photocatalytic TiO2 nanoparticles have been performed on the basis of widely accepted, standardized test systems which originally had been developed for the characterization of chemicals. The methods were adapted to the special requirements of testing photocatalytic nanoparticles. Suspensions of two different nanoparticles were illuminated to induce their photocatalytic activity. For testing, the growth inhibition test with the green alga Desmodesmus subspicatus and the immobilization test with the daphnid Daphnia magna were selected and performed following the relevant guidelines (algae: ISO 8692, OECD 201, DIN 38412-33; daphnids: ISO 6341, OECD 202, DIN 38412-30). The guidelines were adapted to meet the special requirements for testing photocatalytic nanoparticles. The results indicate that it is principally possible to determine the ecotoxicity of nanoparticles. It was shown that nanoparticles may have ecotoxicological effects which depend on the nature of the particles. Both products tested differ in their toxicity. Product 1 shows a clear concentration-effect curve in the test with algae (EC50: 44 mg/L). It could be proven that the observed toxicity was not caused by accompanying contaminants, since the toxic effect was comparable for the cleaned and the commercially available product. For product 2, no toxic effects were determined (maximum concentration: 50 mg/L). In the tests with daphnids, toxicity was observed for both products, although the concentration effect-curves were less pronounced. The two products differed in their toxicity; moreover, there was a difference in the toxicity of illuminated and non-illuminated products. Both products differ in size and crystalline form, so that these parameters are assumed to contribute to the different toxicities. The concentration-effect curves for daphnids, which are less-pronounced than the curves obtained for algae, may be due to the different test organisms and/or the differing test designs. The increased toxicity of pre-illuminated particles in the tests with daphnids demonstrates that the photocatalytic activity of nanoparticles lasts for a period of time. The following conclusions can be drawn from the test results: (I) It is principally possible to determine the ecotoxicity of (photocatalytic) nanoparticles. Therefore, they can be assessed using methods comparable to the procedures applied for assessing soluble chemicals. (II) Nanoparticles may exert ecotoxicological effects, which depend on the specific nanoparticle. (III) Comparable to traditional chemicals, the ecotoxicity depends on the test organisms and their physiology. (IV) The photocatalytic activity of nanoparticles lasts for a relevant period of time. Therefore, pre-illumination may be sufficient to detect a photocatalytic activity even by using test organisms which are not suitable for application in the pre-illumination-phase. First results are presented which indicate that the topic 'ecotoxicity and environmental effects of nanoparticles' should not be neglected. In testing photocatalytic nanoparticles, there are still many topics that need clarification or improvement, such as the cause for an observed toxicity, the improvement of the test design, the elaboration of a test battery and an assessment strategy. On the basis of optimized test systems, it will be possible to test nanoparticles systematically. If a potential risk by specific photocatalytic particles is known, a risk-benefit analysis can be performed and, if required, risk reducing measures can be taken.

Bayesian Multi-Trait Analysis Reveals a Useful Tool to Increase Oil Concentration and to Decrease Toxicity in Jatropha curcas L.

PubMed Central

Silva Junqueira, Vinícius; de Azevedo Peixoto, Leonardo; Galvêas Laviola, Bruno; Lopes Bhering, Leonardo; Mendonça, Simone; Agostini Costa, Tania da Silveira; Antoniassi, Rosemar

2016-01-01

The biggest challenge for jatropha breeding is to identify superior genotypes that present high seed yield and seed oil content with reduced toxicity levels. Therefore, the objective of this study was to estimate genetic parameters for three important traits (weight of 100 seed, oil seed content, and phorbol ester concentration), and to select superior genotypes to be used as progenitors in jatropha breeding. Additionally, the genotypic values and the genetic parameters estimated under the Bayesian multi-trait approach were used to evaluate different selection indices scenarios of 179 half-sib families. Three different scenarios and economic weights were considered. It was possible to simultaneously reduce toxicity and increase seed oil content and weight of 100 seed by using index selection based on genotypic value estimated by the Bayesian multi-trait approach. Indeed, we identified two families that present these characteristics by evaluating genetic diversity using the Ward clustering method, which suggested nine homogenous clusters. Future researches must integrate the Bayesian multi-trait methods with realized relationship matrix, aiming to build accurate selection indices models. PMID:27281340

Design, Synthesis and Pharmacological Evaluation of Novel Vanadium-Containing Complexes as Antidiabetic Agents

PubMed Central

Fedorova, Elena V.; Buryakina, Anna V.; Zakharov, Alexey V.; Filimonov, Dmitry A.; Lagunin, Alexey A.; Poroikov, Vladimir V.

2014-01-01

Based on the data about structure and antidiabetic activity of twenty seven vanadium and zinc coordination complexes collected from literature we developed QSAR models using the GUSAR program. These QSAR models were applied to 10 novel vanadium coordination complexes designed in silico in order to predict their hypoglycemic action. The five most promising substances with predicted potent hypoglycemic action were selected for chemical synthesis and pharmacological evaluation. The selected coordination vanadium complexes were synthesized and tested in vitro and in vivo for their hypoglycemic activities and acute rat toxicity. Estimation of acute rat toxicity of these five vanadium complexes was performed using a freely available web-resource (http://way2drug.com/GUSAR/acutoxpredict.html). It has shown that the selected compounds belong to the class of moderate toxic pharmaceutical agents, according to the scale of Hodge and Sterner. Comparison with the predicted data has demonstrated a reasonable correspondence between the experimental and predicted values of hypoglycemic activity and toxicity. Bis{tert-butyl[amino(imino)methyl]carbamato}oxovanadium (IV) and sodium(2,2′-Bipyridyl)oxo-diperoxovanadate(V) octahydrate were identified as the most potent hypoglycemic agents among the synthesized compounds. PMID:25057899

Racial Variations in Radiation-Induced Skin Toxicity Severity: Data From a Prospective Cohort Receiving Postmastectomy Radiation

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

Wright, Jean L., E-mail: jwrigh71@jhmi.edu; Takita, Cristiane; Reis, Isildinha M.

2014-10-01

Purpose: Radiation-induced skin toxicity is one of the most symptomatic side effects of postmastectomy radiation therapy (PMRT). We sought to determine whether the severity of acute skin toxicity was greater in black patients in a prospective cohort receiving PMRT and to identify other predictors of more severe skin toxicity. Methods and Materials: We evaluated the first 110 patients in an ongoing prospective study assessing radiation-induced skin toxicity in patients receiving PMRT. We recorded patient demographics, body mass index (BMI), and disease and treatment characteristics. Logistic regression analyses were conducted to evaluate the effect of potential predictors on the risk ofmore » skin toxicity. Results: A total of 23.6% respondents self-identified as black, 5.5% as non-Hispanic white, 69.1% as Hispanic white, and 1.8% as other; 57% were postmenopausal, and 70.9% had BMI of >25. Median chest wall dose was 50 Gy, and mastectomy scar dose was 60 Gy. Most patients, 95.5%, were treated with a 0.5-cm bolus throughout treatment. There were no significant differences in patient characteristics in black versus non-black patients. At RT completion, moist desquamation was more common in black patients (73.1% vs 47.6%, respectively, P=.023), in postmenopausal patients (63.5% vs 40.4%, respectively, P=.016), and in those with BMI of ≥25 (60.3% vs 37.5%, respectively, P=.030). On multivariate analysis, the effects of black race (odds ratio [OR] = 7.46, P=.031), BMI ≥25 (OR = 2.95, P=.043) and postmenopausal status (OR = 8.26, P=.004) remained significant risk factors for moist desquamation. Conclusions: In this prospectively followed, racially diverse cohort of breast cancer patients receiving PMRT delivered in a uniform fashion, including the routine use of chest wall boost and bolus, black race, higher BMI, and postmenopausal status emerged as significant predictors of moist desquamation. There was a high frequency of moist desquamation, particularly in those patients with elevated risk. Continued study of patient selection for chest wall boost and bolus as well improved skin toxicity management strategies are needed.« less

CYP 2E1 mutant mice are resistant to DDC-induced enhancement of MPTP toxicity.

PubMed

Viaggi, C; Vaglini, F; Pardini, C; Sgadò, P; Caramelli, A; Corsini, G U

2007-01-01

In order to reach a deeper insight into the mechanism of diethyldithiocarbamate (DDC)-induced enhancement of MPTP toxicity in mice, we showed that CYP450 (2E1) inhibitors, such as diallyl sulfide (DAS) or phenylethylisothiocyanate (PIC), also potentiate the selective DA neuron degeneration in C57/bl mice. Furthermore we showed that CYP 2E1 is present in the brain and in the basal ganglia of mice (Vaglini et al., 2004). However, because DAS and PIC are not selective CYP 2E1 inhibitors and in order to provide direct evidence for CYP 2E1 involvement in the enhancement of MPTP toxicity, CYP 2E1 knockout mice (GONZ) and wild type animals (SVI) of the same genetic background were treated with MPTP or the combined DDC + MPTP treatment. In CYP 2E1 knockout mice, DDC pretreatment completely fails to enhance MPTP toxicity, although enhancement of MPTP toxicity was regularly present in the SVI control animals. The immunohistochemical study confirms our results and suggests that CYP 2E1 may have a detoxifying role.

Occurrence of toxicity among protease, amylase, and color mutants of a nontoxic soy sauce koji mold

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

Kalayanamitr, A.; Bhumiratana, A.; Flegel, T.W.

A soy sauce koji mold, Aspergillus flavus var. columnaris Raper and Fennel (ATCC 44310), was treated with UV irradiation to obtain mutant strains possessing high protease activities, high amylase activities, and light-colored conidia. Selected mutant strains were tested for toxicity, and some were found acutely toxic to weanling rats, although all were negative for aflatoxin production.

Toxic effects of brominated flame retardants in man and in wildlife.

PubMed

Darnerud, Per Ola

2003-09-01

Brominated flame retardants (BFRs) are ubiquitous industrial chemicals, and many of them are produced in large volumes. Due to this fact, several BFRs are found in quantifiable levels in wildlife, as well as in humans. However, we are still lacking information on the effects of BFR in wildlife and, especially, in man. This review summarises the biological effects of polybrominated diphenyl ethers (PBDEs), tetrabromobisphenol A (TBBPA) and derivates, hexabromocyclododecane (HBCD) and polybrominated biphenyls (PBBs), however excluding other aspects such as environmental levels. These BFR groups were selected because of a large volume production (PBDEs, TBBPA and derivates), and availability of some toxicity data in spite of much lower production volumes (HBCD and PBBs). In addition, the increase in levels of PBDEs in human (breast milk) and wildlife samples during later time made it especially interesting to include this BFR group. PBDES: The commercial PBDE products predominantly consist of so-called penta-, octa- and decabromodiphenyl ether products. Each product consists of a rather narrow range of congeners and is named after the dominating congener as regards the bromination pattern. Generally, the PentaBDEs seem to cause adverse effects at the comparably lowest dose, whereas much higher doses were needed for effects of the DecaBDEs. The critical effects of PentaBDEs are those on neurobehavioural development (from 0.6 mg/kg body weight) and, at somewhat higher dose, thyroid hormone levels in rats and mice, of OctaBDEs on fetal toxicity/teratogenicity in rats and rabbits (from 2 mg/kg body weight), and of DecaBDEs on thyroid, liver and kidney morphology in adult animals (from 80 mg/kg body weight). Carcinogenicity studies, only performed for DecaBDEs, show some effects at very high levels, and IARC (1990) evaluates DecaBDEs not classifiable as to its carcinogenicity to humans. TBBPA: The toxicity of TBBPA in the experimental in vivo studies is suggested to be low. In most reported studies, only doses in g/kg body weight were effective, but at least one study suggested renal effects at around 250 mg/kg body weight. Although difficult to include and interpret in a quantitative risk assessment, the in vitro effects on immunological and thyroid hormones, as well as binding to erythrocytes should be noted. Before a solid standpoint could be reached on TBBPA toxicity additional studies must be performed. This statement is even more valid regarding the TBBPA derivates, where there is an almost complete lack of toxicity data. HBCD: Also in the case of HBCD, relevant toxicity studies are lacking. Based on the present animal studies, a critical effect is seen in the liver and on thyroid hormones (LOAEL 100 mg/kg body weight/day). However, in a recent short paper behavioural effects in mice pups were observed already at 0.9 mg/kg body weight, and behavioural effects may be a sensitive endpoint for HBCD, as well as for other BFRs. PBBS: Due to the Michigan accident in 1973-1974, many toxicity studies on PBBs are available. The critical experimental effects are those on reproduction and carcinogenicity, and a NOAEL of 0.15 mg/kg body weight/day could be suggested based on the cancer effects. In man no unequivocal effects have been observed, although in some studies neurological and musculoskeletal symptoms were suggested. Based on the carcinogenic effects in animals, a human TDI of 0.15 microg/kg body weight has been presented. To conclude, the toxicity data are almost entirely based on experimental models. There are differences among the BFR groups, as well as within these groups, both regarding type of toxic effect and at what dose it appears. As BFRs will continue to appear both in industrial applications and, even if the production has ceased, in our environment, there is a continued need for effects studies on BFRs.

Toxicity of five forest insecticides to cutthroat trout and two species of aquatic invertebrates

USGS Publications Warehouse

Woodward, D.F.; Mauck, W.L.

1980-01-01

The Northern Rocky Mountain region has had scattered infestation of the western spruce budworm Christoneura occidentalis since the early 1900's (U.S. DEPARTMENT OF AGRICULTURE (USDA) 1976b). On the basis of aerial surveys in 1975, TUNNOCK et al. (1976), estimated that budworm defoliation occurred on 2,278,804 acres of six National Forests in Montana. Since the use of DDT was banned in 1972, there has been a need to develop alternative insecticides with the efficacy of DDT but without its environmental risk. These insecticides must be effective in controlling the budworm, but should not persist in the environment or be toxic to other organisms. The organophosphate and carbamate insecticides are relatively nonpersistent and generally present only a moderate hazard to fish when applied according to label recommendations. The USDA Forest Service has been investigating the effectiveness of these two classes of insecticides against the budworm, and the Columbia National Fisheries Research Laboratory of the U.S. Fish and Wildlife Service has been cooperating with the Forest Service conducted pilot control projects in eastern Montana in 1975 and 1976 to determine the efficacy and environmental impact of acephate, carbaryl, and trichlorfon in controlling the western budworm (USDA 1976 b). In 1975, a similar type project was carried out in Maine with aminocarb, fenitrothion, and trichlorfon (USDA 1976 a).Acephate, fenitrothion, and trichlorfon (organophosphate insecticides) and aminocarb and carbaryl (carbamate insecticides) were selected for toxicity tests against cutthroat trout (Salmo clarki), a stonefly (Pteronarcella badia), and a freshwater amphipod (Gammarus pseudolimnaeus) edemic in streams of the northern Rocky Mountains. Populations of cutthroat trout inhabit lakes and streams in the Rocky Mountains which include some of the most pristine habitat and fisheries in North America. Pteronarcella and Gammarus provide forage for cutthroat trout and feed on decaying vegetation in riffle areas in streams and rivers. Stonefly naiads and amphipods were selected as test organisms because of their importance as trout food and their wide distribution in mountain stream communities. We determined the effect of various water types representing different biogeographical areas in the Intermountain West on the toxicity of these five forest insecticides.

Study of the antimicrobial activity of cyclic cation-based ionic liquids via experimental and group contribution QSAR model.

PubMed

Ghanem, Ouahid Ben; Shah, Syed Nasir; Lévêque, Jean-Marc; Mutalib, M I Abdul; El-Harbawi, Mohanad; Khan, Amir Sada; Alnarabiji, Mohamad Sahban; Al-Absi, Hamada R H; Ullah, Zahoor

2018-03-01

Over the past decades, Ionic liquids (ILs) have gained considerable attention from the scientific community in reason of their versatility and performance in many fields. However, they nowadays remain mainly for laboratory scale use. The main barrier hampering their use in a larger scale is their questionable ecological toxicity. This study investigated the effect of hydrophobic and hydrophilic cyclic cation-based ILs against four pathogenic bacteria that infect humans. For that, cations, either of aromatic character (imidazolium or pyridinium) or of non-aromatic nature, (pyrrolidinium or piperidinium), were selected with different alkyl chain lengths and combined with both hydrophilic and hydrophobic anionic moieties. The results clearly demonstrated that introducing of hydrophobic anion namely bis((trifluoromethyl)sulfonyl)amide, [NTF 2 ] and the elongation of the cations substitutions dramatically affect ILs toxicity behaviour. The established toxicity data [50% effective concentration (EC 50 )] along with similar endpoint collected from previous work against Aeromonas hydrophila were combined to developed quantitative structure-activity relationship (QSAR) model for toxicity prediction. The model was developed and validated in the light of Organization for Economic Co-operation and Development (OECD) guidelines strategy, producing good correlation coefficient R 2 of 0.904 and small mean square error (MSE) of 0.095. The reliability of the QSAR model was further determined using k-fold cross validation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Evaluation and comparison of bisphenol A analog activity ...

EPA Pesticide Factsheets

Bisphenol A (BPA) is used in consumer products and industrial applications, primarily in plastics, and has been detected in the environment, human urine, blood, and breast milk. Mainly studied as an endocrine disruptor, other toxicities, including obesity, metabolic conditions such as diabetes, and neurodevelopmental effects have also been associated with exposure to BPA, indicating that its effects may not be limited to estrogenicity. In addition, a number of BPA analogs are in use and may exhibit other additional toxicities. To address these unknowns, we examined the bioactivity of 21 BPA analogs across a selection of ToxCast/Tox21 assays grouped by 7 gene sets including estrogen receptor (ER), androgen receptor (AR), thyroid receptor (TR), peroxisome proliferator-activated receptor (PPAR), pregnane x receptor (PXR), aromatase (AROM), and aryl hydrocarbon receptor (AHR). The most active compounds were bisphenol AF (BPAF) (ER, AR, AROM, AHR), bisphenol A glycidyl methacrylate (TR), 3,3’,5,5’-tetrabromobisphenol A (PPAR) and bisphenol B (BPB) (PXR). We used these data to produce toxicological prioritization index (ToxPi) scores and images to integrate and visually compare the toxicity profiles across all gene sets. The compounds with highest ToxPi scores were BPAF, BPA and BPB. We also mapped the intended gene targets for all ToxCast assays to their associated KEGG BRITE protein families in order to characterize their toxicity profiles on a broader spectr

Fungicide sensitivity of Trichoderma spp. from Agaricus bisporus farms in Serbia.

PubMed

Kosanović, Dejana; Potočnik, Ivana; Vukojević, Jelena; Stajić, Mirjana; Rekanović, Emil; Stepanović, Miloš; Todorović, Biljana

2015-01-01

Trichoderma species, the causal agents of green mould disease, induce great losses in Agaricus bisporus farms. Fungicides are widely used to control mushroom diseases although green mould control is encumbered with difficulties. The aims of this study were, therefore, to research in vitro toxicity of several commercial fungicides to Trichoderma isolates originating from Serbian and Bosnia-Herzegovina farms, and to evaluate the effects of pH and light on their growth. The majority of isolates demonstrated optimal growth at pH 5.0, and the rest at pH 6.0. A few isolates also grew well at pH 7. The weakest mycelial growth was noted at pH 8.0-9.0. Generally, light had an inhibitory effect on the growth of tested isolates. The isolates showed the highest susceptibility to chlorothalonil and carbendazim (ED50 less than 1 mg L(-1)), and were less sensitive to iprodione (ED50 ranged 0.84-6.72 mg L(-1)), weakly resistant to thiophanate-methyl (ED50 = 3.75-24.13 mg L(-1)), and resistant to trifloxystrobin (ED50 = 10.25-178.23 mg L(-1)). Considering the toxicity of fungicides to A. bisporus, carbendazim showed the best selective toxicity (0.02), iprodione and chlorothalonil moderate (0.16), and thiophanate-methyl the lowest (1.24), while trifloxystrobin toxicity to A. bisporus was not tested because of its inefficiency against Trichoderma isolates.

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

Effect of DNA sequence of Fab fragment on yield characteristics and cell growth of E. coli.

PubMed

Kulmala, Antti; Huovinen, Tuomas; Lamminmäki, Urpo

2017-06-19

Codon usage is one of the factors influencing recombinant protein expression. We were interested in the codon usage of an antibody Fab fragment gene exhibiting extreme toxicity in the E. coli host. The toxic synthetic human Fab gene contained domains optimized by the "one amino acid-one codon" method. We redesigned five segments of the Fab gene with a "codon harmonization" method described by Angov et al. and studied the effects of these changes on cell viability, Fab yield and display on filamentous phage using different vectors and bacterial strains. The harmonization considerably reduced toxicity, increased Fab expression from negligible levels to 10 mg/l, and restored the display on phage. Testing the impact of the individual redesigned segments revealed that the most significant effects were conferred by changes in the constant domain of the light chain. For some of the Fab gene variants, we also observed striking differences in protein yields when cloned from a chloramphenicol resistant vector into an identical vector, except with ampicillin resistance. In conclusion, our results show that the expression of a heterodimeric secretory protein can be improved by harmonizing selected DNA segments by synonymous codons and reveal additional complexity involved in heterologous protein expression.

Toxicity of Select Organic Acids to the Slightly Thermophilic Acidophile Acidithiobaccillus Caldus

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

John E Aston; William A Apel; Brady D Lee

2009-02-01

Acidithiobacillus caldus is a thermophilic acidophile found in commercial biomining, acid mine drainage systems, and natural environments. Previous work has characterized A. caldus as a chemolithotrophic autotroph capable of utilizing reduced sulfur compounds under aerobic conditions. Organic acids are especially toxic to chemolithotrophs in low-pH environments, where they diffuse more readily into the cell and deprotonate within the cytoplasm. In the present study, the toxic effects of oxaloacetate, pyruvate, 2-ketoglutarate, acetate, malate, succinate, and fumarate on A. caldus strain BC13 were examined under batch conditions. All tested organic acids exhibited some inhibitory effect. Oxaloacetate was observed to inhibit growth completelymore » at a concentration of 250 µM, whereas other organic acids were completely inhibitory at concentrations of between 1,000 and 5,000 µM. In these experiments, the measured concentrations of organic acids decreased with time, indicating uptake or assimilation by the cells. Phospholipid fatty acid analyses indicated an effect of organic acids on the cellular envelope. Notable differences included an increase in cyclic fatty acids in the presence of organic acids, indicating possible instability of the cellular envelope. This was supported by field emission scanning-electron micrographs showing blebbing and sluffing in cells grown in the presence of organic acids.« less

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

Life-stage-, sex-, and dose-dependent dietary toxicokinetics and relationship to toxicity of 2,4-dichlorophenoxyacetic acid (2,4-D) in rats: implications for toxicity test dose selection, design, and interpretation.

PubMed

Saghir, Shakil A; Marty, Mary S; Zablotny, Carol L; Passage, Julie K; Perala, Adam W; Neal, Barbara H; Hammond, Larry; Bus, James S

2013-12-01

Life-stage-dependent toxicity and dose-dependent toxicokinetics (TK) were evaluated in Sprague Dawley rats following dietary exposure to 2,4-dichlorophenoxyacetic acid (2,4-D). 2,4-D renal clearance is impacted by dose-dependent saturation of the renal organic anion transporter; thus, this study focused on identifying inflection points of onset of dietary nonlinear TK to inform dose selection decisions for toxicity studies. Male and female rats were fed 2,4-D-fortified diets at doses to 1600 ppm for 4-weeks premating, <2 weeks during mating, and to test day (TD) 71 to parental (P1) males and to P1 females through gestation/lactation to TD 96. F1 offspring were exposed via milk with continuing diet exposure until postnatal day (PND) 35. As assessed by plasma area under the curve for the time-course plasma concentration, nonlinear TK was observed ≥ 1200 ppm (63 mg/kg/day) for P1 males and between 200 and 400 ppm (14-27 mg/kg/day) for P1 females. Dam milk and pup plasma levels were higher on lactation day (LD) 14 than LD 4. Relative to P1 adults, 2,4-D levels were higher in dams during late gestation/lactation and postweaning pups (PND 21-35) and coincided with elevated intake of diet/kg body weight. Using conventional maximum tolerated dose (MTD) criteria based on body weight changes for dose selection would have resulted in excessive top doses approximately 2-fold higher than those identified incorporating critical TK data. These data indicate that demonstration of nonlinear TK, if present at dose levels substantially above real-world human exposures, is a key dose selection consideration for improving the human relevance of toxicity studies compared with studies employing conventional MTD dose selection strategies.

Life-Stage-, Sex-, and Dose-Dependent Dietary Toxicokinetics and Relationship to Toxicity of 2,4-Dichlorophenoxyacetic Acid (2,4-D) in Rats: Implications for Toxicity Test Dose Selection, Design, and Interpretation

PubMed Central

Marty, Mary S.

2013-01-01

Life-stage-dependent toxicity and dose-dependent toxicokinetics (TK) were evaluated in Sprague Dawley rats following dietary exposure to 2,4-dichlorophenoxyacetic acid (2,4-D). 2,4-D renal clearance is impacted by dose-dependent saturation of the renal organic anion transporter; thus, this study focused on identifying inflection points of onset of dietary nonlinear TK to inform dose selection decisions for toxicity studies. Male and female rats were fed 2,4-D-fortified diets at doses to 1600 ppm for 4-weeks premating, <2 weeks during mating, and to test day (TD) 71 to parental (P1) males and to P1 females through gestation/lactation to TD 96. F1 offspring were exposed via milk with continuing diet exposure until postnatal day (PND) 35. As assessed by plasma area under the curve for the time-course plasma concentration, nonlinear TK was observed ≥1200 ppm (63mg/kg/day) for P1 males and between 200 and 400 ppm (14–27mg/kg/day) for P1 females. Dam milk and pup plasma levels were higher on lactation day (LD) 14 than LD 4. Relative to P1 adults, 2,4-D levels were higher in dams during late gestation/lactation and postweaning pups (PND 21–35) and coincided with elevated intake of diet/kg body weight. Using conventional maximum tolerated dose (MTD) criteria based on body weight changes for dose selection would have resulted in excessive top doses approximately 2-fold higher than those identified incorporating critical TK data. These data indicate that demonstration of nonlinear TK, if present at dose levels substantially above real-world human exposures, is a key dose selection consideration for improving the human relevance of toxicity studies compared with studies employing conventional MTD dose selection strategies. PMID:24105888

Comparative toxicities of selected rare earth elements: Sea urchin embryogenesis and fertilization damage with redox and cytogenetic effects.

PubMed

Pagano, Giovanni; Guida, Marco; Siciliano, Antonietta; Oral, Rahime; Koçbaş, Fatma; Palumbo, Anna; Castellano, Immacolata; Migliaccio, Oriana; Thomas, Philippe J; Trifuoggi, Marco

2016-05-01

Broad-ranging adverse effects are known for rare earth elements (REE), yet only a few studies tested the toxicity of several REE, prompting studies focusing on multi-parameter REE toxicity. Trichloride salts of Y, La, Ce, Nd, Sm, Eu and Gd were tested in Paracentrotus lividus sea urchin embryos and sperm for: (1) developmental defects in either REE-exposed larvae or in the offspring of REE-exposed sperm; (2) fertilization success; (3) mitotic anomalies in REE-exposed embryos and in the offspring of REE-exposed sperm, and (4) reactive oxygen species (ROS) formation, and malondialdehyde (MDA) and nitric oxide (NO) levels. REEs affected P. lividus larvae with concentration-related increase in developmental defects, 10(-6) to 10(-4)M, ranking as: Gd(III)>Y(III)>La(III)>Nd(III)≅Eu(III)>Ce(III)≅Sm(III). Nominal concentrations of REE salts were confirmed by inductively coupled plasma mass spectrometry (ICP-MS). Significant increases in MDA levels, ROS formation, and NO levels were found in REE-exposed embryos. Sperm exposure to REEs (10(-5) to 10(-4)M) resulted in concentration-related decrease in fertilization success along with increase in offspring damage. Decreased mitotic activity and increased aberration rates were detected in REE-exposed embryos and in the offspring of REE-exposed sperm. REE-associated toxicity affecting embryogenesis, fertilization, cytogenetic and redox endpoints showed different activities of tested REEs. Damage to early life stages, along with redox and cytogenetic anomalies should be the focus of future REE toxicity studies. Copyright © 2016 Elsevier Inc. All rights reserved.

An evaluation of inorganic toxicity reference values for use in assessing hazards to American robins (Turdus migratorius)

USGS Publications Warehouse

Beyer, W. Nelson; Sample, Bradley E.

2017-01-01

When performing screening-level and baseline risk assessments, assessors usually compare estimated exposures of wildlife receptor species with toxicity reference values (TRVs). We modeled the exposure of American robins (Turdus migratorius) to 10 elements (As, Cd, Cr, Cu, Hg, Mn, Pb, Se, Zn, and V) in spring and early summer, a time when earthworms are the preferred prey. We calculated soil benchmarks associated with possible toxic effects to these robins from 6 sets of published TRVs. Several of the resulting soil screening-level benchmarks were inconsistent with each other and less than soil background concentrations. Accordingly, we examined the derivations of the TRVs as a possible source of error. In the case of V, a particularly toxic chemical compound (ammonium vanadate) containing V, not normally present in soil, had been used to estimate a TRV. In the cases of Zn and Cu, use of uncertainty values of 10 in estimating TRVs led to implausibly low soil screening values. In the case of Pb, a TRV was calculated from studies demonstrating reductions in egg production in Japanese quail (Coturnix coturnix japonica) exposed to Pb concentrations well below than those causing toxic effects in other species of birds. The results on quail, which were replicated in additional trials, are probably not applicable to other, unrelated species, although we acknowledge that only a small fraction of all species of birds has been tested. These examples underscore the importance of understanding the derivation and relevance of TRVs before selecting them for use in screening or in ecological risk assessment.

Sediment-contact fish embryo toxicity assay with Danio rerio to assess particle-bound pollutants in the Tietê River Basin (São Paulo, Brazil).

PubMed

Rocha, Paula Suares; Bernecker, Conny; Strecker, Ruben; Mariani, Carolina Fiorillo; Pompêo, Marcelo Luiz Martins; Storch, Volker; Hollert, Henner; Braunbeck, Thomas

2011-10-01

The Tietê River and its tributary Pinheiros River receive a highly complex organic and inorganic pollutants load from sanitary sewage and industrial sources, as well as agricultural and agroindustrial activities. The aim of the present study was to evaluate the embryotoxic and teratogenic effects of sediments from selected locations in the Tietê River Basin by means of the sediment contact embryo toxicity assay with Danio rerio, in order to provide a comprehensive and realistic insight into the bioavailable hazard potential of these sediment samples. Lethal and sub-lethal effects were recorded, and high embryo toxicity could be found in the samples not only in the vicinity of the megacity São Paulo (Billings reservoir and Pinheiros River samples), but also downstream (in the reservoirs Barra Bonita, Promissão and Três Irmãos). Results confirm that most toxicity is due to the discharges of the metropolitan area of São Paulo. However, they also indicate additional sources of pollutants along the river course, probably from industrial, agricultural and agroindustrial residues, which contribute to the degradation of each area. The sediment contact fish embryo test showed to be powerful tool to detect embryo toxicity in sediments, not only by being a sensitive method, but also for taking into account bioavailability. This test provides an ecological highly realistic and relevant exposure scenario, and should therefore be added in ecotoxicological sediment quality assessments. Copyright © 2011 Elsevier Inc. All rights reserved.

Respiratory Toxicity of Lunar Highland Dust

NASA Technical Reports Server (NTRS)

James, John T.; Lam, Chiu-wing; Wallace, William T.

2009-01-01

Lunar dust exposures occurred during the Apollo missions while the crew was on the lunar surface and especially when microgravity conditions were attained during rendezvous in lunar orbit. Crews reported that the dust was irritating to the eyes and in some cases respiratory symptoms were elicited. NASA s vision for lunar exploration includes stays of 6 months on the lunar surface hence the health effects of periodic exposure to lunar dust need to be assessed. NASA has performed this assessment with a series of in vitro and in vivo tests on authentic lunar dust. Our approach is to "calibrate" the intrinsic toxicity of lunar dust by comparison to a nontoxic dust (TiO2) and a highly toxic dust (quartz) using intratrachael instillation of the dusts in mice. A battery of indices of toxicity is assessed at various time points after the instillations. Cultures of selected cells are exposed to test dusts to assess the adverse effects on the cells. Finally, chemical systems are used to assess the nature of the reactivity of various dusts and to determine the persistence of reactivity under various environmental conditions that are relevant to a space habitat. Similar systems are used to assess the dissolution of the dust. From these studies we will be able to set a defensible inhalation exposure standard for aged dust and predict whether we need a separate standard for reactive dust. Presently-available data suggest that aged lunar highland dust is slightly toxic, that it can adversely affect cultured cells, and that the surface reactivity induced by grinding the dust persists for a few hours after activation.

Reactive chromophores for sensitive and selective detection of chemical warfare agents and toxic industrial chemicals

NASA Astrophysics Data System (ADS)

Frye-Mason, Greg; Leuschen, Martin; Wald, Lara; Paul, Kateri; Hancock, Lawrence F.

2005-05-01

A reactive chromophore developed at MIT exhibits sensitive and selective detection of surrogates for G-class nerve agents. This reporter acts by reacting with the agent to form an intermediate that goes through an internal cyclization reaction. The reaction locks the molecule into a form that provides a strong fluorescent signal. Using a fluorescent sensor platform, Nomadics has demonstrated rapid and sensitive detection of reactive simulants such as diethyl chloro-phosphate (simulant for sarin, soman, and related agents) and diethyl cyanophosphate (simulant for tabun). Since the unreacted chromophore does not fluoresce at the excitation wavelength used for the cyclized reporter, the onset of fluo-rescence can be easily detected. This fluorescence-based detection method provides very high sensitivity and could enable rapid detection at permissible exposure levels. Tests with potential interferents show that the reporter is very selective, with responses from only a few highly toxic, electrophilic chemicals such as phosgene, thionyl chloride, and strong acids such as HF, HCl, and nitric acid. Dimethyl methyl phosphonate (DMMP), a common and inactive simu-lant for other CW detectors, is not reactive enough to generate a signal. The unique selectivity to chemical reactivity means that a highly toxic and hazardous chemical is present when the reporter responds and illustrates that this sensor can provide very low false alarm rates. Current efforts focus on demonstrating the sensitivity and range of agents and toxic industrial chemicals detected with this reporter as well as developing additional fluorescent reporters for a range of chemical reactivity classes. The goal is to produce a hand-held sensor that can sensitively detect a broad range of chemical warfare agent and toxic industrial chemical threats.

Avoiding Toxic Levels of Essential Minerals: A Forgotten Factor in Deer Diet Preferences

PubMed Central

Ceacero, Francisco; Landete-Castillejos, Tomás; Olguín, Augusto; Miranda, María; García, Andrés; Martínez, Alberto; Cassinello, Jorge; Miguel, Valentín; Gallego, Laureano

2015-01-01

Ungulates select diets with high energy, protein, and sodium contents. However, it is scarcely known the influence of essential minerals other than Na in diet preferences. Moreover, almost no information is available about the possible influence of toxic levels of essential minerals on avoidance of certain plant species. The aim of this research was to test the relative importance of mineral content of plants in diet selection by red deer (Cervus elaphus) in an annual basis. We determined mineral, protein and ash content in 35 common Mediterranean plant species (the most common ones in the study area). These plant species were previously classified as preferred and non-preferred. We found that deer preferred plants with low contents of Ca, Mg, K, P, S, Cu, Sr and Zn. The model obtained was greatly accurate identifying the preferred plant species (91.3% of correct assignments). After a detailed analysis of these minerals (considering deficiencies and toxicity levels both in preferred and non-preferred plants) we suggest that the avoidance of excessive sulphur in diet (i.e., selection for plants with low sulphur content) seems to override the maximization for other nutrients. Low sulphur content seems to be a forgotten factor with certain relevance for explaining diet selection in deer. Recent studies in livestock support this conclusion, which is highlighted here for the first time in diet selection by a wild large herbivore. Our results suggest that future studies should also take into account the toxicity levels of minerals as potential drivers of preferences. PMID:25615596

Avoiding toxic levels of essential minerals: a forgotten factor in deer diet preferences.

PubMed

Ceacero, Francisco; Landete-Castillejos, Tomás; Olguín, Augusto; Miranda, María; García, Andrés; Martínez, Alberto; Cassinello, Jorge; Miguel, Valentín; Gallego, Laureano

2015-01-01

Ungulates select diets with high energy, protein, and sodium contents. However, it is scarcely known the influence of essential minerals other than Na in diet preferences. Moreover, almost no information is available about the possible influence of toxic levels of essential minerals on avoidance of certain plant species. The aim of this research was to test the relative importance of mineral content of plants in diet selection by red deer (Cervus elaphus) in an annual basis. We determined mineral, protein and ash content in 35 common Mediterranean plant species (the most common ones in the study area). These plant species were previously classified as preferred and non-preferred. We found that deer preferred plants with low contents of Ca, Mg, K, P, S, Cu, Sr and Zn. The model obtained was greatly accurate identifying the preferred plant species (91.3% of correct assignments). After a detailed analysis of these minerals (considering deficiencies and toxicity levels both in preferred and non-preferred plants) we suggest that the avoidance of excessive sulphur in diet (i.e., selection for plants with low sulphur content) seems to override the maximization for other nutrients. Low sulphur content seems to be a forgotten factor with certain relevance for explaining diet selection in deer. Recent studies in livestock support this conclusion, which is highlighted here for the first time in diet selection by a wild large herbivore. Our results suggest that future studies should also take into account the toxicity levels of minerals as potential drivers of preferences.

Trends in base flows and extreme flows in the Beaver Kill Basin, Catskill Mountains, New York, 1915-94

USGS Publications Warehouse

Baldigo, Barry P.

1999-01-01

The increases in peak stormflows in the lower Beaver Kill basin through the period of record may have increased the rates of bed-sediment erosion (degradation) and deposition and accelerated changes in stream-channel morphology, however, these possible effects were not examined. Suggestions for further investigation of the effects of NY 17 and of other factors on hydrology, channel morphology, fish habitat, and fish populations in the Beaver Kill Basin include (1) addition of streamflow gages or a creststage gage network at critical locations, (2) a review of engineering records and other aerial photographs for indications of changes in channel morphology, (3) compilation of temperature data and modeling spatial extent and magnitude of stressful summer temperatures (to selected trout species), and (4) confirming the extent and severity of toxic thermal episodes using in-situ fish toxicity tests.

Postconditioning Effectively Prevents Trimethyltin Induced Neuronal Damage in the Rat Brain.

PubMed

Lalkovicova, Maria; Burda, Jozef; Nemethova, Miroslava; Burda, Rastislav; Danielisova, Viera

Trimethyltin (TMT) is a toxic substance formerly used as a catalyst in the production of organic substances, as well as in industry and agriculture. TMT poisoning has caused death or severe injury in many dozens of people. The toxicity of TMT is mediated by dose dependent selective damage to the limbic system in humans and other animals, specifically the degeneration of CA1 neurons in the hippocampus. The typical symptoms include memory loss and decreased learning ability. Using knowledge gained in previous studies of global ischaemia, we used delayed postconditioning after TMT intoxication (8 mg/kg i.p.), consisting of applying a stressor (BR, bradykinin 150 μg/kg i.p.) 24 or 48 hours after the injection of TMT. We found that BR had preventive effects on neurodegenerative changes as well as learning and memory deficits induced by TMT intoxication.

Research on the influence of ozone dissolved in the fuel-water emulsion on the parameters of the CI engine

NASA Astrophysics Data System (ADS)

Wojs, M. K.; Orliński, P.; Kamela, W.; Kruczyński, P.

2016-09-01

The article presents the results of empirical research on the impact of ozone dissolved in fuel-water emulsion on combustion process and concentration of toxic substances in CI engine. The effect of ozone presence in the emulsion and its influence on main engine characteristics (power, torque, fuel consumption) and selected parameters that characterize combustion process (levels of pressures and temperatures in combustion chamber, period of combustion delay, heat release rate, fuel burnt rate) is shown. The change in concentration of toxic components in exhausts gases when engine is fueled with ozonized emulsion was also identified. The empirical research and their analysis showed significant differences in the combustion process when fuel-water emulsion containing ozone was used. These differences include: increased power and efficiency of the engine that are accompanied by reduction in time of combustion delay and beneficial effects of ozone on HC, PM, CO and NOX emissions.

Fenbendazole as a Potential Anticancer Drug

PubMed Central

DUAN, QIWEN; LIU, YANFENG; ROCKWELL, SARA

2013-01-01

Background/Aims To evaluate the anticancer activity of fenbendazole, a widely used antihelminth with mechanisms of action that overlap with those of the hypoxia-selective nitroheterocyclic cytotoxins/radiosensitizers and the taxanes. Materials and Methods We used EMT6 mouse mammary tumor cells in cell culture and as solid tumors in mice to examine the cytotoxic and antitumor effects of fenbendazole as a single agent and in combination regimens. Results Intensive treatments with fenbendazole were toxic to EMT6 cells in vitro; toxicity increased with incubation time and under conditions of severe hypoxia. Fenbendazole did not alter the dose-response curves for radiation or docetaxel; instead, the agents produced additive cytotoxicities. Febendazole in maximally-intensive regimens did not alter the growth of EMT6 tumors, or increase the antineoplastic effects of radiation. Conclusion These studies provided no evidence that fenbendazole would have value in cancer therapy, but suggested that this general class of compounds merits further investigation. PMID:23393324