A review of environmental impacts of salts from produced waters on aquatic resources

USGS Publications Warehouse

Farag, Aïda M.; Harper, David D.

2014-01-01

Salts are frequently a major constituent of waste waters produced during oil and gas production. These produced waters or brines must be treated and/or disposed and provide a daily challenge for operators and resource managers. Some elements of salts are regulated with water quality criteria established for the protection of aquatic wildlife, e.g. chloride (Cl−), which has an acute standard of 860 mg/L and a chronic standard of 230 mg/L. However, data for establishing such standards has only recently been studied for other components of produced water, such as bicarbonate (HCO3−), which has acute median lethal concentrations (LC50s) ranging from 699 to > 8000 mg/L and effects on chronic toxicity from 430 to 657 mg/L. While Cl− is an ion of considerable importance in multiple geographical regions, knowledge about the effects of hardness (calcium and magnesium) on its toxicity and about mechanisms of toxicity is not well understood. A multiple-approach design that combines studies of both individuals and populations, conducted both in the laboratory and the field, was used to study toxic effects of bicarbonate (as NaHCO3). This approach allowed interpretations about mechanisms related to growth effects at the individual level that could affect populations in the wild. However, additional mechanistic data for HCO3−, related to the interactions of calcium (Ca2 +) precipitation at the microenvironment of the gill would dramatically increase the scientific knowledge base about how NaHCO3 might affect aquatic life. Studies of the effects of mixtures of multiple salts present in produced waters and more chronic effect studies would give a better picture of the overall potential toxicity of these ions. Organic constituents in hydraulic fracturing fluids, flowback waters, etc. are a concern because of their carcinogenic properties and this paper is not meant to minimize the importance of maintaining vigilance with respect to potential organic contamination.

Prediction of lethal/effective concentration/dose in the presence of multiple auxiliary covariates and components of variance

USGS Publications Warehouse

Gutreuter, S.; Boogaard, M.A.

2007-01-01

Predictors of the percentile lethal/effective concentration/dose are commonly used measures of efficacy and toxicity. Typically such quantal-response predictors (e.g., the exposure required to kill 50% of some population) are estimated from simple bioassays wherein organisms are exposed to a gradient of several concentrations of a single agent. The toxicity of an agent may be influenced by auxiliary covariates, however, and more complicated experimental designs may introduce multiple variance components. Prediction methods lag examples of those cases. A conventional two-stage approach consists of multiple bivariate predictions of, say, medial lethal concentration followed by regression of those predictions on the auxiliary covariates. We propose a more effective and parsimonious class of generalized nonlinear mixed-effects models for prediction of lethal/effective dose/concentration from auxiliary covariates. We demonstrate examples using data from a study regarding the effects of pH and additions of variable quantities 2???,5???-dichloro-4???- nitrosalicylanilide (niclosamide) on the toxicity of 3-trifluoromethyl-4- nitrophenol to larval sea lamprey (Petromyzon marinus). The new models yielded unbiased predictions and root-mean-squared errors (RMSEs) of prediction for the exposure required to kill 50 and 99.9% of some population that were 29 to 82% smaller, respectively, than those from the conventional two-stage procedure. The model class is flexible and easily implemented using commonly available software. ?? 2007 SETAC.

Toxicity interactions between manganese (Mn) and lead (Pb) or cadmium (Cd) in a model organism the nematode C. elegans.

PubMed

Lu, Cailing; Svoboda, Kurt R; Lenz, Kade A; Pattison, Claire; Ma, Hongbo

2018-06-01

Manganese (Mn) is considered as an emerging metal contaminant in the environment. However, its potential interactions with companying toxic metals and the associated mixture effects are largely unknown. Here, we investigated the toxicity interactions between Mn and two commonly seen co-occurring toxic metals, Pb and Cd, in a model organism the nematode Caenorhabditis elegans. The acute lethal toxicity of mixtures of Mn+Pb and Mn+Cd were first assessed using a toxic unit model. Multiple toxicity endpoints including reproduction, lifespan, stress response, and neurotoxicity were then examined to evaluate the mixture effects at sublethal concentrations. Stress response was assessed using a daf-16::GFP transgenic strain that expresses GFP under the control of DAF-16 promotor. Neurotoxicity was assessed using a dat-1::GFP transgenic strain that expresses GFP in dopaminergic neurons. The mixture of Mn+Pb induced a more-than-additive (synergistic) lethal toxicity in the worm whereas the mixture of Mn+Cd induced a less-than-additive (antagonistic) toxicity. Mixture effects on sublethal toxicity showed more complex patterns and were dependent on the toxicity endpoints as well as the modes of toxic action of the metals. The mixture of Mn+Pb induced additive effects on both reproduction and lifespan, whereas the mixture of Mn+Cd induced additive effects on lifespan but not reproduction. Both mixtures seemed to induce additive effects on stress response and neurotoxicity, although a quantitative assessment was not possible due to the single concentrations used in mixture tests. Our findings demonstrate the complexity of metal interactions and the associated mixture effects. Assessment of metal mixture toxicity should take into consideration the unique property of individual metals, their potential toxicity mechanisms, and the toxicity endpoints examined.

A COMPARISON OF MULTIPLE TOXICITIES FOLLOWING DEVELOPMENTAL EXPOSURE TO PESTICIDES: NEUROTOXICITY, IMMUNOTOXICITY, AND REPRODUCTIVE TOXICITY.

EPA Science Inventory

The NAS report (Pesticides in the Diets of Infants and Children, 1993) called for significant research effort into the long-term effects of perinatal pesticide exposure on the nervous, immune, and reproductive systems. In response, the US EPA and NIEHS collaborated on a series o...

Multiple stress effects on marine planktonic organisms: Influence of temperature on the toxicity of polycyclic aromatic hydrocarbons to Tetraselmis chuii

NASA Astrophysics Data System (ADS)

Vieira, L. R.; Guilhermino, L.

2012-08-01

In the present context of global warming and increasing long-range transport of oil and goods by sea potentially resulting in oil spills, more knowledge on the toxicological interactions between temperature and oil components on marine organisms is urgently needed. Therefore, the effects of temperature increase on the toxicity of three polycyclic aromatic hydrocarbons (PAH; anthracene, phenanthrene and naphthalene) to the marine planktonic algae Tetraselmis chuii were investigated under laboratory conditions. T. chuii cultures were exposed for 96 h to different concentrations of each of the test substances at both 20 and 25 °C. Effect criterion was the inhibition of culture growth assessed at 24 h intervals. All the PAHs significantly reduced T. chuii growth after 96 h of exposure with 20% inhibition concentrations between 0.052 and 1.124 mg L- 1 at 20 °C, and between 0.048 and 0.831 mg L- 1 at 25 °C. At both temperatures, the ranking, in order of decreasing toxicity based on the 50% inhibition concentration, was phenanthrene > naphthalene > anthracene. The increase of temperature by 5 °C significantly increased the toxicity of all the PAHs tested. These findings highlight the importance of considering temperature variation in the ecological risk assessment of oil and other chemical spills in the marine environment, and the need of more research on the toxic effects of multiple stressors on marine organisms.

A toxicity-based method for evaluating safety of reclaimed water for environmental reuses.

PubMed

Xu, Jianying; Zhao, Chuntao; Wei, Dongbin; Du, Yuguo

2014-10-01

A large quantity of toxic chemical pollutants possibly remains in reclaimed water due to the limited removal efficiency in traditional reclamation processes. It is not enough to guarantee the safety of reclaimed water using conventional water quality criteria. An integrated assessment method based on toxicity test is necessary to vividly depict the safety of reclaimed water for reuse. A toxicity test battery consisting of lethality, genotoxicity and endocrine disrupting effect was designed to screen the multiple biological effects of residual toxic chemicals in reclaimed water. The toxicity results of reclaimed water were converted into the equivalent concentrations of the corresponding positive reference substances (EQC). Simultaneously, the predicted no-effect concentration (PNEC) of each positive reference substance was obtained by analyzing the species sensitivity distribution (SSD) of toxicity data. An index "toxicity score" was proposed and valued as 1, 2, 3, or 4 depending on the ratio of the corresponding EQC to PNEC. For vividly ranking the safety of reclaimed water, an integrated assessment index "toxicity rank" was proposed, which was classified into A, B, C, or D rank with A being the safest. The proposed method was proved to be effective in evaluating reclaimed water samples in case studies. Copyright © 2014. Published by Elsevier B.V.

Petroleum hydrocarbon toxicity to corals: A review.

PubMed

Turner, Nicholas R; Renegar, D Abigail

2017-06-30

The proximity of coral reefs to coastal urban areas and shipping lanes predisposes corals to petroleum pollution from multiple sources. Previous research has evaluated petroleum toxicity to coral using a variety of methodology, including monitoring effects of acute and chronic spills, in situ exposures, and ex situ exposures with both adult and larval stage corals. Variability in toxicant, bioassay conditions, species and other methodological disparities between studies prevents comprehensive conclusions regarding the toxicity of hydrocarbons to corals. Following standardized protocols and quantifying the concentration and composition of toxicant will aid in comparison of results between studies and extrapolation to actual spills. Copyright © 2017 Elsevier Ltd. All rights reserved.

Supplementation of Nigella sativa fixed and essential oil mediates potassium bromate induced oxidative stress and multiple organ toxicity.

PubMed

Sultan, Muhammad Tauseef; Butt, Masood Sadiq; Ahmad, Rabia Shabeer; Pasha, Imran; Ahmad, Atif Nisar; Qayyum, Mir Muhammad Nasir

2012-01-01

The plants and their functional ingredients hold potential to cure various maladies and number of plants hold therapeutic potential. The present research was designed study the health promoting potential of black cumin (Nigella sativa) fixed oil (BCFO) and essential oil (BCEO) against oxidative stress with special reference to multiple organ toxicity. For the purpose, thirty rats (Strain: Sprague Dawley) were procured and divided into three groups (10 rats/group). The groups were fed on their respective diets i.e. D1 (control), D2 (BCFO @ 4.0%) and D3 (BCEO @ 0.30%) for a period of 56 days. Mild oxidative stress was induced with the help of potassium bromate injection @ 45 mg/Kg body weight. Furthermore, the levels of cardiac and liver enzymes were assayed. The results indicated that oxidative stress increased the activities of cardiac and liver enzymes. However, supplementation of BCFO and BCEO was effective in reducing the abnormal values of enzymes. Elevated levels of lactate dehydrogenase (LDH), CPK and CPK-MB were reduced from 456 to 231, 176 to 122 and 45 to 36mg/dL, respectively. Similarly, liver enzymes were also reduced. However, the results revealed that BCEO supplementation @ 0.30% is more effectual in ameliorating the multiple organ toxicity in oxidative stressed animal modelling. In the nutshell, it can be assumed that black cumin essential oil is more effective in reducing the extent of potassium bromate induced multiple organ toxicity (cardiac and liver enzymes imbalance) that will ultimately helpful in reducing the extent of myocardial and liver necrosis.

Cardiotoxicity screening: a review of rapid-throughput in vitro approaches.

PubMed

Li, Xichun; Zhang, Rui; Zhao, Bin; Lossin, Christoph; Cao, Zhengyu

2016-08-01

Cardiac toxicity represents one of the leading causes of drug failure along different stages of drug development. Multiple very successful pharmaceuticals had to be pulled from the market or labeled with strict usage warnings due to adverse cardiac effects. In order to protect clinical trial participants and patients, the International Conference on Harmonization published guidelines to recommend that all new drugs to be tested preclinically for hERG (Kv11.1) channel sensitivity before submitting for regulatory reviews. However, extensive studies have demonstrated that measurement of hERG activity has limitations due to the multiple molecular targets of drug compound through which it may mitigate or abolish a potential arrhythmia, and therefore, a model measuring multiple ion channel effects is likely to be more predictive. Several phenotypic rapid-throughput methods have been developed to predict the potential cardiac toxic compounds in the early stages of drug development using embryonic stem cells- or human induced pluripotent stem cell-derived cardiomyocytes. These rapid-throughput methods include microelectrode array-based field potential assay, impedance-based or Ca(2+) dynamics-based cardiomyocytes contractility assays. This review aims to discuss advantages and limitations of these phenotypic assays for cardiac toxicity assessment.

Soil Sorption and Plant Uptake of 2,4,6-Trinitrotoluene

DTIC Science & Technology

1988-09-01

may be magnified, Toxicity of TNT wastes to duckweed ( Lemna • •r2usiAl) has been demonstrated by Schott and Worthley (1974), and depression of yields... Minor , 134 J. L.,and Helton, D. 0. 1977. "Mammalian Toxicity of Munitions Compounds Phase II: Effects of Multiple Doses, Part I TrinitroSlycerin...Schott, C. b., and Worthley, , 0, 1974, "The Toxicity of TNT and Related Wastes to an Aquatic Flowering Plant: Lemna oarpusilla Torr,," Technical

Integrating copper toxicity and climate change to understand extinction risk to two species of pond-breeding anurans.

PubMed

Weir, Scott M; Scott, David E; Salice, Christopher J; Lance, Stacey L

2016-09-01

Chemical contamination is often suggested as an important contributing factor to amphibian population declines, but direct links are rarely reported. Population modeling provides a quantitative method to integrate toxicity data with demographic data to understand the long-term effects of contaminants on population persistence. In this study we use laboratory-derived embryo and larval toxicity data for two anuran species to investigate the potential for toxicity to contribute to population declines. We use the southern toad (Anaxyrus terrestris) and the southern leopard frog (Lithobates sphenocephalus) as model species to investigate copper (Cu) toxicity. We use matrix models to project populations through time and quantify extinction risk (the probability of quasi-extinction in 35 yr). Life-history parameters for toads and frogs were obtained from previously published literature or unpublished data from a long-term (>35 yr) data set. In addition to Cu toxicity, we investigate the role of climate change on amphibian populations by including the probability of early pond drying that results in catastrophic reproductive failure (CRF, i.e., complete mortality of all larval individuals). Our models indicate that CRF is an important parameter for both species as both were unable to persist when CRF probability was >50% for toads or 40% for frogs. Copper toxicity alone did not result in significant effects on extinction risk unless toxicity was very high (>50% reduction in survival parameters). For toads, Cu toxicity and high probability of CRF both resulted in high extinction risk but no synergistic (or greater than additive) effects between the two stressors occurred. For leopard frogs, in the absence of CRF survival was high even under Cu toxicity, but with CRF Cu toxicity increased extinction risk. Our analyses highlight the importance of considering multiple stressors as well as species differences in response to those stressors. Our models were consistently most sensitive to juvenile and adult survival, further suggesting the importance of terrestrial stages to population persistence. Future models will incorporate multiple wetlands with different combinations of stressors to understand if our results for a single wetland result in a population sink within the landscape. © 2016 by the Ecological Society of America.

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

Principals Of Radiation Toxicology: Important Aspects.

NASA Astrophysics Data System (ADS)

Popov, Dmitri; Maliev, Slava; Jones, Jeffrey

“All things are poison, and nothing is without poison; only the dose permits something not to be poisonous.” Paracelsus Key Words: Radiation Toxins (RT), Radiation Toxicants (RTc), Radiation Poisons (RP), Radiation Exposure (RE), Radiation Toxicology is the science about radiation poisons. [D.Popov et al. 2012,J.Zhou et al. 2007,] Radiation Toxins is a specific proteins with high enzymatic activity produced by living irradiated mammals. [D.Popov et al. 2012,] Radiation Toxicants is a substances that produce radiomimetics effects, adverse biological effects which specific for radiation. [D.Popov et al. 2012,] Radiation Toxic agent is specific proteins that can produce pathological biological effects specific for physical form of radiation.[D.Popov et al. 1990,2012,V. Maliev 2007] Different Toxic Substances isolated from cells or from blood or lymph circulation. [Kudriashov I. et al. 1970, D.Popov et al. 1990,2012,V. Maliev et al. 2007,] Radiation Toxins may affects many organs or specific organ, tissue, specific group of cells. [Kudriashov I. et al. 1970, D.Popov et al. 1990,2012,V. Maliev et al. 2007] For example: Radiation Toxins could induce collective toxic clinical states to include: systemic inflammatory response syndrome (SIRS),toxic multiple organ injury (TMOI), toxic multiple organ dysfunction syndromes (TMODS),and finally, toxic multiple organ failure (TMOF). [T. Azizova et al. 2005, Konchalovsky et al., 2005, D. Popov et al 2012] However, Radiation Toxins could induce specific injury of organs or tissue and induce Acute Radiation Syndromes such as Acute Radiation Cerebrovascular Syndrome, Acute Radiation Cardiovascular Syndrome, Acute Radiation Hematopoietic Syndrome, Acute Radiation GastroIntestinal Syndrome. [ D.Popov et al. 1990, 2012, V. Maliev et al. 2007] Radiation Toxins correlates with Radiation Exposure and the dose-response relationship is a fundamental and essential concept in classic Toxicology and Radiation Toxicology.[ D.Popov et al. 1990, 2012] Moderate and high doses of radiation induces necrosis of radiosensitive cells with the subsequent formation of radiation toxins and their induced acute inflammatory processes. Radiation necrosis is the most substantial and most severe form of radiation induced injury, and when widespread, has grave therapeutic implications. [D. Popov et al. 1990, 2012,Claudio A. et al. 2002, Robertson J. et al. 2002, ] Relatively small doses of Radiation Toxins induce apoptosis and high doses of Radiation Toxins induce necrosis. [Rastogi P. et al. 2009, D. Popov et al. 1990, 2012,] Threshold of Toxic Effects occurs and can be defined. [D. Popov et al. 2012, ] Radiation Toxins affects Somatic cells and Germ Cells. Radiation Toxins can induce teratogenic processes. Specific Toxicity of Radiation Toxins can affects developing fetus. Material and Methods, Results: http://www.intechopen.com/books/current-topics-in-ionizing-radiation-research/radiation-toxins-molecular-mechanisms-of-toxicity-and-radiomimetic-properties- Conclusion: Radiation is a physical agent - induce activation of some secretory proteins with high enzymatic activity. This proteins called as Radiation Toxins can produce specific for radiation biological and toxic effects after administration to radiation naive mammals. [V. Maliev et al. 2007, D. Popov et al. 1990, 2012] Radiation Toxins are teratogenic and oncogenic. Radiation Toxins effects depend on Administered Dose and Radiation effects depend on Exposure Dose and Absorbed Dose. The levels of Radiation Toxins correlates with Radiation Exposure.

Heavy Metals Toxicity and the Environment

PubMed Central

Tchounwou, Paul B; Yedjou, Clement G; Patlolla, Anita K; Sutton, Dwayne J

2013-01-01

Heavy metals are naturally occurring elements that have a high atomic weight and a density at least 5 times greater than that of water. Their multiple industrial, domestic, agricultural, medical and technological applications have led to their wide distribution in the environment; raising concerns over their potential effects on human health and the environment. Their toxicity depends on several factors including the dose, route of exposure, and chemical species, as well as the age, gender, genetics, and nutritional status of exposed individuals. Because of their high degree of toxicity, arsenic, cadmium, chromium, lead, and mercury rank among the priority metals that are of public health significance. These metallic elements are considered systemic toxicants that are known to induce multiple organ damage, even at lower levels of exposure. They are also classified as human carcinogens (known or probable) according to the U.S. Environmental Protection Agency, and the International Agency for Research on Cancer. This review provides an analysis of their environmental occurrence, production and use, potential for human exposure, and molecular mechanisms of toxicity, genotoxicity, and carcinogenicity. PMID:22945569

Administering multiple doses of a non N-(methylsuccinimido) anthranoyllycoctonine (MSAL)-containing tall larkspur (Delphinium occidentale) to cattle.

PubMed

Welch, K D; Stonecipher, C A; Green, B T; Gardner, D R; Cook, D; Pfister, J A

2017-03-15

Larkspurs (Delphinium spp.) are a serious toxic plant problem for cattle in western North America. There are two chemotypes of D. occidentale, a more toxic and a less toxic chemotype. The objective of this study was to evaluate the acute toxicity of the less toxic chemotype when administered in multiple doses to cattle. These results suggest that cattle could consume enough of the less toxic chemotype to be poisoned in a range setting. Published by Elsevier Ltd.

Mammalian Toxicity of Munition Compounds. Phase II. Effects of Multiple Doses. Part III. 2,6-Dinitrotoluene

DTIC Science & Technology

1976-07-01

Histopathology , Statistical Analysis, and Normal Values ..... ...... ........... 131 I Ii A.mmALIAN TOXICITY OF MUNITION COMPOUNDS PHASE II: Effects of...chemistry tests and histopathology , and the normal values are given in Appendix I. The concentrations of Ca 2+, Mg2 +, Na+ and K+ in serum were determined...mice fed 2,6-DNT included focal epicarditis or myocarditis, focal cystitis, chronic murine pneumonia or bronchopneumonia, metritis and focal myositis

Is the Factor-of-2 Rule Broadly Applicable for Evaluating the Prediction Accuracy of Metal-Toxicity Models?

PubMed

Meyer, Joseph S; Traudt, Elizabeth M; Ranville, James F

2018-01-01

In aquatic toxicology, a toxicity-prediction model is generally deemed acceptable if its predicted median lethal concentrations (LC50 values) or median effect concentrations (EC50 values) are within a factor of 2 of their paired, observed LC50 or EC50 values. However, that rule of thumb is based on results from only two studies: multiple LC50 values for the fathead minnow (Pimephales promelas) exposed to Cu in one type of exposure water, and multiple EC50 values for Daphnia magna exposed to Zn in another type of exposure water. We tested whether the factor-of-2 rule of thumb also is supported in a different dataset in which D. magna were exposed separately to Cd, Cu, Ni, or Zn. Overall, the factor-of-2 rule of thumb appeared to be a good guide to evaluating the acceptability of a toxicity model's underprediction or overprediction of observed LC50 or EC50 values in these acute toxicity tests.

A Standardized Nursing Intervention Protocol for HCT Patients

ClinicalTrials.gov

2015-06-03

Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Psychosocial Effects of Cancer and Its Treatment; Therapy-related Toxicity

USE OF GENOTOXIC ACTIVITY PROFILES IN ASSESSMENT OF CARCINOGENESIS AND TRANSMISSIBLE GENETIC EFFECTS

EPA Science Inventory

A methodology has been developed to display and evaluate multiple test quantitative information on genetic toxicants for purposes of assessing carcinogenesis and transmissible genetic effects. ose Information is collected from the open literature: either the lowest effective dose...

Effects of ethanol on methyl mercury toxicity in rats

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

Tamashiro, H.; Arakaki, M.; Akagi, H.

1986-01-01

This study was designed to investigate the effect of different doses of ethanol on the morbidity, mortality, and distribution of mercury in the tissues of groups of rats treated orally once daily with methyl mercury chloride (MMC: 5 mg/kg d) for 10 consecutive days. Ethanol potentiated the toxicity of methyl mercury in terms of neurological manifestations (hindleg crossings and abnormal gait) and mortality. The magnitude of effect depended on the concentration of ethanol administered. The concentration of mercury in the kidney and brain also increased with the dose of ethanol given. These findings indicate that epidemiologic studies designed to evaluatemore » methyl mercury toxicity must take into account the multiple environmental burdens that can affect the population cumulatively and simultaneously.« less

HEALTH EFFECTS INSTITUTE (2005-2010)

EPA Science Inventory

The center is conducting research in a number of priority areas, including: new approaches to understanding exposure to and health effect of multiple pollutants including particulate matter, gases, and air toxics; measuring health outcomes and benefits resulting from air qu...

HEALTH EFFECTS INSTITUTE (2010-2015)

EPA Science Inventory

The center is conducting research in a number of priority areas, including: new approaches to understanding exposure to and health effect of multiple pollutants )including particulate matter, gases, and air toxics; measuring health outcomes and benefits resulting from air qual...

Research Advances on Pathways of Nickel-Induced Apoptosis

PubMed Central

Guo, Hongrui; Chen, Lian; Cui, Hengmin; Peng, Xi; Fang, Jing; Zuo, Zhicai; Deng, Junliang; Wang, Xun; Wu, Bangyuan

2015-01-01

High concentrations of nickel (Ni) are harmful to humans and animals. Ni targets a number of organs and produces multiple toxic effects. Apoptosis is important in Ni-induced toxicity of the kidneys, liver, nerves, and immune system. Apoptotic pathways mediated by reactive oxygen species (ROS), mitochondria, endoplasmic reticulum (ER), Fas, and c-Myc participate in Ni-induced cell apoptosis. However, the exact mechanism of apoptosis caused by Ni is still unclear. Understanding the mechanism of Ni-induced apoptosis may help in designing measures to prevent Ni toxicity. PMID:26703593

Mediating toxic emotions in the workplace--the impact of abusive supervision.

PubMed

Chu, Li-Chuan

2014-11-01

This study explores whether abusive supervision can effectively predict employees' counterproductive work behaviour (CWB) and organisational citizenship behaviour (OCB) and the role of toxic emotions at work as a potential mediator of these relationships in nursing settings. Workplace bullying is widespread in nursing. Despite the growing literature on abusive supervision and employees' counterproductive work behaviour and organisational citizenship behaviour, few studies have examined the relationships between abusive supervision and these work behaviours from the viewpoint of the victimed employee's emotion process. This study adopted a two-stage survey of 212 nurses, all of whom were employed by hospitals in Taiwan. Hypotheses were tested through the use of hierarchical multiple regression. The results showed that abusive supervision was positively associated with toxic emotions. Moreover, toxic emotions could effectively predict nurses' counterproductive work behaviour and organisational citizenship behaviour. Finally, it was found that toxic emotions partially mediated the negative effects of abusive supervision on both work behaviours. Toxic emotions at work are a critical mediating variable between abusive supervision and both counterproductive work behaviour and organisational citizenship behaviour. Hospital administrators can implement policies designed to manage events effectively that can spark toxic emotions in their employees. Work empowerment may be an effective way to reduce counterproductive work behaviour and to enhance organisational citizenship behaviour among nurses when supervisors do not promote a healthy work environment for them. © 2013 John Wiley & Sons Ltd.

Arsenic toxicity in the human nerve cell line SK-N-SH in the presence of chromium and copper

PubMed Central

HU, LIGANG; GREER, JUSTIN B.; SOLO-GABRIELE, HELENA; FIEBER, LYNNE A.; CAI, YONG

2013-01-01

As, Cr, and Cu represent one potential combination of multiple metals/metalloids exposures since these three elements are simultaneously leached from chromated copper arsenate (CCA)-treated wood, a common product used for building construction, at levels that can be potentially harmful. This study investigated the neurotoxicity of As associated with CCA-treated wood when accompanied by Cr and Cu. The toxicity was evaluated on basis of a cytotoxicity model using human neuroblastoma cell line SK-N-SH. The cells were cultured with CCA-treated wood leachates or with solutions containing arsenate [As(V)], divalent copper [Cu(II)], trivalent chromium [Cr(III)] alone or in different combinations of the three elements. The toxicity was evaluated using variations in cell replication compared to controls after 96 hrs exposure. Among the three elements present in wood leachates, As played the primary role in the observed toxic effects, which exerted through multiple pathways, including the generation of oxidative stress. DOM affected the absorption of metals/metalloids into the test cells, which however did not obviously appear to impact toxicity. As toxicity was enhanced by Cu(II) and inhibited by Cr(III) at concentrations below U.S. EPA’s allowable maximum contaminant levels in drinking waters. Thus assessing As toxicity in real environments is not sufficient if based solely on the result from As. PMID:23473430

Evaluation of multiple low doses of copper oxide wire particles compared with levamisole for control of Haemonchus contortus in lambs.

PubMed

Burke, J M; Miller, J E

2006-06-30

High levels of anthelmintic resistance in gastrointestinal nematodes (GIN) of small ruminants have created the need for alternative approaches to parasite control. Copper oxide wire particles (COWP; 2g) have proven effective in decreasing GIN infection in lambs. However, the risk of copper toxicity has limited the usefulness of this approach. Recently, smaller doses (0.5 and 1g) have proven effective in GIN control, reducing the risk of toxicity. The objective of this study was to examine the effectiveness and risk of toxicity using multiple small doses of COWP for GIN control in lambs between weaning and market weight. Dorper crossbred ram lambs were orally administered levamisole (Levasol, 8.0mg/kg; n=8), 0.5g (n=9), or 1g COWP (n=9) at weaning (Day 0; 118+/-2 days of age; late May 2005) and again at 6-week intervals for a total of four treatments. A pooled fecal culture determined that Haemonchus contortus was the predominant gastrointestinal parasite at weaning. Lambs grazed bermudagrass pastures and were supplemented with up to 500g corn/soybean meal and free choice trace mineralized salt. Fecal egg counts (FEC), packed cell volume (PCV), and plasma aspartate aminotransferase (AST) activity were determined every 14 days and lambs weighed every 28 days. GIN infection reached a peak at Day 42 (high FEC, low PCV). COWP effectively reduced FEC on Days 0 and 42 compared with the previous week, but did not reduce FEC on Days 84 and 126 (treatment by time interaction, P<0.005). Plasma AST activity and weight gains were similar among treatment groups throughout the study period. Concentrations of copper in the liver on Day 155 were greater in COWP-treated lambs (P<0.001), but all concentrations were normal. Multiple doses of COWP were as effective as levamisole for control of H. contortus without risk of copper toxicity.

A systematic review on the role of environmental toxicants in stem cells aging.

PubMed

Hodjat, Mahshid; Rezvanfar, Mohammad Amin; Abdollahi, Mohammad

2015-12-01

Stem cells are an important target for environmental toxicants. As they are the main source for replenishing of organs in the body, any changes in their normal function could affect the regenerative potential of organs, leading to the appearance of age-related disease and acceleration of the aging process. Environmental toxicants could exert their adverse effect on stem cell function via multiple cellular and molecular mechanisms, resulting in changes in the stem cell differentiation fate and cell transformation, and reduced self-renewal capacity, as well as induction of stress-induced cellular senescence. The present review focuses on the effect of environmental toxicants on stem cell function associated with the aging process. We categorized environmental toxicants according to their preferred molecular mechanism of action on stem cells, including changes in genomic, epigenomic, and proteomic levels and enhancing oxidative stress. Pesticides, tobacco smoke, radiation and heavy metals are well-studied toxicants that cause stem cell dysfunction via induction of oxidative stress. Transgenerational epigenetic changes are the most important effects of a variety of toxicants on germ cells and embryos that are heritable and could affect health in the next several generations. A better understanding of the underlying mechanisms of toxicant-induced stem cell aging will help us to develop therapeutic intervention strategies against environmental aging. Meanwhile, more efforts are required to find the direct in vivo relationship between adverse effect of environmental toxicants and stem cell aging, leading to organismal aging. Copyright © 2015 Elsevier Ltd. All rights reserved.

Predicting the synergy of multiple stress effects

NASA Astrophysics Data System (ADS)

Liess, Matthias; Foit, Kaarina; Knillmann, Saskia; Schäfer, Ralf B.; Liess, Hans-Dieter

2016-09-01

Toxicants and other, non-chemical environmental stressors contribute to the global biodiversity crisis. Examples include the loss of bees and the reduction of aquatic biodiversity. Although non-compliance with regulations might be contributing, the widespread existence of these impacts suggests that for example the current approach of pesticide risk assessment fails to protect biodiversity when multiple stressors concurrently affect organisms. To quantify such multiple stress effects, we analysed all applicable aquatic studies and found that the presence of environmental stressors increases individual sensitivity to toxicants (pesticides, trace metals) by a factor of up to 100. To predict this dependence, we developed the “Stress Addition Model” (SAM). With the SAM, we assume that each individual has a general stress capacity towards all types of specific stress that should not be exhausted. Experimental stress levels are transferred into general stress levels of the SAM using the stress-related mortality as a common link. These general stress levels of independent stressors are additive, with the sum determining the total stress exerted on a population. With this approach, we provide a tool that quantitatively predicts the highly synergistic direct effects of independent stressor combinations.

Complex Mixture-Associated Hormesis and Toxicity: The Case of Leather Tanning Industry

PubMed Central

Pagano, Giovanni; Castello, Giuseppe; Gallo, Marialuisa; Borriello, Ilaria; Guida, Marco

2008-01-01

A series of studies investigated the toxicities of tannery-derived complex mixtures, i.e. vegetable tannin (VT) from Acacia sp. or phenol-based synthetic tannin (ST), and waste-water from tannin-based vs. chromium-based tanneries. Toxicity was evaluated by multiple bioassays including developmental defects and loss of fertilization rate in sea urchin embryos and sperm (Paracentrotus lividus and Sphaerechinus granularis), and algal growth inhibition (Dunaliella tertiolecta and Selenastrum capricornutum). Both VT and ST water extracts resulted in hormetic effects at concentrations ranging 0.1 to 0.3%, and toxicity at levels ≥1%, both in sea urchin embryo and sperm, and in algal growth bioassays. When comparing tannin-based tannery wastewater (TTW) vs. chromium-based tannery effluent (CTE), a hormesis to toxicity trend was observed for TTW both in terms of developmental and fertilization toxicity in sea urchins, and in algal growth inhibition, with hormetic effects at 0.1 to 0.2% TTW, and toxicity at TTW levels ≥1%. Unlike TTW, CTE showed a monotonic toxicity increase from the lowest tested level (0.1%) and CTE toxicity at higher levels was significantly more severe than TTW-induced toxicity. The results support the view that leather production utilizing tannins might be regarded as a more environmentally friendly procedure than chromium-based tanning process. PMID:19088903

Complex mixture-associated hormesis and toxicity: the case of leather tanning industry.

PubMed

Pagano, Giovanni; Castello, Giuseppe; Gallo, Marialuisa; Borriello, Ilaria; Guida, Marco

2008-01-01

A series of studies investigated the toxicities of tannery-derived complex mixtures, i.e. vegetable tannin (VT) from Acacia sp. or phenol-based synthetic tannin (ST), and waste-water from tannin-based vs. chromium-based tanneries. Toxicity was evaluated by multiple bioassays including developmental defects and loss of fertilization rate in sea urchin embryos and sperm (Paracentrotus lividus and Sphaerechinus granularis), and algal growth inhibition (Dunaliella tertiolecta and Selenastrum capricornutum). Both VT and ST water extracts resulted in hormetic effects at concentrations ranging 0.1 to 0.3%, and toxicity at levels > or =1%, both in sea urchin embryo and sperm, and in algal growth bioassays. When comparing tannin-based tannery wastewater (TTW) vs. chromium-based tannery effluent (CTE), a hormesis to toxicity trend was observed for TTW both in terms of developmental and fertilization toxicity in sea urchins, and in algal growth inhibition, with hormetic effects at 0.1 to 0.2% TTW, and toxicity at TTW levels > or =1%. Unlike TTW, CTE showed a monotonic toxicity increase from the lowest tested level (0.1%) and CTE toxicity at higher levels was significantly more severe than TTW-induced toxicity. The results support the view that leather production utilizing tannins might be regarded as a more environmentally friendly procedure than chromium-based tanning process.

Taking Multiple Exposure Into Account Can Improve Assessment of Chemical Risks.

PubMed

Clerc, Frédéric; Bertrand, Nicolas Jean Hyacinthe; La Rocca, Bénédicte

2017-12-15

During work, operators may be exposed to several chemicals simultaneously. Most exposure assessment approaches only determine exposure levels for each substance individually. However, such individual-substance approaches may not correctly estimate the toxicity of 'cocktails' of chemicals, as the toxicity of a cocktail may differ from the toxicity of substances on their own. This study presents an approach that can better take into account multiple exposure when assessing chemical risks. Almost 30000 work situations, monitored between 2005 and 2014 and recorded in two French databases, were analysed using MiXie software. The algorithms employed in MiXie can identify toxicological classes associated with several substances, based on the additivity of the selected effects of each substance. The results of our retrospective analysis show that MiXie was able to identify almost 20% more potentially hazardous situations than identified using a single-substance approach. It therefore appears essential to review the ways in which multiple exposure is taken into account during risk assessment. © The Author(s) 2017. Published by Oxford University Press on behalf of the British Occupational Hygiene Society.

Toxicity evaluation of methoxy poly(ethylene oxide)-block-poly(ε-caprolactone) polymeric micelles following multiple oral and intraperitoneal administration to rats.

PubMed

Binkhathlan, Ziyad; Qamar, Wajhul; Ali, Raisuddin; Kfoury, Hala; Alghonaim, Mohammed

2017-09-01

Methoxy poly(ethylene oxide)- block -poly(ɛ-caprolactone) (PEO- b -PCL) copolymers are amphiphilic and biodegradable copolymers designed to deliver a variety of drugs and diagnostic agents. The aim of this study was to synthesize PEO- b -PCL block copolymers and assess the toxic effects of drug-free PEO- b -PCL micelles after multiple-dose administrations via oral or intraperitoneal (ip) administration in rats. Assembly of block copolymers was achieved by co-solvent evaporation method. To investigate the toxicity profile of PEO- b -PCL micelles, sixty animals were divided into two major groups: The first group received PEO- b -PCL micelles (100 mg/kg) by oral gavage daily for seven days, while the other group received the same dose of micelles by ip injections daily for seven days. Twenty-four hours following the last dose, half of the animals from each group were sacrificed and blood and organs (lung, liver, kidneys, heart and spleen) were collected. Remaining animals were observed for further 14 days and was sacrificed at the end of the third week, and blood and organs were collected. None of the polymeric micelles administered caused any significant effects on relative organ weight, animal body weight, leucocytes count, % lymphocytes, liver and kidney toxicity markers and organs histology. Although the dose of copolymers used in this study is much higher than those used for drug delivery, it did not cause any significant toxic effects in rats. Histological examination of all the organs confirmed the nontoxic nature of the micelles.

Evaluation of the Possible Sources and Controlling Factors of Toxic Metals/Metalloids in the Florida Everglades and Their Potential Risk of Exposure.

PubMed

Li, Yanbin; Duan, Zhiwei; Liu, Guangliang; Kalla, Peter; Scheidt, Daniel; Cai, Yong

2015-08-18

The Florida Everglades is an environmentally sensitive wetland ecosystem with a number of threatened and endangered fauna species susceptible to the deterioration of water quality. Several potential toxic metal sources exist in the Everglades, including farming, atmospheric deposition, and human activities in urban areas, causing concerns of potential metal exposure risks. However, little is known about the pollution status of toxic metals/metalloids of potential concern, except for Hg. In this study, eight toxic metals/metalloids (Cd, Cr, Pb, Ni, Cu, Zn, As, and Hg) in Everglades soils were investigated in both dry and wet seasons. Pb, Cr, As, Cu, Cd, and Ni were identified to be above Florida SQGs (sediment quality guidelines) at a number of sampling sites, particularly Pb, which had a level of potential risk to organisms similar to that of Hg. In addition, a method was developed for quantitative source identification and controlling factor elucidation of toxic metals/metalloids by introducing an index, enrichment factor (EF), in the conventional multiple regression analysis. EFs represent the effects of anthropogenic sources on metals/metalloids in soils. Multiple regression analysis showed that Cr and Ni were mainly controlled by anthropogenic loading, whereas soil characteristics, in particular natural organic matter (NOM), played a more important role for Hg, As, Cd, and Zn. NOM may control the distribution of these toxic metals/metalloids by affecting their mobility in soils. For Cu and Pb, the effects of EFs and environmental factors are comparable, suggesting combined effects of loading and soil characteristics. This study is the first comprehensive research with a vast amount of sampling sites on the distribution and potential risks of toxic metals/metalloids in the Everglades. The finding suggests that in addition to Hg other metals/metalloids could also potentially be an environmental problem in this wetland ecosystem.

Toxicity of environmentally realistic concentrations of chlorpyrifos and terbuthylazine in indoor microcosms.

PubMed

Pereira, Ana Santos; Cerejeira, Maria José; Daam, Michiel A

2017-09-01

Few studies have been conducted into the evaluation of environmentally realistic pesticide mixtures using model ecosystems. In the present study, the effects of single and combined environmentally realistic concentrations of the herbicide terbuthylazine and the insecticide chlorpyrifos were evaluated using laboratory microcosms. Direct toxic effects of chlorpyrifos were noted on copepod nauplii and cladocerans and the recovery of the latter was likely related with the decrease observed in rotifer abundances. Terbuthylazine potentiated the effect of chlorpyrifos on feeding rates of Daphnia magna, presumably by triggering the transformation of chlorpyrifos to more toxic oxon-analogs. Possible food-web interactions resulting from multiple chemical (and other) stressors likely to be present in edge-of-field water bodies need to be further evaluated. Copyright © 2017 Elsevier Ltd. All rights reserved.

Zebrafish embryotoxicity test for developmental (neuro)toxicity: Demo case of an integrated screening approach system using anti-epileptic drugs.

PubMed

Beker van Woudenberg, Anna; Snel, Cor; Rijkmans, Eke; de Groot, Didima; Bouma, Marga; Hermsen, Sanne; Piersma, Aldert; Menke, Aswin; Wolterbeek, André

2014-11-01

To improve the predictability of the zebrafish embryotoxicity test (ZET) for developmental (neuro)toxicity screening, we used a multiple-endpoints strategy, including morphology, motor activity (MA), histopathology and kinetics. The model compounds used were antiepileptic drugs (AEDs): valproic acid (VPA), carbamazepine (CBZ), ethosuximide (ETH) and levetiracetam (LEV). For VPA, histopathology was the most sensitive parameter, showing effects already at 60μM. For CBZ, morphology and MA were the most sensitive parameters, showing effects at 180μM. For ETH, all endpoints showed similar sensitivity (6.6mM), whereas MA was the most sensitive parameter for LEV (40mM). Inclusion of kinetics did not alter the absolute ranking of the compounds, but the relative potency was changed considerably. Taking all together, this demo-case study showed that inclusion of multiple-endpoints in ZET may increase the sensitivity of the assay, contribute to the elucidation of the mode of toxic action and to a better definition of the applicability domain of ZET. Copyright © 2014 Elsevier Inc. All rights reserved.

The use of high-throughput screening techniques to evaluate mitochondrial toxicity.

PubMed

Wills, Lauren P

2017-11-01

Toxicologists and chemical regulators depend on accurate and effective methods to evaluate and predict the toxicity of thousands of current and future compounds. Robust high-throughput screening (HTS) experiments have the potential to efficiently test large numbers of chemical compounds for effects on biological pathways. HTS assays can be utilized to examine chemical toxicity across multiple mechanisms of action, experimental models, concentrations, and lengths of exposure. Many agricultural, industrial, and pharmaceutical chemicals classified as harmful to human and environmental health exert their effects through the mechanism of mitochondrial toxicity. Mitochondrial toxicants are compounds that cause a decrease in the number of mitochondria within a cell, and/or decrease the ability of mitochondria to perform normal functions including producing adenosine triphosphate (ATP) and maintaining cellular homeostasis. Mitochondrial dysfunction can lead to apoptosis, necrosis, altered metabolism, muscle weakness, neurodegeneration, decreased organ function, and eventually disease or death of the whole organism. The development of HTS techniques to identify mitochondrial toxicants will provide extensive databases with essential connections between mechanistic mitochondrial toxicity and chemical structure. Computational and bioinformatics approaches can be used to evaluate compound databases for specific chemical structures associated with toxicity, with the goal of developing quantitative structure-activity relationship (QSAR) models and mitochondrial toxicophores. Ultimately these predictive models will facilitate the identification of mitochondrial liabilities in consumer products, industrial compounds, pharmaceuticals and environmental hazards. Copyright © 2017 Elsevier B.V. All rights reserved.

Effects of elevated total dissolved solids on bivalves

EPA Science Inventory

A series of experiments were performed to assess the toxicity of different dominant salt recipes of excess total dissolved solids (TDS) to organisms in mesocosms. Multiple endpoints were measured across trophic levels. We report here the effects of four different TDS recipes on b...

Noninvasive monitoring of treatment response in a rabbit cyanide toxicity model reveals differences in brain and muscle metabolism

NASA Astrophysics Data System (ADS)

Kim, Jae G.; Lee, Jangwoen; Mahon, Sari B.; Mukai, David; Patterson, Steven E.; Boss, Gerry R.; Tromberg, Bruce J.; Brenner, Matthew

2012-10-01

Noninvasive near infrared spectroscopy measurements were performed to monitor cyanide (CN) poisoning and recovery in the brain region and in foreleg muscle simultaneously, and the effects of a novel CN antidote, sulfanegen sodium, on tissue hemoglobin oxygenation changes were compared using a sub-lethal rabbit model. The results demonstrated that the brain region is more susceptible to CN poisoning and slower in endogenous CN detoxification following exposure than peripheral muscles. However, sulfanegen sodium rapidly reversed CN toxicity, with brain region effects reversing more quickly than muscle. In vivo monitoring of multiple organs may provide important clinical information regarding the extent of CN toxicity and subsequent recovery, and facilitate antidote drug development.

The effect of pH on the toxicity of fatty acids and fatty acid amides to rainbow trout gill cells.

PubMed

Bertin, Matthew J; Voronca, Delia C; Chapman, Robert W; Moeller, Peter D R

2014-01-01

Harmful algal blooms (HABs) expose aquatic organisms to multiple physical and chemical stressors during an acute time period. Algal toxins themselves may be altered by water chemistry parameters affecting their bioavailability and resultant toxicity. The purpose of this study was to determine the effects of two abiotic parameters (pH, inorganic metal salts) on the toxicity of fatty acid amides and fatty acids, two classes of lipids produced by harmful algae, including the golden alga, Prymnesium parvum, that are toxic to aquatic organisms. Rainbow trout gill cells were used as a model of the fish gill and exposed to single compounds and mixtures of compounds along with variations in pH level and concentration of inorganic metal salts. We employed artificial neural networks (ANNs) and standard ANOVA statistical analysis to examine and predict the effects of these abiotic parameters on the toxicity of fatty acid amides and fatty acids. Our results demonstrate that increasing pH levels increases the toxicity of fatty acid amides and inhibits the toxicity of fatty acids. This phenomenon is reversed at lower pH levels. Exposing gill cells to complex mixtures of chemical factors resulted in dramatic increases in toxicity compared to tests of single compounds for both the fatty acid amides and fatty acids. These findings highlight the potential of physicochemical factors to affect the toxicity of chemicals released during algal blooms and demonstrate drastic differences in the effect of pH on fatty acid amides and fatty acids. Published by Elsevier B.V.

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

Injectable SN-38-loaded Polymeric Depots for Cancer Chemotherapy of Glioblastoma Multiforme.

PubMed

Manaspon, Chawan; Nasongkla, Norased; Chaimongkolnukul, Khuanjit; Nittayacharn, Pinunta; Vejjasilpa, Ketpat; Kengkoom, Kanchana; Boongird, Atthaporn; Hongeng, Suradej

2016-12-01

SN-38, a potent chemotherapeutic drug, has not been used clinically because of its severe side effects and poor solubility. In this work, we aimed to evaluate the effect of dose and multiple injections of SN-38-loaded polymeric depots on antitumor efficacy and toxicity in vivo. Preparation and characterization of SN-38-loaded depots were performed and evaluated in vitro using human glioblastoma cell line, U-87MG. Antitumor efficacy with different depot administrations including dose, position of depot injection and number of injections were evaluated in tumor model in nude mice. Depots encapsulated SN-38 with high encapsulation efficiency (~98.3%). High amount of SN-38 (3.0 ± 0.1 mg) was prolonged and controlled release over time and showed anticancer activity against U-87MG cell line in vitro. For one course administration, depots exhibited better antitumor efficacy and reduced toxicity compared to free SN-38. Elevated doses and multiple injections of SN-38-loaded depots and free SN-38 provided greater tumor growth inhibition and animal survival. All animals received SN-38-loaded depots were well tolerated and survived while most of those received free SN-38 died at day 30. Free SN-38 showed severe toxic effect compared to minimal toxicity from SN-38-loaded depots which was due to lower SN-38 level in systemic circulation. Fluorescence imaging and histopathology confirmed that SN-38 released from depots was detected throughout tumors 35 days post administration. SN-38-loaded depots were proved as a promising new treatment for highly invasive glioblastoma multiforme with low acute toxicity due to controlled release of SN-38.

OVERVIEW OF EXPOSURE TO DIOXIN-LIKE COMPOUNDS AND PCBS ON DEVELOPMENTAL, IMMUNOSUPPRESSIVE, AND HORMONE-RELATED EFFECTS IN MAMMALS, INCLUDING HUMANS

EPA Science Inventory

Exposure to TCDD and related compounds leads to a plethora of effects in multiple species, tissues and stages of development. The response spectrum ranges from simple biochemical alterations to overtly toxic responses, including lethality. Many of the effects of TCDD and relate...

A new approach for modeling patient overall radiosensitivity and predicting multiple toxicity endpoints for breast cancer patients.

PubMed

Mbah, Chamberlain; De Ruyck, Kim; De Schrijver, Silke; De Sutter, Charlotte; Schiettecatte, Kimberly; Monten, Chris; Paelinck, Leen; De Neve, Wilfried; Thierens, Hubert; West, Catharine; Amorim, Gustavo; Thas, Olivier; Veldeman, Liv

2018-05-01

Evaluation of patient characteristics inducing toxicity in breast radiotherapy, using simultaneous modeling of multiple endpoints. In 269 early-stage breast cancer patients treated with whole-breast irradiation (WBI) after breast-conserving surgery, toxicity was scored, based on five dichotomized endpoints. Five logistic regression models were fitted, one for each endpoint and the effect sizes of all variables were estimated using maximum likelihood (MLE). The MLEs are improved with James-Stein estimates (JSEs). The method combines all the MLEs, obtained for the same variable but from different endpoints. Misclassification errors were computed using MLE- and JSE-based prediction models. For associations, p-values from the sum of squares of MLEs were compared with p-values from the Standardized Total Average Toxicity (STAT) Score. With JSEs, 19 highest ranked variables were predictive of the five different endpoints. Important variables increasing radiation-induced toxicity were chemotherapy, age, SATB2 rs2881208 SNP and nodal irradiation. Treatment position (prone position) was most protective and ranked eighth. Overall, the misclassification errors were 45% and 34% for the MLE- and JSE-based models, respectively. p-Values from the sum of squares of MLEs and p-values from STAT score led to very similar conclusions, except for the variables nodal irradiation and treatment position, for which STAT p-values suggested an association with radiosensitivity, whereas p-values from the sum of squares indicated no association. Breast volume was ranked as the most significant variable in both strategies. The James-Stein estimator was used for selecting variables that are predictive for multiple toxicity endpoints. With this estimator, 19 variables were predictive for all toxicities of which four were significantly associated with overall radiosensitivity. JSEs led to almost 25% reduction in the misclassification error rate compared to conventional MLEs. Finally, patient characteristics that are associated with radiosensitivity were identified without explicitly quantifying radiosensitivity.

Key physicochemical properties of nanomaterials in view of their toxicity: an exploratory systematic investigation for the example of carbon-based nanomaterial

NASA Astrophysics Data System (ADS)

Salieri, Beatrice; Pasteris, Andrea; Netkueakul, Woranan; Hischier, Roland

2017-03-01

Currently, a noncomprehensive understanding of the physicochemical properties of carbon-based nanomaterial (CBNs), which may affect toxic effects, is still observable. In this study, an exploratory systematic investigation into the key physicochemical properties of multiwall carbon nanotube (MWCNT), single-wall carbon nanotube (SWCNT), and C60-fullerene on their ecotoxicity has been undertaken. We undertook an extensive survey of the literature pertaining to the ecotoxicity of organism representative of the trophic level of algae, crustaceans, and fish. Based on this, a set of data reporting both the physicochemical properties of carbon-based nanomaterial and the observed toxic effect has been established. The relationship between physicochemical properties and observed toxic effect was investigated based on various statistical approaches. Specifically, analysis of variance by one-way ANOVA was used to assess the effect of categorical properties (use of a dispersant or treatments in the test medium, type of carbon-based nanomaterial, i.e., SWCNT, MWCNT, C60-fullerene, functionalization), while multiple regression analysis was used to assess the effect of quantitative properties (i.e., diameter length of nanotubes, secondary size) on the toxicity values. The here described investigations revealed significant relationships among the physicochemical properties and observed toxic effects. The research was mainly affected by the low availability of data and also by the low variability of the studies collected. Overall, our results demonstrate that the here proposed and applied approach could have a major role in identifying the physicochemical properties of relevance for the toxicity of nanomaterial. However, the future success of the approach would require that the ENMs and the experimental conditions used in the toxicity studies are fully characterized.

Stormwater-related transport of the insecticides bifenthrin, fipronil, imidacloprid, and chlorpyrifos into a tidal wetland, San Francisco Bay, California.

PubMed

Weston, Donald P; Chen, Da; Lydy, Michael J

2015-09-15

Suisun Marsh, in northern San Francisco Bay, is the largest brackish marsh in California, and provides critical habitat for many fish species. Storm runoff enters the marsh through many creeks that drain agricultural uplands and the urban areas of Fairfield and Suisun City. Five creeks were sampled throughout a major storm event in February 2014, and analyzed for representatives of several major insecticide classes. Concentrations were greatest in creeks with urban influence, though sampling was done outside of the primary season for agricultural pesticide use. Urban creek waters reached maximum concentrations of 9.9 ng/l bifenthrin, 27.4 ng/l fipronil, 11.9 ng/l fipronil sulfone, 1462 ng/l imidacloprid, and 4.0 ng/l chlorpyrifos. Water samples were tested for toxicity to Hyalella azteca and Chironomus dilutus, and while few samples caused mortality, 70% of the urban creek samples caused paralysis of either or both species. Toxic unit analysis indicated that bifenthrin was likely responsible for effects to H. azteca, and fipronil and its sulfone degradate were responsible for effects to C. dilutus. These results demonstrate the potential for co-occurrence of multiple insecticides in urban runoff, each with the potential for toxicity to particular species, and the value of toxicity monitoring using multiple species. In the channels of Suisun Marsh farther downstream, insecticide concentrations and toxicity diminished as creek waters mixed with brackish waters entering from San Francisco Bay. Only fipronil and its degradates remained measurable at 1-10 ng/l. These concentrations are not known to present a risk based on existing data, but toxicity data for estuarine and marine invertebrates, particularly for fipronil's degradates, are extremely limited. Copyright © 2015 Elsevier B.V. All rights reserved.

Outcomes of stereotactic body radiotherapy (SBRT) treatment of multiple synchronous and recurrent lung nodules.

PubMed

Owen, Dawn; Olivier, Kenneth R; Mayo, Charles S; Miller, Robert C; Nelson, Kathryn; Bauer, Heather; Brown, Paul D; Park, Sean S; Ma, Daniel J; Garces, Yolanda I

2015-02-18

Stereotactic body radiotherapy (SBRT) is evolving into a standard of care for unresectable lung nodules. Local control has been shown to be in excess of 90% at 3 years. However, some patients present with synchronous lung nodules in the ipsilateral or contralateral lobe or metasynchronous disease. In these cases, patients may receive multiple courses of lung SBRT or a single course for synchronous nodules. The toxicity of such treatment is currently unknown. Between 2006 and 2012, 63 subjects with 128 metasynchronous and synchronous lung nodules were treated at the Mayo Clinic with SBRT. Demographic patient data and dosimetric data regarding SBRT treatments were collected. Acute toxicity (defined as toxicity < 90 days) and late toxicity (defined as toxicity > = 90 days) were reported and graded as per standardized CTCAE 4.0 criteria. Local control, progression free survival and overall survival were also described. The median age of patients treated was 73 years. Sixty five percent were primary or recurrent lung cancers with the remainder metastatic lung nodules of varying histologies. Of 63 patients, 18 had prior high dose external beam radiation to the mediastinum or chest. Dose and fractionation varied but the most common prescriptions were 48 Gy/4 fractions, 54 Gy/3 fractions, and 50 Gy/5 fractions. Only 6 patients demonstrated local recurrence. With a median follow up of 12.6 months, median SBRT specific overall survival and progression free survival were 35.7 months and 10.7 months respectively. Fifty one percent (32/63 patients) experienced acute toxicity, predominantly grade 1 and 2 fatigue. One patient developed acute grade 3 radiation pneumonitis at 75 days. Forty six percent (29/63 patients) developed late effects. Most were grade 1 dyspnea. There was one patient with grade 5 pneumonitis. Multiple courses of SBRT and SBRT delivery after external beam radiotherapy appear to be feasible and safe. Most toxicity was grade 1 and 2 but the risk was approximately 50% for both acute and late effects.

Treatment of local-anesthetic toxicity with lipid emulsion therapy.

PubMed

Burch, Melissa S; McAllister, Russell K; Meyer, Tricia A

2011-01-15

The use of lipid emulsion to treat local-anesthetic toxicity is discussed. Systemic toxicity from local anesthetics is a rare but potentially fatal complication of regional anesthesia. There is increasing evidence that lipid emulsion may be an effective treatment to reverse the cardiac and neurologic effects of local-anesthetic toxicity. A literature search identified seven case reports of local-anesthetic toxicity in which lipid emulsion was used. Lipid emulsion was found to be successful in the treatment of local-anesthetic toxicity associated with various regional anesthetic techniques and multiple local anesthetics. The majority of patients in the case reports reviewed were unresponsive to initial management of local-anesthetic toxicity with standard resuscitative measures, but all recovered completely after receiving lipid emulsion therapy. The initial dose of lipid emulsion administered varied among the case reports, as well as whether a lipid emulsion infusion was started and at what point during resuscitation. Based on the case reports reviewed, an initial bolus dose of 1.5 mL/kg followed by an infusion of 10 mL/min as soon as local-anesthetic toxicity is suspected seems most beneficial. The pharmacokinetics of lipid emulsion therapy in the treatment of local-anesthetic toxicity has not been fully elucidated but likely involves increasing metabolism, distribution, or partitioning of the local anesthetic away from receptors into lipid within tissues. Lipid emulsion has been reported useful in the treatment of systemic toxicity caused by local anesthetics. The mechanism of effect is unclear, and evidence for the benefit of lipid therapy in humans is from case reports only.

Piperidine alkaloids: Human and food animal teratogens

USDA-ARS?s Scientific Manuscript database

Piperidine alkaloids are acutely toxic to adult livestock species and produce musculoskeletal deformities in neonatal animals. These teratogenic effects include multiple congenital contracture (MCC) deformities and cleft palate in cattle, pigs, sheep, and goats. Poisonous plants containing teratogen...

Determining the effects of ammonia on fathead minnow (Pimephales promelas) reproduction

EPA Science Inventory

Aquatic organisms are exposed to a multitude of contaminants and to fully understand the impact of multiple stressors on fish populations, we should first understand the mechanism of action for each toxicant and how the combined effects manifest at the level of the individual. Am...

Acute and Subchronic Toxicity of Inhaled Toluene in Male Long-Evans Rats: Oxidative Stress Markers in Brain

EPA Science Inventory

The effects of exposure to volatile organic compounds (VOCs), which are of concern to the EPA, are poorly understood, in part because of insufficient characterization of how human exposure duration impacts VOC effects. Two inhalation studies with multiple endpoints, one acute an...

Amifostine reduces gastro-intestinal toxicity after autologous transplantation for multiple myeloma.

PubMed

Malek, Ehsan; Gupta, Vinita; Creger, Richard; Caimi, Paolo; Vatsayan, Anant; Covut, Fahrettin; Bashir, Qaiser; Champlin, Richard; Delgado, Ruby; Rondon, Gabriela; Cooper, Brenda; de Lima, Marcos; Lazarus, Hillard M; Qazilbash, Muzaffar

2018-01-02

High-dose melphalan (HDM) followed by autologous hematopoietic cell transplantation (auto-HCT) remains the standard-of-care therapy for multiple myeloma (MM) even with the availability of proteasome inhibitors and immunomodulatory drugs. Gastrointestinal (GI) toxicity is the main cause of morbidity after HDM. Amifostine, a cytoprotective agent, may reduce HDM-associated GI toxicity. We conducted a case control study comparing HDM + auto-HCT with or without amifostine for MM patients. One hundred and seven patients treated at University Hospitals Cleveland Medical Center who received pre-transplant amifostine were compared to 114 patients treated at MD Anderson Cancer Center without use of this agent. Amifostine 740 mg/m 2 was administered as a bolus infusion at 24 h and 15 min before HDM. Patients' characteristics were similar in both the groups. Amifostine therapy was well tolerated without any significant adverse effects. Grade II or greater oral mucositis (27.1% vs 47.4%; p = .002), nausea (31.8% vs. 86.0%; p = .0001), vomiting (18.7% vs. 52.6%; p = .0001) and diarrhea (56.1% vs. 72.7%; p = .006) occurred less frequently in the amifostine-treated group. There was no discernable effect of amifostine on engraftment, progression-free or overall survival. Our results indicate that amifostine decreases GI toxicity while preserving anti-myeloma efficacy of HDM and auto-HCT.

Acute and additive toxicity of ten photosystem-II herbicides to seagrass

NASA Astrophysics Data System (ADS)

Wilkinson, Adam D.; Collier, Catherine J.; Flores, Florita; Negri, Andrew P.

2015-11-01

Photosystem II herbicides are transported to inshore marine waters, including those of the Great Barrier Reef, and are usually detected in complex mixtures. These herbicides inhibit photosynthesis, which can deplete energy reserves and reduce growth in seagrass, but the toxicity of some of these herbicides to seagrass is unknown and combined effects of multiple herbicides on seagrass has not been tested. Here we assessed the acute phytotoxicity of 10 PSII herbicides to the seagrass Halophila ovalis over 24 and/or 48 h. Individual herbicides exhibited a broad range of toxicities with inhibition of photosynthetic activity (ΔF/Fm‧) by 50% at concentrations ranging from 3.5 μg l-1 (ametryn) to 132 μg l-1 (fluometuron). We assessed potential additivity using the Concentration Addition model of joint action for binary mixtures of diuron and atrazine as well as complex mixtures of all 10 herbicides. The effects of both mixture types were largely additive, validating the application of additive effects models for calculating the risk posed by multiple PSII herbicides to seagrasses. This study extends seagrass ecotoxicological data to ametryn, metribuzin, bromacil, prometryn and fluometuron and demonstrates that low concentrations of PSII herbicide mixtures have the potential to impact ecologically relevant endpoints in seagrass, including ΔF/Fm‧.

Acute and additive toxicity of ten photosystem-II herbicides to seagrass

PubMed Central

Wilkinson, Adam D.; Collier, Catherine J.; Flores, Florita; Negri, Andrew P.

2015-01-01

Photosystem II herbicides are transported to inshore marine waters, including those of the Great Barrier Reef, and are usually detected in complex mixtures. These herbicides inhibit photosynthesis, which can deplete energy reserves and reduce growth in seagrass, but the toxicity of some of these herbicides to seagrass is unknown and combined effects of multiple herbicides on seagrass has not been tested. Here we assessed the acute phytotoxicity of 10 PSII herbicides to the seagrass Halophila ovalis over 24 and/or 48 h. Individual herbicides exhibited a broad range of toxicities with inhibition of photosynthetic activity (∆F/Fm′) by 50% at concentrations ranging from 3.5 μg l−1 (ametryn) to 132 μg l−1 (fluometuron). We assessed potential additivity using the Concentration Addition model of joint action for binary mixtures of diuron and atrazine as well as complex mixtures of all 10 herbicides. The effects of both mixture types were largely additive, validating the application of additive effects models for calculating the risk posed by multiple PSII herbicides to seagrasses. This study extends seagrass ecotoxicological data to ametryn, metribuzin, bromacil, prometryn and fluometuron and demonstrates that low concentrations of PSII herbicide mixtures have the potential to impact ecologically relevant endpoints in seagrass, including ∆F/Fm′. PMID:26616444

Acute and additive toxicity of ten photosystem-II herbicides to seagrass.

PubMed

Wilkinson, Adam D; Collier, Catherine J; Flores, Florita; Negri, Andrew P

2015-11-30

Photosystem II herbicides are transported to inshore marine waters, including those of the Great Barrier Reef, and are usually detected in complex mixtures. These herbicides inhibit photosynthesis, which can deplete energy reserves and reduce growth in seagrass, but the toxicity of some of these herbicides to seagrass is unknown and combined effects of multiple herbicides on seagrass has not been tested. Here we assessed the acute phytotoxicity of 10 PSII herbicides to the seagrass Halophila ovalis over 24 and/or 48 h. Individual herbicides exhibited a broad range of toxicities with inhibition of photosynthetic activity (∆F/F(m)') by 50% at concentrations ranging from 3.5 μg l(-1) (ametryn) to 132 μg l(-1) (fluometuron). We assessed potential additivity using the Concentration Addition model of joint action for binary mixtures of diuron and atrazine as well as complex mixtures of all 10 herbicides. The effects of both mixture types were largely additive, validating the application of additive effects models for calculating the risk posed by multiple PSII herbicides to seagrasses. This study extends seagrass ecotoxicological data to ametryn, metribuzin, bromacil, prometryn and fluometuron and demonstrates that low concentrations of PSII herbicide mixtures have the potential to impact ecologically relevant endpoints in seagrass, including ∆F/F(m)'.

The toxicity of cationic surfactant HDTMA-Br, desorbed from surfactant modified zeolite, towards faecal indicator and environmental microorganisms.

PubMed

Reeve, Peter J; Fallowfield, Howard J

2017-10-05

Surfactant Modified Zeolite (SMZ) represents a versatile, cost-effective permeable reactive material, capable of treating multiple classes of contaminants. The potential for HDTMA-Br, a cationic surfactant commonly used to modify zeolite, to desorb from the zeolite surface has been identified as a potential issue for the ongoing use of SMZ in water remediation contexts. This paper investigates the toxicity of HDTMA-Br towards enteric virus surrogates, F-RNA bacteriophage MS2 and E. coli, Bacillus subtilis, and soil microflora. The concentration of surfactant desorbing from SMZ was quantified through a bioassay using E. coli. Results showed HDTMA-Br concentrations of ≥10 -5 M were toxic to MS2, ≥10 -4 M were toxic to E. coli and ≥10 -6 M were toxic to B. subtilis. No toxic relationship was established between HDTMA-Br and soil microflora. Desorption of ≥10 -4 M of HDTMA-Br was shown for the two SMZ samples under the mixing conditions used. Effects of this surfactant on total soil microflora were ambiguous since no toxic relationship could be established, however, HDTMA-Br, at concentrations desorbing from SMZ, were shown to impact the soil bacterium B. subtilis. Further research is required to determine the effect of this surfactant on microbial populations and species diversity in soils. Copyright © 2017 Elsevier B.V. All rights reserved.

The Role of Mediators in the Indirect Effects of Religiosity on Therapeutic Compliance in African Migrant HIV-Positive Patients.

PubMed

Mambet Doue, Constance; Roussiau, Nicolas

2016-12-01

This research investigates the indirect effects of religiosity (practice and belief) on therapeutic compliance in 81 HIV-positive patients who are migrants from sub-Saharan Africa (23 men and 58 women). Using analyses of mediation and standard multiple regression, including a resampling procedure by bootstrapping, the role of these mediators (magical-religious beliefs and nonuse of toxic substances) was tested. The results show that, through magical-religious beliefs, religiosity has a negative indirect effect, while with the nonuse of toxic substances, religious practice has a positive indirect effect. Beyond religiosity, the role of mediators is highlighted in the interaction with therapeutic compliance.

[Perfluoroalkyl substances: emerging environmental contaminants involving potential health risk].

PubMed

Li, Jingguang

2015-06-01

Perfluoroalkyl substances (PFASs) have been distributed in environment and human body worldwide. Due to their bioaccumulative and multiple organ toxic, these compounds have raised more and more attention in recent years. The precursors of PFASs can be metabolized to PFASs both in environment and human body, which makes an important contribution to human body burdens. Apart from transformation into PFASs, some of these precursors themselves or their metabolic intermediates also have toxicity effects, such as estrogen-like properties, protein binding, cytotoxicity and so on, and there might be a potential harmful impact on human health. In this paper, the toxicity and biotransformation of PFASs and their precursors were introduced briefly.

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.

GENETIC ACTIVITY PROFILES AND HAZARD ASSESSMENT

EPA Science Inventory

A methodology has been developed to display and evaluate multiple test quantitative information on genetic toxicants for purposes of hazard/risk assessment. ose information is collected from the open literature: either the lowest effective dose (LED) or the highest ineffective do...

A combined evaluation of the characteristics and acute toxicity of antibiotic wastewater.

PubMed

Yu, Xin; Zuo, Jiane; Li, Ruixia; Gan, Lili; Li, Zaixing; Zhang, Fei

2014-08-01

The conventional parameters and acute toxicities of antibiotic wastewater collected from each treatment unit of an antibiotic wastewater treatment plant have been investigated. The investigation of the conventional parameters indicated that the antibiotic wastewater treatment plant performed well under the significant fluctuation in influent water quality. The results of acute toxicity indicated that the toxicity of antibiotic wastewater could be reduced by 94.3 percent on average after treatment. However, treated antibiotic effluents were still toxic to Vibrio fischeri. The toxicity of antibiotic production wastewater could be attributed to the joint effects of toxic compound mixtures in wastewater. Moreover, aerobic biological treatment processes, including sequencing batch reactor (SBR) and aerobic biofilm reactor, played the most important role in reducing toxicity by 92.4 percent. Pearson׳s correlation coefficients revealed that toxicity had a strong and positive linear correlation with organic substances, nitrogenous compounds, S(2-), volatile phenol, cyanide, As, Zn, Cd, Ni and Fe. Ammonia nitrogen (NH4(+)) was the greatest contributor to toxicity according to the stepwise regression method. The multiple regression model was a good fit for [TU50-15 min] as a function of [NH₄(+)] with the determination coefficient of 0.981. Copyright © 2014 Elsevier Inc. All rights reserved.

A cell impedance measurement device for the cytotoxicity assay dependent on the velocity of supplied toxic fluid

NASA Astrophysics Data System (ADS)

Kang, Yoon-Tae; Kim, Min-Ji; Cho, Young-Ho

2018-04-01

We present a cell impedance measurement chip capable of characterizing the toxic response of cells depending on the velocity of the supplied toxic fluid. Previous impedance-based devices using a single open-top chamber have been limited to maintaining a constant supply velocity, and devices with a single closed-top chamber present difficulties in simultaneous cytotoxicity assay for varying levels of supply velocities. The present device, capable of generating constant and multiple levels of toxic fluid velocity simultaneously within a single stepwise microchannel, performs a cytotoxicity assay dependent on toxic fluid velocity, in order to find the effective velocity of toxic fluid to cells for maximizing the cytotoxic effect. We analyze the cellular toxic response of 5% ethanol media supplied to cancer cells within a toxic fluid velocity range of 0-8.3 mm s-1. We observe the velocity-dependent cell detachment rate, impedance, and death rate. We find that the cell detachment rate decreased suddenly to 2.4% at a velocity of 4.4 mm s-1, and that the change rates of cell resistance and cell capacitance showed steep decreases to 8% and 41%, respectively, at a velocity of 5.7 mm s-1. The cell death rate and impedance fell steeply to 32% at a velocity of 5.7 mm s-1. We conclude that: (1) the present device is useful in deciding on the toxic fluid velocity effective to cytotoxicity assay, since the cellular toxic response is dependent on the velocity of toxic fluid, and; (2) the cell impedance analysis facilitates a finer cellular response analysis, showing better correlation with the cell death rate, compared to conventional visual observation. The present device, capable of performing the combinational analysis of toxic fluid velocity and cell impedance, has potential for application to the fine cellular toxicity assay of drugs with proper toxic fluid velocity.

DOPA Decarboxylase Modulates Tau Toxicity.

PubMed

Kow, Rebecca L; Sikkema, Carl; Wheeler, Jeanna M; Wilkinson, Charles W; Kraemer, Brian C

2018-03-01

The microtubule-associated protein tau accumulates into toxic aggregates in multiple neurodegenerative diseases. We found previously that loss of D 2 -family dopamine receptors ameliorated tauopathy in multiple models including a Caenorhabditis elegans model of tauopathy. To better understand how loss of D 2 -family dopamine receptors can ameliorate tau toxicity, we screened a collection of C. elegans mutations in dopamine-related genes (n = 45) for changes in tau transgene-induced behavioral defects. These included many genes responsible for dopamine synthesis, metabolism, and signaling downstream of the D 2 receptors. We identified one dopamine synthesis gene, DOPA decarboxylase (DDC), as a suppressor of tau toxicity in tau transgenic worms. Loss of the C. elegans DDC gene, bas-1, ameliorated the behavioral deficits of tau transgenic worms, reduced phosphorylated and detergent-insoluble tau accumulation, and reduced tau-mediated neuron loss. Loss of function in other genes in the dopamine and serotonin synthesis pathways did not alter tau-induced toxicity; however, their function is required for the suppression of tau toxicity by bas-1. Additional loss of D 2 -family dopamine receptors did not synergize with bas-1 suppression of tauopathy phenotypes. Loss of the DDC bas-1 reduced tau-induced toxicity in a C. elegans model of tauopathy, while loss of no other dopamine or serotonin synthesis genes tested had this effect. Because loss of activity upstream of DDC could reduce suppression of tau by DDC, this suggests the possibility that loss of DDC suppresses tau via the combined accumulation of dopamine precursor levodopa and serotonin precursor 5-hydroxytryptophan. Published by Elsevier Inc.

Multiple emulsions as effective platforms for controlled anti-cancer drug delivery.

PubMed

Dluska, Ewa; Markowska-Radomska, Agnieszka; Metera, Agata; Tudek, Barbara; Kosicki, Konrad

2017-09-01

Developing pH-responsive multiple emulsion platforms for effective glioblastoma multiforme therapy with reduced toxicity, a drug release study and modeling. Cancer cell line: U87 MG, multiple emulsions with pH-responsive biopolymer and encapsulated doxorubicin (DOX); preparation of multiple emulsions in a Couette-Taylor flow biocontactor, in vitro release study of DOX (fluorescence intensity analysis), in vitro cytotoxicity study (alamarBlue cell viability assay) and numerical simulation of DOX release rates. The multiple emulsions offered a high DOX encapsulation efficiency (97.4 ± 1%) and pH modulated release rates of a drug. Multiple emulsions with a low concentration of DOX (0.02 μM) exhibited broadly advanced cell (U87 MG) cytotoxicity than free DOX solution used at the same concentration. Emulsion platforms could be explored for potential delivery of chemotherapeutics in glioblastoma multiforme therapy.

Ion toxicity and the development of a salinity toxicity relationship (STR) model for marine species

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

Tietge, J.E.; Mount, D.R.

1994-12-31

Salinity in effluents can cause acute toxicity to marine organisms. The toxicity of the water can be due to an excess or deficiency of common ions, which usually are not thought of as toxicants. In order to develop an understanding of this phenomenon, laboratory toxicity tests were conducted to determine the effects of single ion deficiency, single ion excess, multiple ion deficiency, multiple ion excess, and total salinity on survival of three common marine test organisms (Mysidopsis bahia, Cyprinidon variegatus, and Menidia beryllina). The ions which were manipulated in these studies were Na{sup +}, K{sup +}, Ca{sup ++}, Mg{sup ++},more » Sr{sup ++}, Cl{sup {minus}}, Br{sup {minus}}, SO{sub 4}{sup {minus}{minus}}, HCO{sub 3}{sup {minus}}, and B{sub 4}O{sub 7}{sup {minus}{minus}}. Results indicate that Ca{sup ++} and K{sup +} are essential ions at normal salinities, since the deficiency of these two ions causes mortality. In contrast, the complete deficiency of Mg{sup ++}, Sr{sup ++}, B{sub 4}O{sub 7}{sup {minus}{minus}}, and HCO{sub 3}{sup {minus}} did not affect survival. The single ion excess studies demonstrated that K{sup +}, Ca{sup ++}, Mg{sup ++}, and B{sub 4}O{sub 7}{sup {minus}} were acutely toxic in excess at normal salinities. Total salinity studies determined the salinity tolerance range for each species, with upper and lower LC{sub 50}s for Mysidopsis bahia at 44 g/L and 8 g/L, for Cyprinidon variegatus at 73 g/L and < 0 g/L, and for Menidia beryllina at 45 g/L and < 0 g/L. These data will be used to develop a model to predict toxicity due to common ions.« less

Management of multiple myeloma in older adults: Gaining ground with geriatric assessment.

PubMed

Wildes, Tanya M; Campagnaro, Erica

2017-01-01

Multiple myeloma increases in incidence with age. With the aging of the population, the number of cases of multiple myeloma diagnosed in older adults each year will nearly double in the next 20years. The novel therapeutic agents have significantly improved survival in older adults, but their outcomes remain poorer than in younger patients. Older adults may be more vulnerable to toxicity of therapy, resulting in decreased dose intensity and contributing to poorer outcomes. Data are beginning to emerge to aid in identifying which individuals are at greater risk for toxicity of therapy; comorbidities, functional limitations, and age over 80years are among the factors associated with greater risk. Geriatric assessment holds promise in the care of older adults with multiple myeloma, both to allow modification of treatment to prevent toxicity, and to identify vulnerabilities that may require intervention. Emerging treatments with low toxicity and attention to individualizing therapy based on geriatric assessment may aid in further improving outcomes in older adults with multiple myeloma. Copyright © 2016 Elsevier Inc. All rights reserved.

Causes of toxicity to Hyalella azteca in a stormwater management facility receiving highway runoff and snowmelt. Part I: polycyclic aromatic hydrocarbons and metals.

PubMed

Bartlett, A J; Rochfort, Q; Brown, L R; Marsalek, J

2012-01-01

The Terraview-Willowfield Stormwater Management Facility (TWSMF) receives inputs of multiple contaminants, including metals, polycyclic aromatic hydrocarbons (PAHs), road salt, and nutrients, via highway and residential runoff. Contaminant concentrations in runoff are seasonally dependent, and are typically high in early spring, coinciding with the snowmelt. In order to investigate the seasonal fluctuations of contaminant loading and related changes in toxicity to benthic invertebrates, overlying water and sediment samples were collected in the fall and spring, reflecting low and high contaminant loading, respectively, and four-week sediment toxicity tests were conducted with Hyalella azteca. The effects of metals and PAHs are discussed here; the effects of salts, nutrients, and water quality are discussed in a companion paper. Survival and growth of Hyalella after exposure to fall samples were variable: survival was significantly reduced (64-74% of controls) at three out of four sites, but there were no significant growth effects. More dramatic effects were observed after Hyalella were exposed to spring samples: survival was significantly reduced at the two sites furthest downstream (0-75% of controls), and growth was significantly lower in four out of five sites when comparing Hyalella exposed to site sediment with overlying site water versus site sediment with overlying control water. These seasonal changes in toxicity were not related to metals or PAHs: 1. levels of bioavailable metals were below those expected to cause toxicity, and 2. levels of PAHs in sediment were lowest at sites with the greatest toxicity and highest in water and sediment at sites with no toxicity. Although not associated with toxicity, some metals and PAHs exceeded probable and severe effect levels, and could be a cause for concern if contaminant bioavailability changes. Toxicity in the TWSMF appeared to be primarily associated with water-borne contaminants. The cause(s) of these effects are discussed in our companion manuscript. Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.

Challenges for the development of a biotic ligand model predicting copper toxicity in estuaries and seas.

PubMed

de Polo, Anna; Scrimshaw, Mark D

2012-02-01

An effort is ongoing to develop a biotic ligand model (BLM) that predicts copper (Cu) toxicity in estuarine and marine environments. At present, the BLM accounts for the effects of water chemistry on Cu speciation, but it does not consider the influence of water chemistry on the physiology of the organisms. We discuss how chemistry affects Cu toxicity not only by controlling its speciation, but also by affecting the osmoregulatory physiology of the organism, which varies according to salinity. In an attempt to understand the mechanisms of Cu toxicity and predict its impacts, we explore the hypothesis that the common factor linking the main toxic effects of Cu is the enzyme carbonic anhydrase (CA), because it is a Cu target with multiple functions and salinity-dependent expression and activity. According to this hypothesis, the site of action of Cu in marine fish may be not only the gill, but also the intestine, because in this tissue CA plays an important role in ion transport and water adsorption. Therefore, the BLM of Cu toxicity to marine fish should also consider the intestine as a biotic ligand. Finally, we underline the need to incorporate the osmotic gradient into the BLM calculations to account for the influence of physiology on Cu toxicity. Copyright © 2011 SETAC.

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.

Safety of multiple stereotactic radiosurgery treatments for multiple brain lesions.

PubMed

Hillard, Virany H; Shih, Lynn L; Chin, Shing; Moorthy, Chitti R; Benzil, Deborah L

2003-07-01

Stereotactic radiosurgery (SRS) is a widely used therapy for multiple brain lesions, and studies have clearly established the safety and efficacy of single-dose SRS. However, as patient survival has increased, the recurrence of tumors and the development of metastases to new sites within the brain have made it desirable to repeat treatments over time. The cumulative toxicity of multi-isocenter, multiple treatments has not been well defined. We have retrospectively studied 10 patients who received multiple SRS treatments for multiple brain lesions to assess the cumulative toxicity of these treatments. In a retrospective review of all patients treated with SRS using the X-knife (Radionics, Burlington, MA) at Westchester Medical Center/New York Medical College between December 1995 and December 2000, 10 patients were identified who received at least two treatments to at least 3 isocenters and had a minimum follow-up period of 6 months. Image fusion technique was used to determine cumulative doses to targeted lesions, whole brain and critical brain structures. Toxicities and complications were identified by chart and radiological review. The average of the maximum doses (cGy) to a point within the whole brain was 2402 (range 1617-3953); to the brainstem, 1059 (range 48-4126); to the right optic nerve, 223 (range 14-1012); to the left optic nerve, 159 (range 17-475); and to the optic chiasm, 219 (range 15-909). There were no focal neurological toxicities, including visual disturbances, cranial nerve palsies, or ataxia in any of the 10 patients. There were also no global toxicities, including cognitive decline or secondary tumors. Only one patient developed seizures that were difficult to control in association with radiation necrosis. Multiple SRS treatments at the cumulative doses used in our study are a safe therapy for patients with multiple brain lesions.

Irresistible ants: exposure to novel toxic prey increases consumption over multiple temporal scales.

PubMed

Herr, Mark W; Robbins, Travis R; Centi, Alan; Thawley, Christopher J; Langkilde, Tracy

2016-07-01

As species become increasingly exposed to novel challenges, it is critical to understand how evolutionary (i.e., generational) and plastic (i.e., within lifetime) responses work together to determine a species' fate or predict its distribution. The introduction of non-native species imposes novel pressures on the native species that they encounter. Understanding how native species exposed to toxic or distasteful invaders change their feeding behavior can provide insight into their ability to cope with these novel threats as well as broader questions about the evolution of this behavior. We demonstrated that native eastern fence lizards do not avoid consuming invasive fire ants following repeated exposure to this toxic prey. Rather fence lizards increased their consumption of these ants following exposure on three different temporal scales. Lizards ate more fire ants when they were exposed to this toxic prey over successive days. Lizards consumed more fire ants if they had been exposed to fire ants as juveniles 6 months earlier. Finally, lizards from populations exposed to fire ants over multiple generations consumed more fire ants than those from fire ant-free areas. These results suggest that the potentially lethal consumption of fire ants may carry benefits resulting in selection for this behavior, and learning that persists long after initial exposure. Future research on the response of native predators to venomous prey over multiple temporal scales will be valuable in determining the long-term effects of invasion by these novel threats.

Effects of multiple life stage exposure to the fungicide prochloraz in Xenopus laevis: Manifestations of antiandrogenic and other modes of toxicity

EPA Science Inventory

The Larval Amphibian Growth and Development Assay (LAGDA) is an internationally harmonized testing guideline for evaluating effects of chronic chemical exposure in amphibians. To evaluate the utility of the assay design during the development phase antiandrogen prochloraz was te...

RESPONSE OF PLANT COMMUNITIES TO MULTIPLE STRESSES

EPA Science Inventory

Single species tests lack the ecological realism necessary to predict the effects of toxicants in natural environments. Field tests are expensive and the results can be difficult to interpret. To address these conflicting problems, open top chambers were modified to contain pla...

Toxicogenomic Effects Common to Triazole Antifungals and Conserved Between Rats and Humans

EPA Science Inventory

The triazole antifungals myclobutanil, propiconazole and triadimefon cause varying degrees of hepatic toxicity and disrupt steroid hormone homeostasis in rodent in vivo models. To identify biological pathways consistently modulated across multiple time-points and various study d...

Insights into aquatic toxicities of the antibiotics oxytetracycline and ciprofloxacin in the presence of metal: complexation versus mixture.

PubMed

Zhang, Yu; Cai, Xiyun; Lang, Xianming; Qiao, Xianliang; Li, Xuehua; Chen, Jingwen

2012-07-01

Co-contamination of ligand-like antibiotics (e.g., tetracyclines and quinolones) and heavy metals prevails in the environment, and thus the complexation between them is involved in environmental risks of antibiotics. To understand toxicological significance of the complex, effects of metal coordination on antibiotics' toxicity were investigated. The complexation of two antibiotics, oxytetracycline and ciprofloxacin, with three heavy metals, copper, zinc, and cadmium, was verified by spectroscopic techniques. The antibiotics bound metals via multiple coordination sites and rendered a mixture of various complexation speciations. Toxicity analysis indicated that metal coordination did modify the toxicity of the antibiotics and that antibiotic, metal, and their complex acted primarily as concentration addition. Comparison of EC(50) values revealed that the complex commonly was highest toxic and predominately correlated in toxicity to the mixture. Finally, environmental scenario analysis demonstrated that ignoring complexation would improperly classify environmental risks of the antibiotics. Copyright © 2012 Elsevier Ltd. All rights reserved.

Prioritizing ToxCast Chemicals Across Multiple Sectors of Toxicity Using ToxPi

EPA Science Inventory

The Toxicological Prioritization Index (ToxPi™) framework was developed as a decision-support tool to aid in the rational prioritization of chemicals for integrated toxicity testing. ToxPi consolidates information from multiple domains—including ToxCast™ in vitro bioactivity prof...

Post-exposure temperature influence on the toxicity of conventional and new chemistry insecticides to green lacewing Chrysoperla carnea (Stephens) (Neuroptera: Chrysopidae)

PubMed Central

Mansoor, Muhammad Mudassir; Afzal, Muhammad; Raza, Abu Bakar M.; Akram, Zeeshan; Waqar, Adil; Afzal, Muhammad Babar Shahzad

2014-01-01

Chrysoperla carnea (Stephens) is an important biological control agent currently being used in many integrated pest management (IPM) programs to control insect pests. The effect of post-treatment temperature on insecticide toxicity of a spinosyn (spinosad), pyrethroid (lambda cyhalothrin), organophosphate (chlorpyrifos) and new chemistry (acetamiprid) to C. carnea larvae was investigated under laboratory conditions. Temperature coefficients of each insecticide tested were evaluated. From 20 to 40 °C, toxicity of lambda cyhalothrin and spinosad decreased by 2.15- and 1.87-fold while toxicity of acetamiprid and chlorpyrifos increased by 2.00 and 1.79-fold, respectively. The study demonstrates that pesticide effectiveness may vary according to environmental conditions. In cropping systems where multiple insecticide products are used, attention should be given to temperature variation as a key factor in making pest management strategies safer for biological control agents. Insecticides with a negative temperature coefficient may play a constructive role to conserve C. carnea populations. PMID:25972753

Post-exposure temperature influence on the toxicity of conventional and new chemistry insecticides to green lacewing Chrysoperla carnea (Stephens) (Neuroptera: Chrysopidae).

PubMed

Mansoor, Muhammad Mudassir; Afzal, Muhammad; Raza, Abu Bakar M; Akram, Zeeshan; Waqar, Adil; Afzal, Muhammad Babar Shahzad

2015-05-01

Chrysoperla carnea (Stephens) is an important biological control agent currently being used in many integrated pest management (IPM) programs to control insect pests. The effect of post-treatment temperature on insecticide toxicity of a spinosyn (spinosad), pyrethroid (lambda cyhalothrin), organophosphate (chlorpyrifos) and new chemistry (acetamiprid) to C. carnea larvae was investigated under laboratory conditions. Temperature coefficients of each insecticide tested were evaluated. From 20 to 40 °C, toxicity of lambda cyhalothrin and spinosad decreased by 2.15- and 1.87-fold while toxicity of acetamiprid and chlorpyrifos increased by 2.00 and 1.79-fold, respectively. The study demonstrates that pesticide effectiveness may vary according to environmental conditions. In cropping systems where multiple insecticide products are used, attention should be given to temperature variation as a key factor in making pest management strategies safer for biological control agents. Insecticides with a negative temperature coefficient may play a constructive role to conserve C. carnea populations.

Sulfur dioxide: foe or friend for life?

PubMed

Wang, Xin-Bao; Cui, Hong; Liu, Xiaohong; Du, Jun-Bao

2017-12-01

Sulfur dioxide (SO₂) is a toxic gas and air pollutant. The toxic effects of SO₂ have been extensively studied. Oxidative damage due to SO₂ can occur in multiple organs. Inhaled SO₂ can also cause chromosomal aberrations, DNA damage and gene mutations in mammals. However, SO₂ can also be generated from the sulfur-containing amino acid, L-cysteine. Recent studies have shown that SO₂ has a vasorelaxant effect, and ameliorates pulmonary hypertension and vascular remodeling. SO₂ can also reduce lung injury and myocardial injury in rats. In addition, SO₂ reduces myocardial ischemia-reperfusion injury and atherosclerotic lesions. Therefore, SO₂ exerts both detrimental and protective effects in mammals. Is SO₂ a foe or friend for life?.

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.

Using passive sampling and zebrafish to identify developmental toxicants in complex mixtures.

PubMed

Bergmann, Alan J; Tanguay, Robert L; Anderson, Kim A

2017-09-01

Using effects-directed analysis, we investigated associations previously observed between polycyclic aromatic hydrocarbons (PAHs) and embryotoxicity in field-deployed low-density polyethylene (LDPE). We conducted effects-directed analysis using a zebrafish embryo assay and iterative fractionation of extracts of LDPE that were deployed in the Portland Harbor superfund megasite, Oregon (USA). Whole extracts induced toxicity including mortality, edema, and notochord distortion at 20% effect concentration (EC20) values of approximately 100, 100, and 10 mg LDPE/mL, respectively. Through fractionation, we determined that PAHs at concentrations similar to previous research did not contribute markedly to toxicity. We also eliminated pesticides, phthalates, musks, and other substances identified in toxic fractions by testing surrogate mixtures. We identified free fatty acids as lethal components of LDPE extracts and confirmed their toxicity with authentic standards. We found chromatographic evidence that dithiocarbamates are responsible for notochord and other sublethal effects, although exact matches were not obtained. Fatty acids and dithiocarbamates were previously unrecorded components of LDPE extracts and likely contribute to the toxicity of the whole mixture. The present study demonstrates the success of effects-directed analysis in nontargeted hazard identification using the zebrafish embryo test as a self-contained battery of bioassays that allows identification of multiple chemicals with different modes of action. This is the first effects-directed analysis to combine LDPE and zebrafish, approaches that are widely applicable to identifying developmental hazards in the bioavailable fraction of hydrophobic organic compounds. Environ Toxicol Chem 2017;36:2290-2298. © 2017 SETAC. © 2017 SETAC.

Simultaneous quantification of twelve compounds in ethyl acetate extracts of Euphorbia kansui before and after fry-baked with vinegar by UPLC-MS/MS and its toxic effect on zebrafish.

PubMed

Zhang, Qiao; Zhang, Kai-Cheng; Lou, Jian-Wei; Guo, Shu-Chen; Zhang, Yi; Yao, Wei-Feng; Tang, Yu-Ping; Wu, Jian-Hua; Zhang, Li

2018-06-05

The dried roots of Euphorbia kansui T.N. Liou ex T.P. Wang have been traditionally used for edema in China. However, the severe toxicity caused by Euphorbia kansui has seriously restricted its clinical application. Therefore, in order to study the material basis of the toxicity attenuation effect of processing with vinegar, a rapid, sensitive, validated and reliable UPLC-MS/MS method was developed to determine twelve compounds in ethyl acetate extracts of Euphorbia kansui before and after fry-baked with vinegar simultaneously. Meanwhile, the study of their toxic effect on zebrafish was conducted. Chromatographic separation was accomplished on Waters BEH C 18 UPLC column. 0.3% formic acid in water and acetonitrile were used as mobile phase with a flow rate of 0.40 mL/min and a temperature at 30 °C. The analysis was performed in multiple reaction monitoring (MRM) mode using positive electrospray ionization (ESI). Furthermore, the toxic research results indicated that the toxicity of Euphorbia kansui was decreased after vinegar-processed, which might because of the increase in the content of 5-O-benzoyl-20-deoxyingenol and the decrease in the contents of the remaining terpenoids in ethyl acetate extracts of Euphorbia kansui fry-baked with vinegar. This study demonstrated that the method used is a powerful approach to determine the content of twelve compounds that responsible for the toxic effect of Euphorbia kansui at the same instant. And provided the experimental evidence for the rationale behind the reduction of toxicity. Copyright © 2018 Elsevier B.V. All rights reserved.

USING DOSE ADDITION TO ESTIMATE CUMULATIVE RISKS FROM EXPOSURES TO MULTIPLE CHEMICALS

EPA Science Inventory

The Food Quality Protection Act (FQPA) of 1996 requires the EPA to consider the cumulative risk from exposure to multiple chemicals that have a common mechanism of toxicity. Three methods, hazard index (HI), point-of-departure index (PODI), and toxicity equivalence factor (TEF), ...

Ecotoxicological effect of ketamine: Evidence of acute, chronic and photolysis toxicity to Daphnia magna.

PubMed

Li, Shih-Wei; Wang, Yu-Hsiang; Lin, Angela Yu-Chen

2017-09-01

Ketamine has been increasingly used in medicine and has the potential for abuse or illicit use around the world. Ketamine cannot be removed by conventional wastewater treatment plants. Although ketamine and its metabolite norketamine have been detected to a significant degree in effluents and aquatic environments, their ecotoxicity effects in aquatic organisms remain undefined. In this study, we investigated the acute toxicity of ketamine and its metabolite, along with the chronic reproductive toxicity of ketamine (5-100μg/L) to Daphnia magna. Multiple environmental scenarios were also evaluated, including drug mixtures and sunlight irradiation toxicity. Ketamine and norketamine caused acute toxicity to D. magna, with half lethal concentration (LC 50 ) values of 30.93 and 25.35mg/L, respectively, after 48h of exposure. Irradiated solutions of ketamine (20mg/L) significantly increased the mortality of D. magna; pre-irradiation durations up to 2h rapidly increased the death rate to 100%. A new photolysis byproduct (M.W. 241) of norketamine that accumulates during irradiation was identified for the first time. The relevant environmental concentration of ketamine produced significant reproductive toxicity effects in D. magna, as revealed by the reduction of the number of total live offspring by 33.6-49.8% (p < 0.05). The toxicity results indicate that the environmental hazardous risks of the relevant ketamine concentration cannot be ignored and warrant further examination. Copyright © 2017 Elsevier Inc. All rights reserved.

Complex mixtures of dissolved pesticides show potential aquatic toxicity in a synoptic study of Midwestern U.S. streams

USGS Publications Warehouse

Nowell, Lisa H.; Moran, Patrick W.; Schmidt, Travis S.; Norman, Julia E.; Nakagaki, Naomi; Shoda, Megan E.; Mahler, Barbara J.; Van Metre, Peter C.; Stone, Wesley W.; Sandstrom, Mark W.; Hladik, Michelle L.

2018-01-01

Aquatic organisms in streams are exposed to pesticide mixtures that vary in composition over time in response to changes in flow conditions, pesticide inputs to the stream, and pesticide fate and degradation within the stream. To characterize mixtures of dissolved-phase pesticides and degradates in Midwestern streams, a synoptic study was conducted at 100 streams during May–August 2013. In weekly water samples, 94 pesticides and 89 degradates were detected, with a median of 25 compounds detected per sample and 54 detected per site. In a screening-level assessment using aquatic-life benchmarks and the Pesticide Toxicity Index (PTI), potential effects on fish were unlikely in most streams. For invertebrates, potential chronic toxicity was predicted in 53% of streams, punctuated in 12% of streams by acutely toxic exposures. For aquatic plants, acute but likely reversible effects on biomass were predicted in 75% of streams, with potential longer-term effects on plant communities in 9% of streams. Relatively few pesticides in water—atrazine, acetochlor, metolachlor, imidacloprid, fipronil, organophosphate insecticides, and carbendazim—were predicted to be major contributors to potential toxicity. Agricultural streams had the highest potential for effects on plants, especially in May–June, corresponding to high spring-flush herbicide concentrations. Urban streams had higher detection frequencies and concentrations of insecticides and most fungicides than in agricultural streams, and higher potential for invertebrate toxicity, which peaked during July–August. Toxicity-screening predictions for invertebrates were supported by quantile regressions showing significant associations for the Benthic Invertebrate-PTI and imidacloprid concentrations with invertebrate community metrics for MSQA streams, and by mesocosm toxicity testing with imidacloprid showing effects on invertebrate communities at environmentally relevant concentrations. This study documents the most complex pesticide mixtures yet reported in discrete water samples in the U.S. and, using multiple lines of evidence, predicts that pesticides were potentially toxic to nontarget aquatic life in about half of the sampled streams.

Sequestration of Sup35 by aggregates of huntingtin fragments causes toxicity of [PSI+] yeast.

PubMed

Zhao, Xiaohong; Park, Yang-Nim; Todor, Horia; Moomau, Christine; Masison, Daniel; Eisenberg, Evan; Greene, Lois E

2012-07-06

Expression of huntingtin fragments with 103 glutamines (HttQ103) is toxic in yeast containing either the [PIN(+)] prion, which is the amyloid form of Rnq1, or [PSI(+)] prion, which is the amyloid form of Sup35. We find that HttQP103, which has a polyproline region at the C-terminal end of the polyQ repeat region, is significantly more toxic in [PSI(+)] yeast than in [PIN(+)], even though HttQP103 formed multiple aggregates in both [PSI(+)] and [PIN(+)] yeast. This toxicity was only observed in the strong [PSI(+)] variant, not the weak [PSI(+)] variant, which has more soluble Sup35 present than the strong variant. Furthermore, expression of the MC domains of Sup35, which retains the C-terminal domain of Sup35, but lacks the N-terminal prion domain, almost completely rescued HttQP103 toxicity, but was less effective in rescuing HttQ103 toxicity. Therefore, the toxicity of HttQP103 in yeast containing the [PSI(+)] prion is primarily due to sequestration of the essential protein, Sup35.

Bisphenol Analogues Other Than BPA: Environmental Occurrence, Human Exposure, and Toxicity-A Review.

PubMed

Chen, Da; Kannan, Kurunthachalam; Tan, Hongli; Zheng, Zhengui; Feng, Yong-Lai; Wu, Yan; Widelka, Margaret

2016-06-07

Numerous studies have investigated the environmental occurrence, human exposure, and toxicity of bisphenol A (BPA). Following stringent regulations on the production and usage of BPA, several bisphenol analogues have been produced as a replacement for BPA in various applications. The present review outlines the current state of knowledge on the occurrence of bisphenol analogues (other than BPA) in the environment, consumer products and foodstuffs, human exposure and biomonitoring, and toxicity. Whereas BPA was still the major bisphenol analogue found in most environmental monitoring studies, BPF and BPS were also frequently detected. Elevated concentrations of BPAF, BPF, and BPS (i.e., similar to or greater than that of BPA) have been reported in the abiotic environment and human urine from some regions. Many analogues exhibit endocrine disrupting effects, cytotoxicity, genotoxicity, reproductive toxicity, dioxin-like effects, and neurotoxicity in laboratory studies. BPAF, BPB, BPF, and BPS have been shown to exhibit estrogenic and/or antiandrogenic activities similar to or even greater than that of BPA. Knowledge gaps and research needs have been identified, which include the elucidation of environmental occurrences, persistence, and fate of bisphenol analogues (other than BPA), sources and pathways for human exposure, effects on reproductive systems and the mammary gland, mechanisms of toxicity from coexposure to multiple analogues, metabolic pathways and products, and the impact of metabolic modification on toxicity.

Toxic potential of palytoxin.

PubMed

Patocka, Jiří; Gupta, Ramesh C; Wu, Qing-hua; Kuca, Kamil

2015-10-01

This review briefly describes the origin, chemistry, molecular mechanism of action, pharmacology, toxicology, and ecotoxicology of palytoxin and its analogues. Palytoxin and its analogues are produced by marine dinoflagellates. Palytoxin is also produced by Zoanthids (i.e. Palythoa), and Cyanobacteria (Trichodesmium). Palytoxin is a very large, non-proteinaceous molecule with a complex chemical structure having both lipophilic and hydrophilic moieties. Palytoxin is one of the most potent marine toxins with an LD50 of 150 ng/kg body weight in mice exposed intravenously. Pharmacological and electrophysiological studies have demonstrated that palytoxin acts as a hemolysin and alters the function of excitable cells through multiple mechanisms of action. Palytoxin selectively binds to Na(+)/K(+)-ATPase with a Kd of 20 pM and transforms the pump into a channel permeable to monovalent cations with a single-channel conductance of 10 pS. This mechanism of action could have multiple effects on cells. Evaluation of palytoxin toxicity using various animal models revealed that palytoxin is an extremely potent neurotoxin following an intravenous, intraperitoneal, intramuscular, subcutaneous or intratracheal route of exposure. Palytoxin also causes non-lethal, yet serious toxic effects following dermal or ocular exposure. Most incidents of palytoxin poisoning have manifested after oral intake of contaminated seafood. Poisonings in humans have also been noted after inhalation, cutaneous/systemic exposures with direct contact of aerosolized seawater during Ostreopsis blooms and/or through maintaining aquaria containing Cnidarian zoanthids. Palytoxin has a strong potential for toxicity in humans and animals, and currently this toxin is of great concern worldwide.

Comparative Toxicity of Simulated Smog Atmospheres in Healthy and Allergic Mice

EPA Science Inventory

Effects of complex regional multipollutant mixtures on disease expression in susceptible populations are dependent on multiple exposure and susceptibility factors. Differing profiles of ozone (O3), nitrogen dioxide (NO2), and particulate matter (PM), which are key components of s...

INTERSPECIES CORRELATION ESTIMATES PREDICT PROTECTIVE ENVIRONMENTAL CONCENTRATIONS

EPA Science Inventory

Environmental risk assessments often use multiple single species toxicity test results and species sensitivity distributions (SSDs) to derive a predicted no-effect concentration in the environment, typically the 5th percentile of the SSD, termed the HC5. The shape and location of...

A novel approach for rapidly and cost-effectively assessing toxicity of toxic metals in acidic water using an acidophilic iron-oxidizing biosensor.

PubMed

Yang, Shih-Hung; Cheng, Kuo-Chih; Liao, Vivian Hsiu-Chuan

2017-11-01

Contamination by heavy metals and metalloids is a serious environmental and health concern. Acidic wastewaters are often associated with toxic metals which may enter and spread into agricultural soils. Several biological assays have been developed to detect toxic metals; however, most of them can only detect toxic metals in a neutral pH, not in an acidic environment. In this study, an acidophilic iron-oxidizing bacterium (IOB) Strain Y10 was isolated, characterized, and used to detect toxic metals toxicity in acidic water at pH 2.5. The colorimetric acidophilic IOB biosensor was based on the inhibition of the iron oxidizing ability of Strain Y10, an acidophilic iron-oxidizing bacterium, by metals toxicity. Our results showed that Strain Y10 is acidophilic iron-oxidizing bacterium. Thiobacillus caldus medium (TCM) (pH 2.5) supplied with both S 4 O 6 2- and glucose was the optimum growth medium for Strain Y10. The optimum temperature and pH for the growth of Strain Y10 was 45 °C and pH 2.5, respectively. Our study demonstrates that the color-based acidophilic IOB biosensor can be semi-quantitatively observed by eye or quantitatively measured by spectrometer to detect toxicity from multiple toxic metals at pH 2.5 within 45 min. Our study shows that monitoring toxic metals in acidic water is possible by using the acidophilic IOB biosensor. Our study thus provides a novel approach for rapid and cost-effective detection of toxic metals in acidic conditions that can otherwise compromise current methods of chemical analysis. This method also allows for increased efficiency when screening large numbers of environmental samples. Copyright © 2017 Elsevier Ltd. All rights reserved.

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.

Definition of metabolism-dependent xenobiotic toxicity with co-cultures of human hepatocytes and mouse 3T3 fibroblasts in the novel integrated discrete multiple organ co-culture (IdMOC) experimental system: results with model toxicants aflatoxin B1, cyclophosphamide and tamoxifen.

PubMed

Li, Albert P; Uzgare, Aarti; LaForge, Yumiko S

2012-07-30

The integrated discrete multiple organ co-culture system (IdMOC) allows the co-culturing of multiple cell types as physically separated cells interconnected by a common overlying medium. We report here the application of IdMOC with two cell types: the metabolically competent primary human hepatocytes, and a metabolically incompetent cell line, mouse 3T3 fibroblasts, in the definition of the role of hepatic metabolism on the cytotoxicity of three model toxicants: cyclophosphamide (CPA), aflatoxin B1 (AFB) and tamoxifen (TMX). The presence of hepatic metabolism in IdMOC with human hepatocytes was demonstrated by the metabolism of the P450 isoform 3A4 substrate, luciferin-IPA. The three model toxicants showed three distinct patterns of cytotoxic profile: TMX was cytotoxic to 3T3 cells in the absence of hepatocytes, with slightly lower cytotoxicity towards both 3T3 cells and hepatocytes in the IdMOC. AFB was selective toxic towards the human hepatocytes and relatively noncytotoxic towards 3T3 cells both in the presence and absence of the hepatocytes. CPA cytotoxicity to the 3T3 cells was found to be significantly enhanced by the presence of the hepatocytes, with the cytotoxicity dependent of the number of hepatocytes, and with the cytotoxicity attenuated by the presence of a non-specific P450 inhibitor, 1-aminobenzotriazole. We propose here the following classification of toxicants based on the role of hepatic metabolism as defined by the human hepatocyte-3T3 cell IdMOC assay: type I: direct-acting cytotoxicants represented by TMX as indicated by cytotoxicity in 3T3 cells in the absence of hepatocytes; type II: metabolism-dependent cytotoxicity represented by AFB1 with effects localized within the site of metabolic activation (i. e. hepatocytes); and type III: metabolism-dependent cytotoxicity with metabolites that can diffuse out of the hepatocytes to cause toxicity in cells distal from the site of metabolism, as exemplified by CPA. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Pollutant Concentrations and Toxic Effects on the Red Alga Ceramium tenuicorne of Sediments from Natural Harbors and Small Boat Harbors on the West Coast of Sweden.

PubMed

Eklund, Britta; Hansson, Tomas; Bengtsson, Henrik; Eriksson Wiklund, Ann-Kristin

2016-04-01

This investigation set out to analyze the toxicity of surface sediments in a number of natural harbors and small boat harbors on the west coast of Sweden. This was done with the growth inhibition method with Ceramium tenuicorne. Also, concentrations of copper (Cu), lead (Pb), zinc (Zn), irgarol, organotin compounds, and polycyclic aromatic hydrocarbons (PAHs) in the sediments were analyzed. The small boat harbors were heavily polluted by Cu, Zn, butyltins, and PAHs, and to a lesser extent by Pb. The Cu, Pb, Zn, and butyltins probably originated from their past and/or present use in antifouling paints, whereas the PAHs probably had multiple sources, including boat motor exhausts. The measured toxicity of the sediment was generally related to their Cu, Zn, and butyltin content, although other toxic substances than those analyzed here probably contributed to the toxicity in some of the harbors. The natural harbor sediments contained less pollutants and were less toxic than the small boat harbor sediments. Nevertheless, our data indicate that the boating pressure today may be high enough to produce toxic effects even in natural harbors in pristine areas. The strongest relationship between toxicity and the major pollutants was obtained when the sediment toxicity was expressed as gram wet weight per liter compared with gram dry weight per liter and gram total organic carbon per liter. Hence, for pollutants that can be elutriated with natural sea water, sediment toxicity expressed as gram wet weight per liter appears preferable.

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.

1,4-Naphthoquinone derivatives potently suppress Candida albicans growth, inhibit formation of hyphae and show no toxicity toward zebrafish embryos.

PubMed

Janeczko, Monika; Kubiński, Konrad; Martyna, Aleksandra; Muzyczka, Angelika; Boguszewska-Czubara, Anna; Czernik, Sławomir; Tokarska-Rodak, Małgorzata; Chwedczuk, Marta; Demchuk, Oleg M; Golczyk, Hieronim; Masłyk, Maciej

2018-04-01

In this study, we applied various assays to find new activities of 1,4-naphthoquinone derivatives for potential anti-Candida albicans applications. These assays determined (a) the antimicrobial effect on growth/cell multiplication in fungal cultures, (b) the effect on formation of hyphae and biofilm, (c) the influence on cell membrane integrity, (d) the effect on cell morphology using atomic force microscopy, and (e) toxicity against zebrafish embryos. We have demonstrated the activity of these compounds against different Candida species and clinical isolates of C. albicans. 1,4-Naphthoquinones significantly affected fungal strains at 8-250 mg l -1 of MIC. Interestingly, at concentrations below MICs, the chemicals showed effectiveness in inhibition of hyphal formation and cell aggregation in Candida. Of note, atomic force microscopy (AFM) analysis revealed an influence of the compounds on cell morphological properties. However, at low concentrations (0.8-31.2 mg l -1 ), it did not exert any evident toxic effects on zebrafish embryos. Our research has evidenced the effectiveness of 1,4-naphthoquinones as potential anti-Candida agents.

Toxic effects of arsenic on semen and hormonal profile and their amelioration with vitamin E in Teddy goat bucks.

PubMed

Zubair, M; Ahmad, M; Jamil, H; Deeba, F

2016-12-01

The present environmental study has been planned to investigate the toxic effects of arsenic on reproductive functions of Teddy bucks as well as to examine whether these toxic effects are ameliorated by vitamin E. Sixteen adult Teddy bucks were divided randomly into four equal groups A, B, C and D with following treatment: A (control), B (sodium arsenite 5 mg kg -1 BW day -1 ), C (vit E 200 mg kg -1 BW day -1  + Arsenic 5 mg kg -1 BW day -1 ) and D (vit E 200 mg kg -1 BW day -1 ). This treatment was continued for 84 days. Semen quality parameters were evaluated weekly. Male testosterone, luteinising hormone (LH), follicle-stimulating hormone (FSH) and cortisol levels were measured through enzyme-linked immunosorbent assay (ELISA) after every 2 weeks. The data were subjected to two-way analysis of variance followed by Duncan test for multiple comparisons. Semen evaluation parameters were reduced significantly (P < 0.05) in arsenic-treated animals. The serum hormonal profile of testosterone, LH and FSH was reduced significantly (P < 0.05) in arsenic group, while the serum level of cortisol was increased. Vitamin E alleviated the toxic effects of arsenic on semen and hormonal parameters. It may be concluded from this study that sodium arsenite causes major toxicity changes in semen and hormonal profile in Teddy goat bucks and vitamin E has ameliorative effects on these toxic changes. © 2016 Blackwell Verlag GmbH.

Determining the effects of a mixture of an endocrine disrupting compound, 17α-ethinylestradiol, and ammonia on fathead minnow (Pimephales promelas) reproduction.

PubMed

Armstrong, Brandon M; Lazorchak, James M; Murphy, Cheryl A; Haring, Herman J; Jensen, Kathleen M; Smith, Mark E

2015-02-01

Aquatic organisms are exposed to a multitude of contaminants and to fully understand the impact of multiple stressors on fish populations, we must first understand the mechanism of action for each toxicant and how the combined effects manifest at the level of the individual. 17α-ethinylestradiol (EE2) has been known to cause adverse reproductive effects including reduced fecundity and fertility, intersex and skewed sex ratios in fish by mimicking naturally produced estrogen at low concentrations. Ammonia can cause adverse reproductive and mortality effects in individual fish through effects or damage to the central nervous system. Both EE2 and ammonia are found in most municipal effluents in various concentrations. A flow-through diluter system was used to test the individual effects of these two contaminants at their respective no observable adverse effect concentration (NOAEC) as well as their combined effects on fathead minnow, (Pimephales promelas) reproduction in a mixture exposure. While neither contaminant nor their mixture altered reproduction in terms of fecundity, their mixture resulted in significant fathead minnow mortality during a 21 d exposure. This study demonstrated the need to consider mixture effects when assessing risk for toxicity testing with multiple stressors. Published by Elsevier Ltd.

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.

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.

USING GENOMICS TO EXAMINE MULTIPLE EXPOSURE VARIABLES IN BIOINDICATORS RESEARCH

EPA Science Inventory

Genomics technologies provide a powerful tool for rapid assessment of differentially expressed genes in laboratory and field animals exposed to toxicants, and a means by which to link the earliest indicators of exposure to diverse effects in organisms and populations. However, a...

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.

High-Density Real-Time PCR-Based in Vivo Toxicogenomic Screen to Predict Organ-Specific Toxicity

PubMed Central

Fabian, Gabriella; Farago, Nora; Feher, Liliana Z.; Nagy, Lajos I.; Kulin, Sandor; Kitajka, Klara; Bito, Tamas; Tubak, Vilmos; Katona, Robert L.; Tiszlavicz, Laszlo; Puskas, Laszlo G.

2011-01-01

Toxicogenomics, based on the temporal effects of drugs on gene expression, is able to predict toxic effects earlier than traditional technologies by analyzing changes in genomic biomarkers that could precede subsequent protein translation and initiation of histological organ damage. In the present study our objective was to extend in vivo toxicogenomic screening from analyzing one or a few tissues to multiple organs, including heart, kidney, brain, liver and spleen. Nanocapillary quantitative real-time PCR (QRT-PCR) was used in the study, due to its higher throughput, sensitivity and reproducibility, and larger dynamic range compared to DNA microarray technologies. Based on previous data, 56 gene markers were selected coding for proteins with different functions, such as proteins for acute phase response, inflammation, oxidative stress, metabolic processes, heat-shock response, cell cycle/apoptosis regulation and enzymes which are involved in detoxification. Some of the marker genes are specific to certain organs, and some of them are general indicators of toxicity in multiple organs. Utility of the nanocapillary QRT-PCR platform was demonstrated by screening different references, as well as discovery of drug-like compounds for their gene expression profiles in different organs of treated mice in an acute experiment. For each compound, 896 QRT-PCR were done: four organs were used from each of the treated four animals to monitor the relative expression of 56 genes. Based on expression data of the discovery gene set of toxicology biomarkers the cardio- and nephrotoxicity of doxorubicin and sulfasalazin, the hepato- and nephrotoxicity of rotenone, dihydrocoumarin and aniline, and the liver toxicity of 2,4-diaminotoluene could be confirmed. The acute heart and kidney toxicity of the active metabolite SN-38 from its less toxic prodrug, irinotecan could be differentiated, and two novel gene markers for hormone replacement therapy were identified, namely fabp4 and pparg, which were down-regulated by estradiol treatment. PMID:22016648

Effects of soil properties on copper toxicity to earthworm Eisenia fetida in 15 Chinese soils.

PubMed

Duan, Xiongwei; Xu, Meng; Zhou, Youya; Yan, Zengguang; Du, Yanli; Zhang, Lu; Zhang, Chaoyan; Bai, Liping; Nie, Jing; Chen, Guikui; Li, Fasheng

2016-02-01

The bioavailability and toxicity of metals in soil are influenced by a variety of soil properties, and this principle should be recognized in establishing soil environmental quality criteria. In the present study, the uptake and toxicity of Cu to the earthworm Eisenia fetida in 15 Chinese soils with various soil properties were investigated, and regression models for predicting Cu toxicity across soils were developed. The results showed that earthworm survival and body weight change were less sensitive to Cu than earthworm cocoon production. The soil Cu-based median effective concentrations (EC50s) for earthworm cocoon production varied from 27.7 to 383.7 mg kg(-1) among 15 Chinese soils, representing approximately 14-fold variation. Soil cation exchange capacity and organic carbon content were identified as key factors controlling Cu toxicity to earthworm cocoon production, and simple and multiple regression models were developed for predicting Cu toxicity across soils. Tissue Cu-based EC50s for earthworm cocoon production were also calculated and varied from 15.5 to 62.5 mg kg(-1) (4-fold variation). Compared to the soil Cu-based EC50s for cocoon production, the tissue Cu-based EC50s had less variation among soils, indicating that metals in tissue were more relevant to toxicity than metals in soil and hence represented better measurements of bioavailability. Copyright © 2015 Elsevier Ltd. All rights reserved.

TOXIC POLLUTANTS IN URBAN WET-WEATHER FLOWS: AN OVERVIEW OF THE MULTI-MEDIA TRANSPORT, IMPACTS, AND CONTROL MEASURES (PRESENTATION)

EPA Science Inventory

This paper presents an oveview of the transport of toxic pollutants through multiple media in the urban environment. Discussions include the sources of particulate-associated toxic substances and the relationship of these toxics to atmospheric deposition, overland accumulation an...

In situ impact of multiple pulses of metal and herbicide on the seagrass, Zostera capricorni.

PubMed

Macinnis-Ng, Catriona M O; Ralph, Peter J

2004-04-28

Tides and freshwater inflow which influence water movement in estuarine areas govern the exposure-regime of pollutants. In this experiment, we examined the in situ impact of double pulses of copper and the herbicide Irgarol 1051 on the photosynthesis of the seagrass, Zostera capricorni. Despite a 4-day recovery period between the two 10h pulses of toxicant, the effective quantum yield of photosystem II (DeltaF/Fm') and total chlorophyll concentrations indicated that multiple-pulses had a greater impact than a single pulse. During the first exposure period, samples exposed to Irgarol 1051 had DeltaF/Fm' values as low as zero while controls remained around 0.6 relative units. After the second exposure period, treated samples recovered to only 0.4 relative units. Samples exposed to copper had DeltaF/Fm' values around 0.3 relative units during the first exposure period and while these samples recovered before the second dose, they remained below 0.2 relative units after the second exposure period. Alternate samples were also exposed to one toxicant, allowed to recover and then exposed to the other toxicant. DeltaF/Fm' values indicated that copper exposure followed by Irgarol 1051 exposure was more toxic than Irgarol 1051 exposure followed by copper exposure.

Mammalian Toxicity of Munitions Compounds. Phase II. Effects of Multiple Doses Part II. 2,4-Dinitrotoluene

DTIC Science & Technology

1978-11-01

middle, or high levels of 2,4-DNT in the feed averaged 34, 93, or 266 mg/kg/day, respectively. The female rats consumed an average of 38, 108, or 145 mg...intake of males fed the low, middle or high levels of 2,4-DNT in the feed averaged 47, 137, or 413 mg/kg/day, respectively. The female mice consumed an...Experimental Procedures All dogs were observed daily for behavioral changes and toxic signs. Body weights of all dogs were recorded weekly. Blood

The Response of Lemna minor to Mixtures of Pesticides That Are Commonly Used in Thailand.

PubMed

Tagun, Rungnapa; Boxall, Alistair B A

2018-04-01

In the field, aquatic organisms are exposed to multiple contaminants rather than to single compounds. It is therefore important to understand the toxic interactions of co-occurring substances in the environment. The aim of the study was to assess the effects of individual herbicides (atrazine, 2,4-D, alachlor and paraquat) that are commonly used in Thailand and their mixtures on Lemna minor. Plants were exposed to individual and binary mixtures for 7 days and the effects on plant growth rate were assesed based on frond area measurements. Experimental observations of mixture toxicity were compared with predictions based on single herbicide exposure data using concentration addition and independent action models. The single compound studies showed that paraquat and alachlor were most toxic to L. minor, followed by atrazine and then 2,4-D. For the mixtures, atrazine with 2,4-D appeared to act antagonistically, whereas alachlor and paraquat showed synergism.

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.

EPA's Reanalysis of Key Issues Related to Dioxin Toxicity and ...

EPA Pesticide Factsheets

EPA is releasing for external peer review and public comment an important draft document reviewing the literature on the health effects of dioxin and related compounds (also referred to as 2,3,7,8-Tetrachlorodibenzo-p-dioxin). At the request of Administrator Jackson, EPA is in the process of re-assessing the science on the effects of dioxin, a toxic chemical that is emitted by multiple sources, on the public’s health. This draft dioxin report is EPA’s response to key comments and recommendations made by the National Academy of Sciences on the Agency’s draft dioxin reassessment. This assessment has been in progress for many years and raises health issues of broad interest to scientists and policymakers across the federal family. The Agency’s draft report includes significant new analyses on potential cancer and non-cancer human health effects that may result from exposures to dioxins and includes an oral reference dose for what is considered to be the most toxic of the dioxin-like compounds. EPA’s Science

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.

Toxicity assessment of diesel- and metal-contaminated soils through elutriate and solid phase assays with the slime mold Dictyostelium discoideum.

PubMed

Rodríguez-Ruiz, Amaia; Dondero, Francesco; Viarengo, Aldo; Marigómez, Ionan

2016-06-01

A suite of organisms from different taxonomical and ecological positions is needed to assess environmentally relevant soil toxicity. A new bioassay based on Dictyostelium is presented that is aimed at integrating slime molds into such a testing framework. Toxicity tests on elutriates and the solid phase developmental cycle assay were successfully applied to a soil spiked with a mixture of Zn, Cd, and diesel fuel freshly prepared (recently contaminated) and after 2 yr of aging. The elutriates of both soils provoked toxic effects, but toxicity was markedly lower in the aged soil. In the D. discoideum developmental cycle assay, both soils affected amoeba viability and aggregation, with fewer multicellular units, smaller fruiting bodies and, overall, inhibition of fruiting body formation. This assay is quick and requires small amounts of test soil, which might facilitate its incorporation into a multispecies multiple-endpoint toxicity bioassay battery suitable for environmental risk assessment in soils. Environ Toxicol Chem 2016;35:1413-1421. © 2015 SETAC. © 2015 SETAC.

Laboratory toxicity and benthic invertebrate field colonization of Upper Columbia River sediments: finding adverse effects using multiple lines of evidence.

PubMed

Fairchild, J F; Kemble, N E; Allert, A L; Brumbaugh, W G; Ingersoll, C G; Dowling, B; Gruenenfelder, C; Roland, J L

2012-07-01

From 1930 to 1995, the Upper Columbia River (UCR) of northeast Washington State received approximately 12 million metric tons of smelter slag and associated effluents from a large smelter facility located in Trail, British Columbia, approximately 10 km north of the United States-Canadian border. Studies conducted during the past two decades have demonstrated the presence of toxic concentrations of heavy metals in slag-based sandy sediments, including cadmium, copper, zinc, and lead in the UCR area as well as the downstream reservoir portion of Lake Roosevelt. We conducted standardized whole-sediment toxicity tests with the amphipod Hyalella azteca (28-day) and the midge Chironomus dilutus (10-day) on 11 samples, including both UCR and study-specific reference sediments. Metal concentrations in sediments were modeled for potential toxicity using three approaches: (1) probable effects quotients (PEQs) based on total recoverable metals (TRMs) and simultaneously extracted metals (SEMs); (2) SEMs corrected for acid-volatile sulfides (AVS; i.e., ∑SEM - AVS); and (3) ∑SEM - AVS normalized to the fractional organic carbon (f(oc)) (i.e., ∑SEM - AVS/f(oc)). The most highly metal-contaminated sample (∑PEQ(TRM) = 132; ∑PEQ(SEM) = 54; ∑SEM - AVS = 323; and ∑SEM - AVS/(foc) = 64,600 umol/g) from the UCR was dominated by weathered slag sediment particles and resulted in 80% mortality and 94% decrease in biomass of amphipods; in addition, this sample significantly decreased growth of midge by 10%. The traditional ∑AVS - SEM, uncorrected for organic carbon, was the most accurate approach for estimating the effects of metals in the UCR. Treatment of the toxic slag sediment with 20% Resinex SIR-300 metal-chelating resin significantly decreased the toxicity of the sample. Samples ∑SEM - AVS > 244 was not toxic to amphipods or midge in laboratory testing, indicating that this value may be an approximate threshold for effects in the UCR. In situ benthic invertebrate colonization studies in an experimental pond (8-week duration) indicated that two of the most metal-contaminated UCR sediments (dominated by high levels of sand-sized slag particles) exhibited decreased invertebrate colonization compared with sand-based reference sediments. Field-exposed SIR-300 resin samples also exhibited decreased invertebrate colonization numbers compared with reference materials, which may indicate behavioral avoidance of this material under field conditions. Multiple lines of evidence (analytical chemistry, laboratory toxicity, and field colonization results), along with findings from previous studies, indicate that high metal concentrations associated with slag-enriched sediments in the UCR are likely to adversely impact the growth and survival of native benthic invertebrate communities. Additional laboratory toxicity testing, refinement of the applications of sediment benchmarks for metal toxicity, and in situ benthic invertebrate studies will assist in better defining the spatial extent, temporal variations, and ecological impacts of metal-contaminated sediments in the UCR system.

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.

Determining the effects of a mixture of an endocrine disrupting compound, 17a-ethinylestradiol, and ammonia on fathead minnow (Pimephales promelas) reproduction

EPA Science Inventory

Aquatic organisms are exposed to a multitude of contaminants and to fully understand the impact of multiple stressors on fish populations, we must first understand the mechanism of action for each toxicant and how the combined effects manifest at the level of the individual. 17α-...

Patterns of Exposure to Multiple Metals and Associations with Neurodevelopment of Preschool Children from Montevideo, Uruguay

PubMed Central

Kordas, Katarzyna; Ardoino, Graciela; Coffman, Donna L.; Queirolo, Elena I.; Ciccariello, Daniela; Mañay, Nelly; Ettinger, Adrienne S.

2015-01-01

While it is known that toxic metals contribute individually to child cognitive and behavioral deficits, we still know little about the effects of exposure to multiple metals, particularly when exposures are low. We studied the association between children's blood lead and hair arsenic, cadmium, and manganese and their performance on the Bayley Scales of Infant Development III. Ninety-two preschool children (age 13–42 months) from Montevideo, Uruguay, provided a hair sample and 78 had a blood lead level (BLL) measurement. Using latent class analysis (LCA), we identified four groups of exposure based on metal concentrations: (1) low metals, (2) low-to-moderate metals, (3) high lead and cadmium, and (4) high metals. Using the four-group exposure variable as the main predictor, and fitting raw scores on the cognitive, receptive vocabulary, and expressive vocabulary scales as dependent variables, both complete-case and multiple imputation (MI) analyses were conducted. We found no association between multiple-metal exposures and neurodevelopment in covariate-adjusted models. This study demonstrates the use of LCA together with MI to determine patterns of exposure to multiple toxic metals and relate these to child neurodevelopment. However, because the overall study population was small, other studies with larger sample sizes are needed to investigate these associations. PMID:25694786

Soil bioretention protects juvenile salmon and their prey from the toxic impacts of urban stormwater runoff.

PubMed

McIntyre, J K; Davis, J W; Hinman, C; Macneale, K H; Anulacion, B F; Scholz, N L; Stark, J D

2015-08-01

Green stormwater infrastructure (GSI), or low impact development, encompasses a diverse and expanding portfolio of strategies to reduce the impacts of stormwater runoff on natural systems. Benchmarks for GSI success are usually framed in terms of hydrology and water chemistry, with reduced flow and loadings of toxic chemical contaminants as primary metrics. Despite the central goal of protecting aquatic species abundance and diversity, the effectiveness of GSI treatments in maintaining diverse assemblages of sensitive aquatic taxa has not been widely evaluated. In the present study we characterized the baseline toxicity of untreated urban runoff from a highway in Seattle, WA, across six storm events. For all storms, first flush runoff was toxic to the daphniid Ceriodaphnia dubia, causing up to 100% mortality or impairing reproduction among survivors. We then evaluated whether soil media used in bioretention, a conventional GSI method, could reduce or eliminate toxicity to juvenile coho salmon (Oncorhynchus kisutch) as well as their macroinvertebrate prey, including cultured C. dubia and wild-collected mayfly nymphs (Baetis spp.). Untreated highway runoff was generally lethal to salmon and invertebrates, and this acute mortality was eliminated when the runoff was filtered through soil media in bioretention columns. Soil treatment also protected against sublethal reproductive toxicity in C. dubia. Thus, a relatively inexpensive GSI technology can be highly effective at reversing the acutely lethal and sublethal effects of urban runoff on multiple aquatic species. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Space Toxicology

NASA Technical Reports Server (NTRS)

James, John T.

2011-01-01

Safe breathing air for space faring crews is essential whether they are inside an Extravehicular Mobility Suit (EMU), a small capsule such as Soyuz, or the expansive International Space Station (ISS). Sources of air pollution can include entry of propellants, excess offgassing from polymeric materials, leakage of systems compounds, escape of payload compounds, over-use of utility compounds, microbial metabolism, and human metabolism. The toxicological risk posed by a compound is comprised of the probability of escaping to cause air pollution and the magnitude of adverse effects on human health if escape occurs. The risk from highly toxic compounds is controlled by requiring multiple levels of containment to greatly reduce the probability of escape; whereas compounds that are virtually non-toxic may require little or no containment. The potential for toxicity is determined by the inherent toxicity of the compound and the amount that could potentially escape into the breathing air.

Myristicin and phenytoin toxicity in an infant

PubMed Central

Sivathanu, Shobhana; Sampath, Sowmya; David, Henry Suresh; Rajavelu, Kulandai Kasthuri

2014-01-01

A developmentally normal infant presented with repeated episodes of afebrile status epilepticus following nutmeg ingestion. He had developed two episodes of afebrile status epilepticus and had received different treatments earlier, but the details of treatment were not available. On admission, he redeveloped convulsions and loading doses of phenytoin, phenobarbitone and midazolam were administered. However, seizures persisted and extrapyramidal movements, nystagmus and visual dysfunction were noted. Iatrogenic phenytoin toxicity was considered and confirmed by drug levels. His symptoms completely disappeared after discontinuation of phenytoin therapy. The initial seizures were attributed to myristicin, an active component of nutmeg, because of the temporal association. However, the subsequent seizures were due to phenytoin toxicity caused by administration of multiple loading doses. This case highlights that nutmeg, a spice, can cause serious toxic effects like status epilepticus. Furthermore, treatment of status epilepticus with phenytoin can cause iatrogenic seizures due to its narrow therapeutic range. PMID:24903724

Toxic Shock Syndrome Toxin-1-Mediated Toxicity Inhibited by Neutralizing Antibodies Late in the Course of Continual in Vivo and in Vitro Exposure

PubMed Central

Stich, Norbert; Model, Nina; Samstag, Aysen; Gruener, Corina S.; Wolf, Hermann M.; Eibl, Martha M.

2014-01-01

Toxic shock syndrome (TSS) results from the host’s overwhelming inflammatory response and cytokine storm mainly due to superantigens (SAgs). There is no effective specific therapy. Application of immunoglobulins has been shown to improve the outcome of the disease and to neutralize SAgs both in vivo and in vitro. However, in most experiments that have been performed, antiserum was either pre-incubated with SAg, or both were applied simultaneously. To mirror more closely the clinical situation, we applied a multiple dose (over five days) lethal challenge in a rabbit model. Treatment with toxic shock syndrome toxin 1 (TSST-1) neutralizing antibody was fully protective, even when administered late in the course of the challenge. Kinetic studies on the effect of superantigen toxins are scarce. We performed in vitro kinetic studies by neutralizing the toxin with antibodies at well-defined time points. T-cell activation was determined by assessing T-cell proliferation (3H-thymidine incorporation), determination of IL-2 release in the cell supernatant (ELISA), and IL-2 gene activation (real-time PCR (RT-PCR)). Here we show that T-cell activation occurs continuously. The application of TSST-1 neutralizing antiserum reduced IL-2 and TNFα release into the cell supernatant, even if added at later time points. Interference with the prolonged stimulation of proinflammatory cytokines is likely to be in vivo relevant, as postexposure treatment protected rabbits against the multiple dose lethal SAg challenge. Our results shed new light on the treatment of TSS by specific antibodies even at late stages of exposure. PMID:24887085

Toxic shock syndrome toxin-1-mediated toxicity inhibited by neutralizing antibodies late in the course of continual in vivo and in vitro exposure.

PubMed

Stich, Norbert; Model, Nina; Samstag, Aysen; Gruener, Corina S; Wolf, Hermann M; Eibl, Martha M

2014-05-30

Toxic shock syndrome (TSS) results from the host's overwhelming inflammatory response and cytokine storm mainly due to superantigens (SAgs). There is no effective specific therapy. Application of immunoglobulins has been shown to improve the outcome of the disease and to neutralize SAgs both in vivo and in vitro. However, in most experiments that have been performed, antiserum was either pre-incubated with SAg, or both were applied simultaneously. To mirror more closely the clinical situation, we applied a multiple dose (over five days) lethal challenge in a rabbit model. Treatment with toxic shock syndrome toxin 1 (TSST-1) neutralizing antibody was fully protective, even when administered late in the course of the challenge. Kinetic studies on the effect of superantigen toxins are scarce. We performed in vitro kinetic studies by neutralizing the toxin with antibodies at well-defined time points. T-cell activation was determined by assessing T-cell proliferation (3H-thymidine incorporation), determination of IL-2 release in the cell supernatant (ELISA), and IL-2 gene activation (real-time PCR (RT-PCR)). Here we show that T-cell activation occurs continuously. The application of TSST-1 neutralizing antiserum reduced IL-2 and TNFα release into the cell supernatant, even if added at later time points. Interference with the prolonged stimulation of proinflammatory cytokines is likely to be in vivo relevant, as postexposure treatment protected rabbits against the multiple dose lethal SAg challenge. Our results shed new light on the treatment of TSS by specific antibodies even at late stages of exposure.

Toxicity of major geochemical ions to freshwater species

EPA Science Inventory

Extensive testing regarding the toxicity of major geochemical ions to Ceriodaphnia dubia, Hyalella azteca, and Pimephales promelas will be presented. For C. dubia, tests of single salts and binary mixtures in various dilution waters demonstrated multiple mechanisms of toxicity an...

USE OF MERCENARIA MERCENARIA IN MULTIPLE SPECIES TESTING

EPA Science Inventory

The Toxicity Identification Evaluation (TIE) approach was first developed for determining the causes of toxicity in effluents discharged into the aquatic environment. Soon, TIEs were being used for assessing the causes of toxicity in sediment interstitial waters. Now, both fres...

Development of Species Sensitivity Distributions for Wildlife Using Interspecies Toxicity Correlation Models

EPA Science Inventory

Species sensitivity distributions (SSD) are cumulative distributions of chemical toxicity of multiple species and have had limited application in wildlife risk assessment because of relatively small datasets of wildlife toxicity values. Interspecies correlation estimation (ICE) m...

Comparative Long-Term Toxicity of Libby Amphibole and Amosite Asbestos after Single or Multiple Intratracheal Exposures

EPA Science Inventory

In former mine workers of Libby, Montana, exposure to amphibole-containing vermiculite has been linked to increased rates of asbestosis, lung cancer, and mesothelioma. Although many studies have shown adverse effects of Libby Amphibole (LA) exposure, little is known regarding th...

Interaction of secalonic acid D with phenobarbital, 3-methyl cholanthrene, and SKF-525A in mice.

PubMed

Reddy, C S; Reddy, R V; Hayes, A W

1983-01-01

Secalonic acid D (SAD) is an acutely toxic and teratogenic fungal metabolite produced by Penicillium oxalium in corn and other cereal grains. Experiments were conducted to study the effects of single and multiple doses of SAD on pentobarbital-induced narcosis, as an index of the modulating effect of SAD on the hepatic drug metabolizing enzymes in mice. The effects of known enzyme modulators-phenobarbital (PB), 3-methyl cholanthrene (3-MC), and diethylaminoethyl diphenylproply acetate hydrochloride (SKF-525A)-on the acute toxicity of SAD in mice were also studied using body weights, mortality, and histopathology as indices. Results of this study failed to demonstrate any modulating effect by SAD of pentobarbital metabolizing enzymes. Pretreatment with SKF-525A, an enzyme inhibitor, enhanced SAD toxicity in mice, whereas pretreatment with PB or 3-MC, known enzyme inducers, had no effect. Further studies of interaction of [14C]SAD with PB and SKF-525A revealed that although neither PB nor SKF-525A altered the ratio of parent compound to total metabolites excreted in bile, SKF-525A significantly reduced the bile flow as well as the elimination of SAD-derived radioactivity in bile. These results strongly suggest the possibility that the effects of SKF-525A, other than the enzyme inhibition, may be responsible for its enhancement of SAD toxicity in mice.

Effects-based spatial assessment of contaminated estuarine sediments from Bear Creek, Baltimore Harbor, MD, USA.

PubMed

Hartzell, Sharon E; Unger, Michael A; McGee, Beth L; Wilson, Sacoby M; Yonkos, Lance T

2017-10-01

Estuarine sediments in regions with prolonged histories of industrial activity are often laden to significant depths with complex contaminant mixtures, including trace metals and persistent organic pollutants. Given the complexity of assessing risks from multi-contaminant exposures, the direct measurement of impacts to biological receptors is central to characterizing contaminated sediment sites. Though biological consequences are less commonly assessed at depth, laboratory-based toxicity testing of subsurface sediments can be used to delineate the scope of contamination at impacted sites. The extent and depth of sediment toxicity in Bear Creek, near Baltimore, Maryland, USA, was delineated using 10-day acute toxicity tests with the estuarine amphipod Leptocheirus plumulosus, and chemical analysis of trace metals and persistent organic pollutants. A gradient of toxicity was demonstrated in surface sediments with 21 of 22 tested sites differing significantly from controls. Effects were most pronounced (100% lethality) at sites proximate to a historic industrial complex. Sediments from eight of nine core samples to depths of 80 cm were particularly impacted (i.e., caused significant lethality to L. plumulosus) even in locations overlain with relatively non-toxic surface sediments, supporting a conclusion that toxicity observed at the surface (top 2 cm) does not adequately predict toxicity at depth. In seven of nine sites, toxicity of surface sediments differed from toxicity at levels beneath by 28 to 69%, in five instances underestimating toxicity (28 to 69%), and in two instances overestimating toxicity (44 to 56%). Multiple contaminants exceeded sediment quality guidelines and correlated positively with toxic responses within surface sediments (e.g., chromium, nickel, polycyclic aromatic hydrocarbon (PAH), total petroleum hydrocarbon). Use of an antibody-based PAH biosensor revealed that porewater PAH concentrations also increased with depth at most sites. This study informs future management decisions concerning the extent of impact to Bear Creek sediments, and demonstrates the benefits of a spatial approach, relying primarily on toxicity testing to assess sediment quality in a system with complex contaminant mixtures.

Dandelion root extract affects colorectal cancer proliferation and survival through the activation of multiple death signalling pathways

PubMed Central

Ovadje, Pamela; Ammar, Saleem; Guerrero, Jose-Antonio; Arnason, John Thor; Pandey, Siyaram

2016-01-01

Dandelion extracts have been studied extensively in recent years for its anti-depressant and anti-inflammatory activity. Recent work from our lab, with in-vitro systems, shows the anti-cancer potential of an aqueous dandelion root extract (DRE) in several cancer cell models, with no toxicity to non-cancer cells. In this study, we examined the cancer cell-killing effectiveness of an aqueous DRE in colon cancer cell models. Aqueous DRE induced programmed cell death (PCD) selectively in > 95% of colon cancer cells, irrespective of their p53 status, by 48 hours of treatment. The anti-cancer efficacy of this extract was confirmed in in-vivo studies, as the oral administration of DRE retarded the growth of human colon xenograft models by more than 90%. We found the activation of multiple death pathways in cancer cells by DRE treatment, as revealed by gene expression analyses showing the expression of genes implicated in programmed cell death. Phytochemical analyses of the extract showed complex multi-component composition of the DRE, including some known bioactive phytochemicals such as α-amyrin, β-amyrin, lupeol and taraxasterol. This suggested that this natural extract could engage and effectively target multiple vulnerabilities of cancer cells. Therefore, DRE could be a non-toxic and effective anti-cancer alternative, instrumental for reducing the occurrence of cancer cells drug-resistance. PMID:27564258

Volatile organic compounds released from Microcystis flos-aquae under nitrogen sources and their toxic effects on Chlorella vulgaris.

PubMed

Xu, Qinghuan; Yang, Lin; Yang, Wangting; Bai, Yan; Hou, Ping; Zhao, Jingxian; Zhou, Lv; Zuo, Zhaojiang

2017-01-01

Eutrophication promotes massive growth of cyanobacteria and algal blooms, which can poison other algae and reduce biodiversity. To investigate the differences in multiple nitrogen (N) sources in eutrophicated water on the emission of volatile organic compounds (VOCs) from cyanobacteria, and their toxic effects on other algal growth, we analyzed VOCs emitted from Microcystis flos-aquae with different types and concentrations of nitrogen, and determined the effects under Normal-N and Non-N conditions on Chlorella vulgaris. M. flos-aquae released 27, 22, 20, 27, 19, 25 and 17 compounds, respectively, with NaNO 3 , NaNO 2 , NH 4 Cl, urea, Ser, Lys and Arg as the sole N source. With the reduction in N amount, the emission of VOCs was increased markedly, and the most VOCs were found under Non-N condition. C. vulgaris cell propagation, photosynthetic pigment and Fv/Fm declined significantly following exposure to M. flos-aquae VOCs under Non-N condition, but not under Normal-N condition. When C. vulgaris cells were treated with two terpenoids, eucalyptol and limonene, the inhibitory effects were enhanced with increasing concentrations. Therefore, multiple N sources in eutrophicated water induce different VOC emissions from cyanobacteria, and reduction in N can cause nutrient competition, which can result in emissions of more VOCs. Those VOCs released from M. flos-aquae cells under Non-N for nutrient competition can inhibit other algal growth. Among those VOCs, eucalyptol and limonene are the major toxic agents. Copyright © 2016 Elsevier Inc. All rights reserved.

Computational ecotoxicology: simultaneous prediction of ecotoxic effects of nanoparticles under different experimental conditions.

PubMed

Kleandrova, Valeria V; Luan, Feng; González-Díaz, Humberto; Ruso, Juan M; Melo, André; Speck-Planche, Alejandro; Cordeiro, M Natália D S

2014-12-01

Nanotechnology has brought great advances to many fields of modern science. A manifold of applications of nanoparticles have been found due to their interesting optical, electrical, and biological/chemical properties. However, the potential toxic effects of nanoparticles to different ecosystems are of special concern nowadays. Despite the efforts of the scientific community, the mechanisms of toxicity of nanoparticles are still poorly understood. Quantitative-structure activity/toxicity relationships (QSAR/QSTR) models have just started being useful computational tools for the assessment of toxic effects of nanomaterials. But most QSAR/QSTR models have been applied so far to predict ecotoxicity against only one organism/bio-indicator such as Daphnia magna. This prevents having a deeper knowledge about the real ecotoxic effects of nanoparticles, and consequently, there is no possibility to establish an efficient risk assessment of nanomaterials in the environment. In this work, a perturbation model for nano-QSAR problems is introduced with the aim of simultaneously predicting the ecotoxicity of different nanoparticles against several assay organisms (bio-indicators), by considering also multiple measures of ecotoxicity, as well as the chemical compositions, sizes, conditions under which the sizes were measured, shapes, and the time during which the diverse assay organisms were exposed to nanoparticles. The QSAR-perturbation model was derived from a database containing 5520 cases (nanoparticle-nanoparticle pairs), and it was shown to exhibit accuracies of ca. 99% in both training and prediction sets. In order to demonstrate the practical applicability of our model, three different nickel-based nanoparticles (Ni) with experimental values reported in the literature were predicted. The predictions were found to be in very good agreement with the experimental evidences, confirming that Ni-nanoparticles are not ecotoxic when compared with other nanoparticles. The results of this study thus provide a single valuable tool toward an efficient prediction of the ecotoxicity of nanoparticles under multiple experimental conditions. Copyright © 2014 Elsevier Ltd. All rights reserved.

Multiple Applications of Alamar Blue as an Indicator of Metabolic Function and Cellular Health in Cell Viability Bioassays

PubMed Central

Rampersad, Sephra N.

2012-01-01

Accurate prediction of the adverse effects of test compounds on living systems, detection of toxic thresholds, and expansion of experimental data sets to include multiple toxicity end-point analysis are required for any robust screening regime. Alamar Blue is an important redox indicator that is used to evaluate metabolic function and cellular health. The Alamar Blue bioassay has been utilized over the past 50 years to assess cell viability and cytotoxicity in a range of biological and environmental systems and in a number of cell types including bacteria, yeast, fungi, protozoa and cultured mammalian and piscine cells. It offers several advantages over other metabolic indicators and other cytotoxicity assays. However, as with any bioassay, suitability must be determined for each application and cell model. This review seeks to highlight many of the important considerations involved in assay use and design in addition to the potential pitfalls. PMID:23112716

Polychaete richness and abundance enhanced in anthropogenically modified estuaries despite high concentrations of toxic contaminants.

PubMed

Dafforn, Katherine A; Kelaher, Brendan P; Simpson, Stuart L; Coleman, Melinda A; Hutchings, Pat A; Clark, Graeme F; Knott, Nathan A; Doblin, Martina A; Johnston, Emma L

2013-01-01

Ecological communities are increasingly exposed to multiple chemical and physical stressors, but distinguishing anthropogenic impacts from other environmental drivers remains challenging. Rarely are multiple stressors investigated in replicated studies over large spatial scales (>1000 kms) or supported with manipulations that are necessary to interpret ecological patterns. We measured the composition of sediment infaunal communities in relation to anthropogenic and natural stressors at multiple sites within seven estuaries. We observed increases in the richness and abundance of polychaete worms in heavily modified estuaries with severe metal contamination, but no changes in the diversity or abundance of other taxa. Estuaries in which toxic contaminants were elevated also showed evidence of organic enrichment. We hypothesised that the observed response of polychaetes was not a 'positive' response to toxic contamination or a reduction in biotic competition, but due to high levels of nutrients in heavily modified estuaries driving productivity in the water column and enriching the sediment over large spatial scales. We deployed defaunated field-collected sediments from the surveyed estuaries in a small scale experiment, but observed no effects of sediment characteristics (toxic or enriching). Furthermore, invertebrate recruitment instead reflected the low diversity and abundance observed during field surveys of this relatively 'pristine' estuary. This suggests that differences observed in the survey are not a direct consequence of sediment characteristics (even severe metal contamination) but are related to parameters that covary with estuary modification such as enhanced productivity from nutrient inputs and the diversity of the local species pool. This has implications for the interpretation of diversity measures in large-scale monitoring studies in which the observed patterns may be strongly influenced by many factors that covary with anthropogenic modification.

Polychaete Richness and Abundance Enhanced in Anthropogenically Modified Estuaries Despite High Concentrations of Toxic Contaminants

PubMed Central

Dafforn, Katherine A.; Kelaher, Brendan P.; Simpson, Stuart L.; Coleman, Melinda A.; Hutchings, Pat A.; Clark, Graeme F.; Knott, Nathan A.; Doblin, Martina A.; Johnston, Emma L.

2013-01-01

Ecological communities are increasingly exposed to multiple chemical and physical stressors, but distinguishing anthropogenic impacts from other environmental drivers remains challenging. Rarely are multiple stressors investigated in replicated studies over large spatial scales (>1000 kms) or supported with manipulations that are necessary to interpret ecological patterns. We measured the composition of sediment infaunal communities in relation to anthropogenic and natural stressors at multiple sites within seven estuaries. We observed increases in the richness and abundance of polychaete worms in heavily modified estuaries with severe metal contamination, but no changes in the diversity or abundance of other taxa. Estuaries in which toxic contaminants were elevated also showed evidence of organic enrichment. We hypothesised that the observed response of polychaetes was not a ‘positive’ response to toxic contamination or a reduction in biotic competition, but due to high levels of nutrients in heavily modified estuaries driving productivity in the water column and enriching the sediment over large spatial scales. We deployed defaunated field-collected sediments from the surveyed estuaries in a small scale experiment, but observed no effects of sediment characteristics (toxic or enriching). Furthermore, invertebrate recruitment instead reflected the low diversity and abundance observed during field surveys of this relatively ‘pristine’ estuary. This suggests that differences observed in the survey are not a direct consequence of sediment characteristics (even severe metal contamination) but are related to parameters that covary with estuary modification such as enhanced productivity from nutrient inputs and the diversity of the local species pool. This has implications for the interpretation of diversity measures in large-scale monitoring studies in which the observed patterns may be strongly influenced by many factors that covary with anthropogenic modification. PMID:24098816

Hydra viridissima (green Hydra) rapidly recovers from multiple magnesium pulse exposures.

PubMed

Prouse, Andrea E; Hogan, Alicia C; Harford, Andrew J; van Dam, Rick A; Nugegoda, Dayanthi

2015-08-01

The time taken for organisms to recover from a pulsed toxicant exposure is an important consideration when water quality guidelines are applied to intermittent events in the environment. Organisms may appear to have recovered by standard toxicity testing methods but could carry residual toxicant or damage that may make them more sensitive to subsequent pulses. Such cumulative effects may render guidelines underprotective. The present study evaluated recovery of the freshwater cnidarian Hydra viridissima following multiple pulse exposure to magnesium (Mg). The H. viridissima were exposed to 4-h pulses of 790 mg/L and 1100 mg/L separated by 2-h, 10-h, 18-h, 24-h, 48-h, and 72-h recovery periods. Twenty-four-hour pulses of 570 mg/L, 910 mg/L, and 940 mg/L were separated by 24-h, 96-h, and 168-h recovery periods. All treatments showed similar or reduced sensitivity to the second pulse when compared with the single pulse, indicating that full recovery occurred prior to a second pulse-exposure. Five variations of equivalent time-weighted average concentrations were used to compare sensitivity of Hydra with various pulse scenarios. The sensitivity of the organisms to the multiple pulses was significantly lower than the time-weighted average continuous exposure response in 3 of the 4 scenarios tested, indicating that the Hydra benefited from interpulse recovery periods. The findings will be utilized alongside those from other species to inform the use of a site-specific, duration-based water quality guideline for Mg, and they provide an example of the use of empirical data in the regulation of toxicant pulses in the environment. © 2015 Commonwealth of Australia.

Radiotherapy.

PubMed

Krause, Sonja; Debus, Jürgen; Neuhof, Dirk

2011-01-01

Solitary plasmocytoma occurring in bone (solitary plasmocytoma of the bone, SBP) or in soft tissue (extramedullary plasmocytoma, EP) can be treated effectively and with little toxicity by local radiotherapy. Ten-year local control rates of up to 90% can be achieved. Patients with multiple myeloma often suffer from symptoms such as pain or neurological impairments that are amenable to palliative radiotherapy. In a palliative setting, short treatment schedules and lower radiation doses are used to reduce toxicity and duration of hospitalization. In future, low-dose total body irradiation (TBI) may play a role in a potentially curative regimen with nonmyeloablative conditioning followed by allogenic peripheral blood stem cell transplantation.

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

Many si/shRNAs can kill cancer cells by targeting multiple survival genes through an off-target mechanism

PubMed Central

van Dongen, Stijn; Haluck-Kangas, Ashley; Sarshad, Aishe A; Bartom, Elizabeth T; Kim, Kwang-Youn A; Scholtens, Denise M; Hafner, Markus; Zhao, Jonathan C; Murmann, Andrea E

2017-01-01

Over 80% of multiple-tested siRNAs and shRNAs targeting CD95 or CD95 ligand (CD95L) induce a form of cell death characterized by simultaneous activation of multiple cell death pathways preferentially killing transformed and cancer stem cells. We now show these si/shRNAs kill cancer cells through canonical RNAi by targeting the 3’UTR of critical survival genes in a unique form of off-target effect we call DISE (death induced by survival gene elimination). Drosha and Dicer-deficient cells, devoid of most miRNAs, are hypersensitive to DISE, suggesting cellular miRNAs protect cells from this form of cell death. By testing 4666 shRNAs derived from the CD95 and CD95L mRNA sequences and an unrelated control gene, Venus, we have identified many toxic sequences - most of them located in the open reading frame of CD95L. We propose that specific toxic RNAi-active sequences present in the genome can kill cancer cells. PMID:29063830

Toxic alveolitis after inhalation of a water repellent.

PubMed

Epping, Guido; Van Baarlen, Joop; Van Der Valk, Paul D L P M

2011-12-01

Inhalation of fluorocarbon polymers can cause pulmonary toxicity. Although multiple cases of lung injury have been reported, cellular characterization of the associated alveolitis occurring acutely after inhalation is limited. We report the case of a previously healthy woman who presented at our Emergency Department with an acute pneumonitis following inhalation of a fluorocarbon polymer-based rain-proofing spray. Bronchoalveolar lavage (BAL) performed shortly after the presentation showed an elevated total cell count, with a high proportion of neutrophils (58%) and eosinophils (9%). In addition, a lipid stain (Oil-Red-O-stain) showed a high level of lipid laden macrophages, a marker that could reflect a direct toxic effect of the spray on alveolar cells. The patient made a full recovery after four days of in-hospital observation with supportive care.

JS-K, a GST-activated nitric oxide donor prodrug, enhances chemo-sensitivity in renal carcinoma cells and prevents cardiac myocytes toxicity induced by Doxorubicin.

PubMed

Qiu, Mingning; Ke, Longzhi; Zhang, Sai; Zeng, Xin; Fang, Zesong; Liu, Jianjun

2017-08-01

Doxorubicin, a highly effective and widely used anthracycline antibiotic in multiple chemotherapy regimens, has been limited by its cardiotoxicity. The aim of this study is to investigate the effect of nitric oxide donor prodrug JS-K on proliferation and apoptosis in renal carcinoma cells and cardiac myocytes toxicity induced by Doxorubicin and to explore possible p53-related mechanism in renal carcinoma cells. The effect of JS-K on anti-cancer activity of Doxorubicin was investigated in renal carcinoma cells via detecting cell proliferation, cytotoxicity, cell death and apoptosis and expressions of apoptotic-related proteins. Effect of p53 on the combination of JS-K and Doxorubicin was determined using p53 inhibitor Pifithrin-α and p53 activator III. Furthermore, the effect of JS-K on cardiac myocytes toxicity of Doxorubicin was investigated in H9c2 (2-1) cardiac myocytes via measuring cell growth, cell death and apoptosis, expressions of proteins involved in apoptosis and intracellular reactive oxygen species. We demonstrated that JS-K could increase Doxorubicin-induced renal carcinoma cell growth suppression and apoptosis and could increase expressions of proteins that are involved in apoptosis. Additionally, Pifithrin-α reversed the promoting effect of JS-K on Doxorubicin-induced renal carcinoma cell apoptosis; conversely, the p53 activator III exacerbated the promoting effect of JS-K on Doxorubicin-induced renal carcinoma cell apoptosis. Furthermore, JS-K protected H9c2 (2-1) cardiac myocytes against Doxorubicin-induced toxicity and decreased Doxorubicin-induced reactive oxygen species production. JS-K enhances the anti-cancer activity of Doxorubicin in renal carcinoma cells by upregulating p53 expression and prevents cardiac myocytes toxicity of Doxorubicin by decreasing oxidative stress.

Interspecies Correlation Estimation (ICE) models predict supplemental toxicity data for SSDs

EPA Science Inventory

Species sensitivity distributions (SSD) require a large number of toxicity values for a diversity of taxa to define a hazard level protective of multiple species. For most chemicals, measured toxicity data are limited to a few standard test species that are unlikely to adequately...

Comparison of Species Sensitivity Distributions Derived from Interspecies Correlation Models to Distributions used to Derive Water Quality Criteria

EPA Science Inventory

Species sensitivity distributions (SSD) require a large number of measured toxicity values to define a chemical’s toxicity to multiple species. This investigation comprehensively evaluated the accuracy of SSDs generated from toxicity values predicted from interspecies correlation...

The environment and male reproduction: The effect of cadmium exposure on reproductive function and its implication in fertility.

PubMed

de Angelis, Cristina; Galdiero, Mariano; Pivonello, Claudia; Salzano, Ciro; Gianfrilli, Daniele; Piscitelli, Prisco; Lenzi, Andrea; Colao, Annamaria; Pivonello, Rosario

2017-10-01

Cadmium is an environmental pollutant known as endocrine disruptor. Testis is particularly susceptible to cadmium, and testis injury occurs at high but even low levels of exposure. Cadmium reproductive toxicity is mediated by multiple mechanisms, including structural damage to testis vasculature and blood-testis barrier, inflammation, cytotoxicity on Sertoli and Leydig cells, oxidative stress mainly by means of mimicry and interference with essential ions, apoptosis, interference with selected signaling pathways and epigenetic regulation of genes involved in the regulation of reproductive function, and disturbance of the hypothalamus-pituitary-gonadal axis. The current review outlines epidemiological observational findings from environmental and occupational exposure in humans, and reports experimental studies in humans and animals. Lastly, a focus on the pathogenetic mechanisms of cadmium toxicity and on the specific mechanisms of cadmium sensitivity and resistance, particularly assessed in animal models, is included. Despite convincing experimental findings in animals and supporting evidences in humans identifying cadmium as reproductive toxicant, observational findings are controversial, suffering from heterogeneity of study design and pattern of exposure, and from co-exposure to multiple pollutants. Copyright © 2017 Elsevier Inc. All rights reserved.

Multilevel eEmpirical Bayes modeling for improved estimation of toxicant formulations tosuppress parasitic sea lamprey in the Upper Great Lakes

USGS Publications Warehouse

Hatfield, Laura A.; Gutreuter, Steve; Boogaard, Michael A.; Carlin, Bradley P.

2011-01-01

Estimation of extreme quantal-response statistics, such as the concentration required to kill 99.9% of test subjects (LC99.9), remains a challenge in the presence of multiple covariates and complex study designs. Accurate and precise estimates of the LC99.9 for mixtures of toxicants are critical to ongoing control of a parasitic invasive species, the sea lamprey, in the Laurentian Great Lakes of North America. The toxicity of those chemicals is affected by local and temporal variations in water chemistry, which must be incorporated into the modeling. We develop multilevel empirical Bayes models for data from multiple laboratory studies. Our approach yields more accurate and precise estimation of the LC99.9 compared to alternative models considered. This study demonstrates that properly incorporating hierarchical structure in laboratory data yields better estimates of LC99.9 stream treatment values that are critical to larvae control in the field. In addition, out-of-sample prediction of the results of in situ tests reveals the presence of a latent seasonal effect not manifest in the laboratory studies, suggesting avenues for future study and illustrating the importance of dual consideration of both experimental and observational data.

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

The effect of administering multiple doses of tall larkspur (Delphinium barbeyi) to cattle

USDA-ARS?s Scientific Manuscript database

Larkspurs (Delphinium spp.) are one of the most serious toxic plant problems on foothill and mountain rangelands in the western U.S. A considerable amount of research has been conducted over the years in both field and pen settings. The results of these research efforts have significantly increased ...

Toxicity testing of restorative dental materials using brine shrimp larvae (Artemia salina).

PubMed

Milhem, Manar M; Al-Hiyasat, Ahmad S; Darmani, Homa

2008-01-01

This study investigated the effect of extracts of different composites, glass ionomer cement (GIC)s and compomers on the viability of brine shrimp larvae. Ethanolic extracts of four dental composites (Z-100; Solitaire 2; Filtek P60 and Synergy), a conventional GIC (Ketac-Fil), a resin-modified glass ionomer cement (Vitremer), two compomers (F2000; Dyract AP), and a flowable compomer (Dyract Flow) were prepared from each material. Following evaporation of the ethanol, the extracts were resuspended in distilled water, which was then used to test the effects on the viability of brine shrimp larvae. For the composites, the extract of Synergy was the least toxic (88% viability) followed by the extracts of Solitaire 2, Z100 and P60 (75%, 67.5% and 50% viability, respectively). One-way ANOVA revealed highly significant differences between the resin composite materials (p<0.001). Follow-up comparison between the composite groups by Tukey's pairwise multiple-comparison test (alpha =0.05) showed that the extract of Synergy was significantly less toxic than the extracts of all the other materials except that of Solitaire 2. The compomers showed 100% lethality, while the percentage of viable larvae for the extracts of Ketac-Fil, and Vitremer were 32.3%, and 37.0%, respectively. One-way ANOVA revealed highly significant differences between the groups of materials (p<0.001). Follow-up comparison between the groups by Tukey's test (alpha = 0.05) showed that the toxic effect of the extracts of the compomers were significantly greater than that of Ketac-Fil, and Vitremer. The differences in the toxic effects of Vitremer and Ketac-Fil were not statistically significant. In conclusion, the toxicity of composite materials varied according to their chemical composition. Compomers were the most lethal materials to brine shrimp larvae followed by GICs and then composites.

Efficacy and toxicity profile of carfilzomib based regimens for treatment of multiple myeloma: A systematic review.

PubMed

Mushtaq, Adeela; Kapoor, Vikas; Latif, Azka; Iftikhar, Ahmad; Zahid, Umar; McBride, Ali; Abraham, Ivo; Riaz, Irbaz Bin; Anwer, Faiz

2018-05-01

Standard induction therapy for multiple myeloma is three-drug combination based on following classes of drugs: proteasome inhibitors, immunomodulators and steroids. Despite its notable efficacy, bortezomib has side effects like peripheral neuropathy (PNP) with reported incidence of grade ≥3 PNP between 2%-23% Schlafer et al., 2017. Carfilzomib (CFZ) has high selectivity and minimal off-target adverse effects including lower rates of PNP. CFZ is already approved for treatment of relapsed and refractory multiple myeloma (RRMM) as single agent as well as in combination with lenalidomide and/or dexamethasone. Extensive literature search identified a total of 1839 articles. Twenty-six articles (n = 5980) met the inclusion criteria, 15 in newly diagnosed multiple myeloma (NDMM) and 11 in RRMM group. CFZ demonstrates comparable or even better efficacy to bortezomib with much favorable AE profile. Deep, rapid and sustainable response using KRd with safer toxicity profile supports extension of KRd therapy to frontline therapy for all risk categories of MM. High incidence of grade ≥3 HTN underscores the importance of serial BP monitoring. In RRMM, CFZ has documented efficacy with standard 20-27mg/m2 dose. Further large-scale trials are needed to study benefit-to-risk profile of 20-56 and 20-70 mg/m2 dose of CFZ vs standard 20-27 mg/m2 dose in NDMM and RRMM. Copyright © 2018 Elsevier B.V. All rights reserved.

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.

Acute Toxicity of Ternary Cd-Cu-Ni and Cd-Ni-Zn Mixtures to Daphnia magna: Dominant Metal Pairs Change along a Concentration Gradient.

PubMed

Traudt, Elizabeth M; Ranville, James F; Meyer, Joseph S

2017-04-18

Multiple metals are usually present in surface waters, sometimes leading to toxicity that currently is difficult to predict due to potentially non-additive mixture toxicity. Previous toxicity tests with Daphnia magna exposed to binary mixtures of Ni combined with Cd, Cu, or Zn demonstrated that Ni and Zn strongly protect against Cd toxicity, but Cu-Ni toxicity is more than additive, and Ni-Zn toxicity is slightly less than additive. To consider multiple metal-metal interactions, we exposed D. magna neonates to Cd, Cu, Ni, or Zn alone and in ternary Cd-Cu-Ni and Cd-Ni-Zn combinations in standard 48 h lethality tests. In these ternary mixtures, two metals were held constant, while the third metal was varied through a series that ranged from nonlethal to lethal concentrations. In Cd-Cu-Ni mixtures, the toxicity was less than additive, additive, or more than additive, depending on the concentration (or ion activity) of the varied metal and the additivity model (concentration-addition or independent-action) used to predict toxicity. In Cd-Ni-Zn mixtures, the toxicity was less than additive or approximately additive, depending on the concentration (or ion activity) of the varied metal but independent of the additivity model. These results demonstrate that complex interactions of potentially competing toxicity-controlling mechanisms can occur in ternary-metal mixtures but might be predicted by mechanistic bioavailability-based toxicity models.

ABC transporters and the proteasome complex are implicated in susceptibility to Stevens-Johnson syndrome and toxic epidermal necrolysis across multiple drugs.

PubMed

Nicoletti, Paola; Bansal, Mukesh; Lefebvre, Celine; Guarnieri, Paolo; Shen, Yufeng; Pe'er, Itsik; Califano, Andrea; Floratos, Aris

2015-01-01

Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) represent rare but serious adverse drug reactions (ADRs). Both are characterized by distinctive blistering lesions and significant mortality rates. While there is evidence for strong drug-specific genetic predisposition related to HLA alleles, recent genome wide association studies (GWAS) on European and Asian populations have failed to identify genetic susceptibility alleles that are common across multiple drugs. We hypothesize that this is a consequence of the low to moderate effect size of individual genetic risk factors. To test this hypothesis we developed Pointer, a new algorithm that assesses the aggregate effect of multiple low risk variants on a pathway using a gene set enrichment approach. A key advantage of our method is the capability to associate SNPs with genes by exploiting physical proximity as well as by using expression quantitative trait loci (eQTLs) that capture information about both cis- and trans-acting regulatory effects. We control for known bias-inducing aspects of enrichment based analyses, such as: 1) gene length, 2) gene set size, 3) presence of biologically related genes within the same linkage disequilibrium (LD) region, and, 4) genes shared among multiple gene sets. We applied this approach to publicly available SJS/TEN genome-wide genotype data and identified the ABC transporter and Proteasome pathways as potentially implicated in the genetic susceptibility of non-drug-specific SJS/TEN. We demonstrated that the innovative SNP-to-gene mapping phase of the method was essential in detecting the significant enrichment for those pathways. Analysis of an independent gene expression dataset provides supportive functional evidence for the involvement of Proteasome pathways in SJS/TEN cutaneous lesions. These results suggest that Pointer provides a useful framework for the integrative analysis of pharmacogenetic GWAS data, by increasing the power to detect aggregate effects of multiple low risk variants. The software is available for download at https://sourceforge.net/projects/pointergsa/.

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

PubMed

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

2015-11-01

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

Comparing probabilistic and descriptive analyses of time–dose–toxicity relationship for determining no-observed-adverse-effect level in drug development

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

Glatard, Anaïs; Berges, Aliénor; Sahota, Tarjinder

The no-observed-adverse-effect level (NOAEL) of a drug defined from animal studies is important for inferring a maximal safe dose in human. However, several issues are associated with its concept, determination and application. It is confined to the actual doses used in the study; becomes lower with increasing sample size or dose levels; and reflects the risk level seen in the experiment rather than what may be relevant for human. We explored a pharmacometric approach in an attempt to address these issues. We first used simulation to examine the behaviour of the NOAEL values as determined by current common practice; andmore » then fitted the probability of toxicity as a function of treatment duration and dose to data collected from all applicable toxicology studies of a test compound. Our investigation was in the context of an irreversible toxicity that is detected at the end of the study. Simulations illustrated NOAEL's dependency on experimental factors such as dose and sample size, as well as the underlying uncertainty. Modelling the probability as a continuous function of treatment duration and dose simultaneously to data from multiple studies allowed the estimation of the dose, along with its confidence interval, for a maximal risk level that might be deemed as acceptable for human. The model-based data integration also reconciled between-study inconsistency and explicitly provided maximised estimation confidence. Such alternative NOAEL determination method should be explored for its more efficient data use, more quantifiable insight to toxic doses, and the potential for more relevant animal-to-human translation. - Highlights: • Simulations revealed issues with NOAEL concept, determination and application. • Probabilistic modelling was used to address these issues. • The model integrated time-dose-toxicity data from multiple studies. • The approach uses data efficiently and may allow more meaningful human translation.« less

Predictions of sediment toxicity using consensus-based freshwater sediment quality guidelines

USGS Publications Warehouse

Ingersoll, C.G.; MacDonald, D.D.; Wang, N.; Crane, J.L.; Field, L.J.; Haverland, P.S.; Kemble, N.E.; Lindskoog, R.A.; Severn, C.; Smorong, D.E.

2001-01-01

The objectives of this study were to compare approaches for evaluating the combined effects of chemical mixtures on the toxicity in field-collected sediments and to evaluate the ability of consensus-based probable effect concentrations (PECs) to predict toxicity in a freshwater database on both a national and regional geographic basis. A database was developed from 92 published reports, which included a total of 1,657 samples with high-quality matching sediment toxicity and chemistry data from across North America. The database was comprised primarily of 10- to 14-day or 28- to 42-day toxicity tests with the amphipod Hyalella azteca (designated as the HA10 or HA28 tests) and 10- to 14-day toxicity tests with the midges Chironomus tentans or C. riparius (designated as the CS10 test). Mean PEC quotients were calculated to provide an overall measure of chemical contamination and to support an evaluation of the combined effects of multiple contaminants in sediments. There was an overall increase in the incidence of toxicity with an increase in the mean quotients in all three tests. A consistent increase in the toxicity in all three tests occurred at a mean quotient > 0.5, however, the overall incidence of toxicity was greater in the HA28 test compared to the short-term tests. The longer-term tests, in which survival and growth are measured, tend to be more sensitive than the shorter-term tests, with acute to chronic ratios on the order of six indicated for H. azteca. Different patterns were observed among the various procedures used to calculate mean quotients. For example, in the HA28 test, a relatively abrupt increase in toxicity was associated with elevated polychlorinated biphenyls (PCBs) alone or with elevated polycyclic aromatic hydrocarbons (PAHs) alone, compared to the pattern of a gradual increase in toxicity observed with quotients calculated using a combination of metals, PAHs, and PCBs. These analyses indicate that the different patterns in toxicity may be the result of unique chemical signals associated with individual contaminants in samples. Though mean quotients can be used to classify samples as toxic or nontoxic, individual quotients might be useful in helping identify substances that may be causing or substantially contributing to the observed toxicity. An increase in the incidence of toxicity was observed with increasing mean quotients within most of the regions, basins, and areas in North America for all three toxicity tests. The results of these analyses indicate that the consensus-based PECs can be used to reliably predict toxicity of sediments on both a regional and national basis.

Laboratory toxicity and benthic invertebrate field colonization of Upper Columbia River sediments: Finding adverse effects using multiple lines of evidence

USGS Publications Warehouse

Fairchild, J.F.; Kemble, N.E.; Allert, A.L.; Brumbaugh, W.G.; Ingersoll, C.G.; Dowling, B.; Gruenenfelder, C.; Roland, J.L.

2012-01-01

From 1930 to 1995, the Upper Columbia River (UCR) of northeast Washington State received approximately 12 million metric tons of smelter slag and associated effluents from a large smelter facility located in Trail, British Columbia, approximately 10 km north of the United States–Canadian border. Studies conducted during the past two decades have demonstrated the presence of toxic concentrations of heavy metals in slag-based sandy sediments, including cadmium, copper, zinc, and lead in the UCR area as well as the downstream reservoir portion of Lake Roosevelt. We conducted standardized whole-sediment toxicity tests with the amphipod Hyalella azteca (28-day) and the midge Chironomus dilutus (10-day) on 11 samples, including both UCR and study-specific reference sediments. Metal concentrations in sediments were modeled for potential toxicity using three approaches: (1) probable effects quotients (PEQs) based on total recoverable metals (TRMs) and simultaneously extracted metals (SEMs); (2) SEMs corrected for acid-volatile sulfides (AVS; i.e., ∑SEM − AVS); and (3) ∑SEM − AVS normalized to the fractional organic carbon (foc) (i.e., ∑SEM − AVS/foc). The most highly metal-contaminated sample (∑PEQTRM = 132; ∑PEQSEM = 54; ∑SEM − AVS = 323; and ∑SEM − AVS/foc = 64,600 umol/g) from the UCR was dominated by weathered slag sediment particles and resulted in 80% mortality and 94% decrease in biomass of amphipods; in addition, this sample significantly decreased growth of midge by 10%. The traditional ∑AVS – SEM, uncorrected for organic carbon, was the most accurate approach for estimating the effects of metals in the UCR. Treatment of the toxic slag sediment with 20% Resinex SIR-300 metal-chelating resin significantly decreased the toxicity of the sample. Samples ∑SEM − AVS > 244 was not toxic to amphipods or midge in laboratory testing, indicating that this value may be an approximate threshold for effects in the UCR. In situ benthic invertebrate colonization studies in an experimental pond (8-week duration) indicated that two of the most metal-contaminated UCR sediments (dominated by high levels of sand-sized slag particles) exhibited decreased invertebrate colonization compared with sand-based reference sediments. Field-exposed SIR-300 resin samples also exhibited decreased invertebrate colonization numbers compared with reference materials, which may indicate behavioral avoidance of this material under field conditions. Multiple lines of evidence (analytical chemistry, laboratory toxicity, and field colonization results), along with findings from previous studies, indicate that high metal concentrations associated with slag-enriched sediments in the UCR are likely to adversely impact the growth and survival of native benthic invertebrate communities. Additional laboratory toxicity testing, refinement of the applications of sediment benchmarks for metal toxicity, and in situ benthic invertebrate studies will assist in better defining the spatial extent, temporal variations, and ecological impacts of metal-contaminated sediments in the UCR system.

New technologies and approaches in toxicity testing and risk assessment (ESOT)

EPA Science Inventory

The release of the National Research Council’s Report “Toxicity Testing in the 21st Century: A Vision and a Strategy” in 2007 initiated a broad-based movement in the toxicology community to re-think how toxicity testing and risk assessment are performed. Multiple efforts in the ...

Web-based Interspecies Correlation Estimation (Web-ICE) for Acute Toxicity: User Manual Version 3.3

EPA Science Inventory

Information on the acute toxicity to multiple species is needed for the assessment of the risks to, and the protection of, individuals, populations, and ecological communities. However, toxicity data are limited for the majority of species, while standard test species are general...

Control of aliphatic halogenated DBP precursors with multiple drinking water treatment processes: Formation potential and integrated toxicity.

PubMed

Zhang, Yimeng; Chu, Wenhai; Yao, Dechang; Yin, Daqiang

2017-08-01

The comprehensive control efficiency for the formation potentials (FPs) of a range of regulated and unregulated halogenated disinfection by-products (DBPs) (including carbonaceous DBPs (C-DBPs), nitrogenous DBPs (N-DBPs), and iodinated DBPs (I-DBPs)) with the multiple drinking water treatment processes, including pre-ozonation, conventional treatment (coagulation-sedimentation, pre-sand filtration), ozone-biological activated carbon (O 3 -BAC) advanced treatment, and post-sand filtration, was investigated. The potential toxic risks of DBPs by combing their FPs and toxicity values were also evaluated. The results showed that the multiple drinking water treatment processes had superior performance in removing organic/inorganic precursors and reducing the formation of a range of halogenated DBPs. Therein, ozonation significantly removed bromide and iodide, and thus reduced the formation of brominated and iodinated DBPs. The removal of organic carbon and nitrogen precursors by the conventional treatment processes was substantially improved by O 3 -BAC advanced treatment, and thus prevented the formation of chlorinated C-DBPs and N-DBPs. However, BAC filtration leads to the increased formation of brominated C-DBPs and N-DBPs due to the increase of bromide/DOC and bromide/DON. After the whole multiple treatment processes, the rank order for integrated toxic risk values caused by these halogenated DBPs was haloacetonitriles (HANs)≫haloacetamides (HAMs)>haloacetic acids (HAAs)>trihalomethanes (THMs)>halonitromethanes (HNMs)≫I-DBPs (I-HAMs and I-THMs). I-DBPs failed to cause high integrated toxic risk because of their very low FPs. The significant higher integrated toxic risk value caused by HANs than other halogenated DBPs cannot be ignored. Copyright © 2017. Published by Elsevier B.V.

Retrospective Analysis of Opioid Medication Incidents Requiring Administration of Naloxone

PubMed Central

Neil, Katherine; Marcil, Allison; Kosar, Lynette; Dumont, Zack; Ruda, Lisa; McMillan, Kaitlyn

2013-01-01

Background: Opioid analgesics are high-alert medications known to cause adverse drug events. Objectives: The purpose of this study was to determine the cause of opioid incidents requiring administration of naloxone, an opioid reversal agent. The specific objectives were to determine the number of opioid incidents and the proportion of incidents documented through occurrence reporting and to characterize the incidents by phase in the medication-use process, by type of incident, and by drug responsible for toxic effects. Methods: A retrospective chart analysis was conducted using records from 2 acute care centres in the Regina Qu’Appelle Health Region. The study included inpatients who received naloxone for reversal of opioid toxicity resulting from licit, in-hospital opioid use. Cases were classified as preventable or nonpreventable. Preventable cases were analyzed to determine the phase of the medication-use process during which the incident occurred. These cases were also grouped thematically by the type of incident. The drug most likely responsible for opioid toxicity was determined for each case. The proportion of cases documented by occurrence reporting was also noted. Results: Thirty-six cases involving administration of naloxone were identified, of which 29 (81%) were deemed preventable. Of these 29 preventable cases, the primary medication incident occurred most frequently in the prescribing phase (23 [79%]), but multiple phases were often involved. The cases were grouped into 6 themes according to the type of incident. Morphine was the drug that most frequently resulted in toxic effects (18 cases [50%]). Only two of the cases (5.6%) were documented by occurrence reports. Conclusion: Preventable opioid incidents occurred in the acute care centres under study. A combination of medication safety initiatives involving multiple disciplines may be required to decrease the incidence of these events and to better document their occurrence. PMID:24159230

Ameliorating activity of ginger (Zingiber officinale) extract against lead induced renal toxicity in male rats.

PubMed

Reddy, Y Amarnath; Chalamaiah, M; Ramesh, B; Balaji, G; Indira, P

2014-05-01

Lead poisoning has been known to be associated with structural and functional abnormalities of multiple organ systems of human body. The aim of this investigation was to study the renal protective effects of ginger (Zingiber officinale) extract in lead induced toxicity rats. In this study renal glutathione (GSH) level, glutathione peroxidase (GPX), glutathione-s-transferase (GST), and catalase enzymes were measured in lead nitrate (300 mg/kg BW), and lead nitrate plus ginger extract (150 mg/kg BW) treated rat groups for 1 week and 3 weeks respectively. The glutathione level and GSH dependent antioxidant enzymes such as glutathione peroxidase, glutathione-s-transferase, and catalase significantly (P < 0.05) increased in ginger extract treated rat groups. In addition, histological studies showed lesser renal changes in lead plus ginger extract treated rat groups than that of lead alone treated rat groups. These results indicate that ginger extract alleviated lead toxic effects by enhancing the levels of glutathione, glutathione peroxidase, glutathione-s-transferase and catalase.

Nutrients versus emerging contaminants-Or a dynamic match between subsidy and stress effects on stream biofilms.

PubMed

Aristi, I; Casellas, M; Elosegi, A; Insa, S; Petrovic, M; Sabater, S; Acuña, V

2016-05-01

Freshwater ecosystems are threatened by multiple anthropogenic stressors, which might be differentiated into two types: those that reduce biological activity at all concentrations (toxic contaminants), and those that subsidize biological activity at low concentrations and reduce it at high concentrations (assimilable contaminants). When occurring in mixtures, these contaminants can have either antagonistic, neutral or synergistic effects; but little is known on their joint effects. We assessed the interaction effects of a mixture of assimilable and toxic contaminants on stream biofilms in a manipulative experiment using artificial streams, and following a factorial design with three nutrient levels (low, medium or high) and either presence or absence of a mixture of emerging contaminants (ciprofloxacin, erythromycin, diclofenac, methylparaben, and sulfamethoxazole). We measured biofilm biomass, basal fluorescence, gross primary production and community respiration. Our initial hypotheses were that biofilm biomass and activity would: increase with medium nutrient concentrations (subsidy effect), but decrease with high nutrient concentrations (stress effect) (i); decrease with emerging contaminants, with the minimum decrease at medium nutrient concentrations (antagonistic interaction between nutrients subsidy and stress by emerging contaminants) and the maximum decrease at high nutrient concentrations (synergistic interaction between nutrients and emerging contaminants stress) (ii). All the measured variables responded linearly to the available nutrients, with no toxic effect at high nutrient concentrations. Emerging contaminants only caused weak toxic effects in some of the measured variables, and only after 3-4 weeks of exposure. Therefore, only antagonistic interactions were observed between nutrients and emerging contaminants, as medium and high nutrient concentrations partly compensated the harmful effects of emerging contaminants during the first weeks of the experiment. Our results show that contaminants with a subsidy effect can alleviate the effects of toxic contaminants, and that long-term experiments are required to detect stress effects of emerging contaminants at environmentally relevant concentrations. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

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

PubMed Central

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

2016-01-01

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

Modern Radiobiology: Contention Of Concepts: Advanced Technology And Development Of Effective Prophylaxis, Prevention And Treatment Of Biological Consequences After Irradiation.

NASA Astrophysics Data System (ADS)

Popov, Dmitri; Maliev, Vecheslav; Jones, Jeffrey

"Alle Ding' sind Gift, und nichts ohn' Gift; allein die Dosis macht, daß ein Ding kein Gift ist." Paracelsus Philippus Aureolus Theophrastus Bombastus von Hohenheim. Key worlds: Apoptosis, Necrosis, Domains associated with Cell Death, Caspase (catalytic) Domains, Death Domains (DDs), Death Effector Domains (DEDs), Caspase-Associated Recruitment Domains (CARDs, BIR Domains (IAPs), Bcl-2 Homology (BH) Domains, death ligands - TRAIL (TNF-Related Apoptosis-Inducing Ligand), FasL (Fas Ligand), TNFalpha (Tumor Necrosis Factor alpha), Toll-like receptors (TLR), Systemic inflammatory response syndrome (SIRS), Toxic Multiple Organ Injury (TMOI), Toxic Multiple Organ Dysfunction Syndromes (TMODS), Toxic Multiple Organ Failure (TMOF), Anaphylatoxins, or complement peptides; membrane attack complex (MAC), ROS - Reactive Oxygen Species; ASMase, acid sphingomyelinase; Neurotoxins, Cytotoxins, Haemotoxins. Introduction: Radiation affects many cell structures, organelles and metabolic pathways. Different doses and types of radiation ( gamma-radiation, neutron, heavy ion radiation) progress to reversible and irreversible forms of cell injury. Consideration: Apoptosis and Necrosis, major forms of post-radiation cell death, can be initiated and modulated by programmed control and proceed by similar or different pathways.[Akadi et al.,1993, Dunlacht J., et al. 1999] Radiation induced cell death by triggering apoptosis pathways was described in many articles and supported by many scientists. [Rio et al. 2002, Rakesh et al. 1997.] However some authors present results that two distinct pathways can initiate or apoptotic or necrotic responses: the death receptors and mitochondrial pathways.

Pharmacology and Toxicology of N-Benzylphenethylamine ("NBOMe") Hallucinogens.

PubMed

Halberstadt, Adam L

2017-01-01

Serotonergic hallucinogens induce profound changes in perception and cognition. The characteristic effects of hallucinogens are mediated by 5-HT 2A receptor activation. One class of hallucinogens are 2,5-dimethoxy-substituted phenethylamines, such as the so-called 2C-X compounds 2,5-dimethoxy-4-bromophenethylamine (2C-B) and 2,5-dimethoxy-4-iodophenethylamine (2C-I). Addition of an N-benzyl group to phenethylamine hallucinogens produces a marked increase in 5-HT 2A -binding affinity and hallucinogenic potency. N-benzylphenethylamines ("NBOMes") such as N-(2-methoxybenzyl)-2,5-dimethoxy-4-iodophenethylamine (25I-NBOMe) show subnanomolar affinity for the 5-HT 2A receptor and are reportedly highly potent in humans. Several NBOMEs have been available from online vendors since 2010, resulting in numerous cases of toxicity and multiple fatalities. This chapter reviews the structure-activity relationships, behavioral pharmacology, metabolism, and toxicity of members of the NBOMe hallucinogen class. Based on a review of 51 cases of NBOMe toxicity reported in the literature, it appears that rhabdomyolysis is a relatively common complication of severe NBOMe toxicity, an effect that may be linked to NBOMe-induced seizures, hyperthermia, and vasoconstriction.

Nutraceuticals against Neurodegeneration: A Mechanistic Insight.

PubMed

Dadhania, Vivekkumar P; Trivedi, Priyanka P; Vikram, Ajit; Tripathi, Durga Nand

2016-01-01

The mechanisms underlying neurodegenerative disorders are complex and multifactorial; however, accumulating evidences suggest few common shared pathways. These common pathways include mitochondrial dysfunction, intracellular Ca2+ overload, oxidative stress and inflammation. Often multiple pathways co-exist, and therefore limit the benefits of therapeutic interventions. Nutraceuticals have recently gained importance owing to their multifaceted effects. These food-based approaches are believed to target multiple pathways in a slow but more physiological manner without causing severe adverse effects. Available information strongly supports the notion that apart from preventing the onset of neuronal damage, nutraceuticals can potentially attenuate the continued progression of neuronal destruction. In this article, we i) review the common pathways involved in the pathogenesis of the toxicants-induced neurotoxicity and neurodegenerative disorders with special emphasis on Alzheimer`s disease (AD), Parkinson`s disease (PD), Huntington`s disease (HD), Multiple sclerosis (MS) and Amyotrophic lateral sclerosis (ALS), and ii) summarize current research advancements on the effects of nutraceuticals against these detrimental pathways.

Nutraceuticals against Neurodegeneration: A Mechanistic Insight

PubMed Central

Dadhania, Vivekkumar P.; Trivedi, Priyanka P.; Vikram, Ajit; Tripathi, Durga Nand

2016-01-01

The mechanisms underlying neurodegenerative disorders are complex and multifactorial; however, accumulating evidences suggest few common shared pathways. These common pathways include mitochondrial dysfunction, intracellular Ca2+ overload, oxidative stress and inflammation. Often multiple pathways co-exist, and therefore limit the benefits of therapeutic interventions. Nutraceuticals have recently gained importance owing to their multifaceted effects. These food-based approaches are believed to target multiple pathways in a slow but more physiological manner without causing severe adverse effects. Available information strongly supports the notion that apart from preventing the onset of neuronal damage, nutraceuticals can potentially attenuate the continued progression of neuronal destruction. In this article, we i) review the common pathways involved in the pathogenesis of the toxicants-induced neurotoxicity and neurodegenerative disorders with special emphasis on Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Multiple sclerosis (MS) and Amyotrophic lateral sclerosis (ALS), and ii) summarize current research advancements on the effects of nutraceuticals against these detrimental pathways. PMID:26725888

NMR-based urine analysis in rats: prediction of proximal tubule kidney toxicity and phospholipidosis.

PubMed

Lienemann, Kai; Plötz, Thomas; Pestel, Sabine

2008-01-01

The aim of safety pharmacology is early detection of compound-induced side-effects. NMR-based urine analysis followed by multivariate data analysis (metabonomics) identifies efficiently differences between toxic and non-toxic compounds; but in most cases multiple administrations of the test compound are necessary. We tested the feasibility of detecting proximal tubule kidney toxicity and phospholipidosis with metabonomics techniques after single compound administration as an early safety pharmacology approach. Rats were treated orally, intravenously, inhalatively or intraperitoneally with different test compounds. Urine was collected at 0-8 h and 8-24 h after compound administration, and (1)H NMR-patterns were recorded from the samples. Variation of post-processing and feature extraction methods led to different views on the data. Support Vector Machines were trained on these different data sets and then aggregated as experts in an Ensemble. Finally, validity was monitored with a cross-validation study using a training, validation, and test data set. Proximal tubule kidney toxicity could be predicted with reasonable total classification accuracy (85%), specificity (88%) and sensitivity (78%). In comparison to alternative histological studies, results were obtained quicker, compound need was reduced, and very importantly fewer animals were needed. In contrast, the induction of phospholipidosis by the test compounds could not be predicted using NMR-based urine analysis or the previously published biomarker PAG. NMR-based urine analysis was shown to effectively predict proximal tubule kidney toxicity after single compound administration in rats. Thus, this experimental design allows early detection of toxicity risks with relatively low amounts of compound in a reasonably short period of time.

Neurotoxic effects of ecstasy on the thalamus.

PubMed

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

2008-10-01

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

The SED-TOX: Toxicity-directed management tool to assess and rank sediments based on their hazard -- concept and application

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

Bombardier, M.; Bermingham, N.

1999-04-01

This article introduces the sediment Toxicity (SED-TOX) Index for the assessment and ranking of toxic hazards in sediment. Major features include expression of toxicity responses on a single scale of measurement (dry weight-based toxic units), consideration of multiple routes of exposure (pore water, organic extract, wet sediment, and whole sediment), application of differential treatments to toxicity data depending on the level of response, and use of weighting factors to discriminate sediment exposure phases and effect endpoints on the basis of sensitivity. A battery of seven bioassays with four test species (Vibrio fischeri, Escherichia coli, Lytechinus pictus, and Amphiporeia virginiana) wasmore » conducted on 49 marine sediment samples collected from six sites at Anse-a-Beaufils and Cap-aux-Meules, which are in the Gulf of St. Lawrence. The SED-TOX scores were calculated for each sampling station and compared with sediment contaminant concentrations. Results indicate that physico-chemical characterization is not sufficient to assess contaminated-sediment hazard for organisms; furthermore, using several exposure phases and test species belonging to various trophic levels increases the possibility of correctly identifying toxic sediments. The results of this study indicate that the SED-TOX approach is valuable as a toxicity assessment and ranking tool for sediments. It could easily be combined with other measures of ecosystem disturbance to discriminate between polluted and unpolluted sites.« less

Electric cell-substrate impedance sensing (ECIS) based real-time measurement of titer dependent cytotoxicity induced by adenoviral vectors in an IPI-2I cell culture model.

PubMed

Müller, Jakob; Thirion, Christian; Pfaffl, Michael W

2011-01-15

Recombinant viral vectors are widespread tools for transfer of genetic material in various modern biotechnological applications like for example RNA interference (RNAi). However, an accurate and reproducible titer assignment represents the basic step for most downstream applications regarding a precise multiplicity of infection (MOI) adjustment. As necessary scaffold for the studies described in this work we introduce a quantitative real-time PCR (qPCR) based approach for viral particle measurement. Still an implicated problem concerning physiological effects is that the appliance of viral vectors is often attended by toxic effects on the individual target. To determine the critical viral dose leading to cell death we developed an electric cell-substrate impedance sensing (ECIS) based assay. With ECIS technology the impedance change of a current flow through the cell culture medium in an array plate is measured in a non-invasive manner, visualizing effects like cell attachment, cell-cell contacts or proliferation. Here we describe the potential of this online measurement technique in an in vitro model using the porcine ileal epithelial cell line IPI-2I in combination with an adenoviral transfection vector (Ad5-derivate). This approach shows a clear dose-depending toxic effect, as the amount of applied virus highly correlates (p<0.001) with the level of cell death. Thus this assay offers the possibility to discriminate the minimal non-toxic dose of the individual transfection method. In addition this work suggests that the ECIS-device bears the feasibility to transfer this assay to multiple other cytotoxicological questions. Copyright © 2010 Elsevier B.V. All rights reserved.

Ternary copper(II) complex: NCI60 screening, toxicity studies, and evaluation of efficacy in xenograft models of nasopharyngeal carcinoma.

PubMed

Ahmad, Munirah; Suhaimi, Shazlan-Noor; Chu, Tai-Lin; Abdul Aziz, Norazlin; Mohd Kornain, Noor-Kaslina; Samiulla, D S; Lo, Kwok-Wai; Ng, Chew-Hee; Khoo, Alan Soo-Beng

2018-01-01

Copper(II) ternary complex, [Cu(phen)(C-dmg)(H2O)]NO3 was evaluated against a panel of cell lines, tested for in vivo efficacy in nasopharyngeal carcinoma xenograft models as well as for toxicity in NOD scid gamma mice. The Cu(II) complex displayed broad spectrum cytotoxicity against multiple cancer types, including lung, colon, central nervous system, melanoma, ovarian, and prostate cancer cell lines in the NCI-60 panel. The Cu(II) complex did not cause significant induction of cytochrome P450 (CYP) 3A and 1A enzymes but moderately inhibited CYP isoforms 1A2, 2C9, 2C19, 2D6, 2B6, 2C8 and 3A4. The complex significantly inhibited tumor growth in nasopharyngeal carcinoma xenograft bearing mice models at doses which were well tolerated without causing significant or permanent toxic side effects. However, higher doses which resulted in better inhibition of tumor growth also resulted in toxicity.

Comparative toxicity of two Iodophors to rainbow trout eggs

USGS Publications Warehouse

Amend, Donald F.

1974-01-01

Toxicity of Wescodyne(R) and Betadine(R) to eyed eggs was not adversely affected by water hardness (as calcium and magnesium) or by exposure periods up to 60 min. Both iodophors were much more toxic below pH 6.0 than at pH 8.0. In general Wescodyne was slightly more toxic than Betadine. Significant egg loss occurred if freshly fertilized eggs were water-hardened in either iodophor at 100 ppm of iodine, but egg loss at 25 ppm of iodine or at 100 ppm if the eggs were disinfected 30 min after water hardening was comparable to the control. Also, there was no effect on the egg mortality or fry development following single or multiple exposures after eggs were water hardened. At pH 6.0 and above, Wescodyne and Betadine at 100 ppm iodine in a 15-min dip would be safe to use on rainbow trout eggs at any stage of development after water hardening. Recommendations and precautions for hatchery use are given.

Deformable microparticles with multiple functions for drug delivery and device testing

NASA Astrophysics Data System (ADS)

Thula, Taili T.

Since the HIV epidemic of the 1990s, researchers have attempted to develop a red blood cell analog. Even though some of these substitutes are now in Phase III of clinical trials, their use is limited by side effects and short half-life in the human body. As a result, there is still a need for an effective erythrocyte analog with minimum immunogenic and side effects, so that it can be used for multiple applications. Finding new approaches to develop more efficient blood substitutes will not only bring valuable advances in the clinical approach, but also in the area of in vitro testing of medical devices. We examined the feasibility of creating a deformable multi-functional, biodegradable, biocompatible particle for applications in drug delivery and device testing. As a preliminary evaluation, we synthesized different types of microcapsules using natural and synthetic polymers, various cross-linking agents, and diverse manufacturing techniques. After fully characterizing of each system, we determined the most promising red blood cell analog in terms of deformability, stability and toxicity. We also examined the encapsulation and release of bovine serum albumin (BSA) within these deformable particles. After removal of cross-linkers, zinc- and copper-alginate microparticles surrounded by multiple polyelectrolyte layers of chitosan oligosaccharide and alginate were deformable and remained stable under physiological pressures applied by the micropipette technique. In addition, multiple coatings decreased toxicity of heavy-metal crosslinked particles. BSA encapsulation and release from chitosan-alginate microspheres were contingent on the crosslinker and number of polyelectrolyte coatings, respectively. Further rheological studies are needed to determine how closely these particles simulate the behavior of erythrocytes. Also, studies on the encapsulation and release of different proteins, including hemoglobin, are needed to establish the desired controlled release of bioactive agents for the proposed delivery system.

Environmental pollutants and lifestyle factors induce oxidative stress and poor prenatal development.

PubMed

Al-Gubory, Kaïs H

2014-07-01

Developmental toxicity caused by exposure to a mixture of environmental pollutants has become a major health concern. Human-made chemicals, including xenoestrogens, pesticides and heavy metals, as well as unhealthy lifestyle behaviours, mainly tobacco smoking, alcohol consumption and medical drug abuse, are major factors that adversely influence prenatal development and increase susceptibility of offspring to diseases. There is evidence to suggest that the developmental toxicological mechanisms of chemicals and lifestyle factors involve the generation of reactive oxygen species (ROS) and cellular oxidative damage. Overproduction of ROS induces oxidative stress, a state where increased ROS generation overwhelms antioxidant protection and subsequently leads to oxidative damage of cellular macromolecules. Data on the involvement of oxidative stress in the mechanism of developmental toxicity following exposure to environmental pollutants are reviewed in an attempt to provide an updated basis for future studies on the toxic effect of such pollutants, particularly the notion of increased risk for developmental toxicity due to combined and cumulative exposure to various environmental pollutants. The aims of such studies are to better understand the mechanisms by which environmental pollutants adversely affect conceptus development and to elucidate the impact of cumulative exposures to multiple pollutants on post-natal development and health outcomes. Developmental toxicity caused by exposure to mixture of environmental pollutants has become a major health concern. Human-made chemicals, including xenoestrogens, pesticides and heavy metals, as well as unhealthy lifestyle behaviors, mainly tobacco smoking, alcohol consumption and medical drug abuse, are major factors that adversely influence prenatal development and increase the susceptibility of offspring to development complications and diseases. There is evidence to suggest that the developmental toxicological mechanisms of human-made chemicals and unhealthy lifestyle factors involve the generation of reactive oxygen species (ROS) and cellular oxidative damage. Overproduction of ROS induces oxidative stress, a state where increased generation of ROS overwhelms antioxidant protection and subsequently leads to oxidative damage of cellular macromolecules. Exposure to various environmental pollutants induces synergic and cumulative dose-additive adverse effects on prenatal development, pregnancy outcomes and neonate health. Data from the literature on the involvement of oxidative stress in the mechanism of developmental toxicity following in vivo exposure to environmental pollutants will be reviewed in an attempt to provide an updated basis for future studies on the toxic effect of such pollutants, particularly the notion of increased risk for developmental toxicity due to combined and cumulative exposure to various environmental pollutants. The aims of such studies are to better understand the mechanisms by which environmental pollutants adversely affect conceptus development and to elucidate the impact of cumulative exposures to multiple pollutants on postnatal development and health outcomes. Copyright © 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Technical basis for using passive sampling as a biomimetic extraction procedure to assess bioavailability and predict toxicity of petroleum substances.

PubMed

Redman, A D; Butler, J D; Letinski, D J; Di Toro, D M; Leon Paumen, M; Parkerton, T F

2018-05-01

Solid-phase microextraction fibers coated with polydimethylsiloxane (PDMS) provide a convenient passive sampling format to characterize bioavailability of petroleum substances. Hydrocarbons absorb onto PDMS in proportion to both freely dissolved concentrations and partitioning properties of the individual constituents, which parallels the mechanistic basis used to predict aquatic toxicity in the PETROTOX model. When deployed in a non-depletive manner, combining SPME with thermal desorption and quantification using gas chromatography-flame ionization creates a biomimetic extraction (BE) procedure that has the potential to simplify aquatic hazard assessments of petroleum substances since the total moles of all hydrocarbons sorbed to the fiber can be related to toxic thresholds in target lipid of aquatic organisms. The objective of this work is to describe the technical basis for applying BE measurements to predict toxicity of petroleum substances. Critical BE-based PDMS concentrations corresponding to adverse effects were empirically derived from toxicity tests on different petroleum substances with multiple test species. The resulting species sensitivity distribution (SSD) of PDMS effect concentrations was then compared and found consistent with the previously reported target lipid-based SSD. Further, BE data collected on samples of aqueous media dosed with a wide range of petroleum substances were highly correlated to predicted toxic units derived using the PETROTOX model. These findings provide justification for applying BE in environmental hazard and risk evaluations of petroleum substances and related mixtures. Copyright © 2018 Elsevier Ltd. All rights reserved.

Administering multiple doses of a non N-(methylsuccinimido) anthranoyllycoctonine (MSAL)-containing tall larkspur (Delphinium occidentale) to cattle

USDA-ARS?s Scientific Manuscript database

Larkspurs (Delphinium spp.) are a serious toxic plant problem for cattle in western North America. There are two chemotypes in the tall larkspur Delphinium occidentale, a more toxic chemotype and a less toxic chemotype. These chemotypes differ in the composition and concentrations of key alkaloids. ...

TOXIC POLLUTANTS IN URBAN WET-WEATHER FLOWS: AN OVERVIEW OF THE MULTI-MEDIA TRANSPORT, IMPACTS, AND CONTROL MEASURES

EPA Science Inventory

This paper presents an overview of the transport of toxic pollutants through multiple media and drainage systems in the urban watershed during wet-weather periods. It includes the origin of the toxic substances; their transport via atmospheric depositon, overland washoff, and urb...

TOXIC POLLUTANTS IN URBAN WET-WEATHER FLOWS: AN OVERVIEW OF THE MULTI-MEDIA TRANSPORT, IMPACTS, AND CONTROL MEASURES

EPA Science Inventory

This paper presents an overview of the transport of toxic pollutants through multiple media and drainage systems in the urban watershed during wet-weather periods. It includes the origin of the toxic substances; their transport via atmospheric deposition, overland washoff, and ur...

Understanding Genetic Toxicity Through Data Mining: The Process of Building Knowledge by Integrating Multiple Genetic Toxicity Databases

EPA Science Inventory

This paper demonstrates the usefulness of representing a chemical by its structural features and the use of these features to profile a battery of tests rather than relying on a single toxicity test of a given chemical. This paper presents data mining/profiling methods applied in...

Effects of acquisition, loss, and neofunctionalization of trichothecene biosynthetic genes on variation in trichothecene structure, pathway regulation, and self-protection mechanisms in the Hypocreales

USDA-ARS?s Scientific Manuscript database

Trichothecenes are secondary metabolites produced by multiple genera in the order Hypocreales, including Fusarium, Myrothecium, Stachybotrys, and Trichoderma. These metabolites are of concern because they are toxic to humans and animals, can contribute to pathogenicity in Fusarium, and are required ...

Environmentally-Relevant Mixtures in Cumulative Assessments: An Acute Study of Toxicokinetics and Effects on Motor Activity in Rats Exposed to a Mixture of Pyrethroids

EPA Science Inventory

Due to extensive use, human exposure to multiple pyrethroid insecticides occurs frequently. Studies of pyrethroid neurotoxicity suggest a common mode of toxicity and that pyrethroids should be considered cumulatively to model risk. The objective of this work was to use a pyrethro...

Modeling Biogeochemical Cycling of Heavy Metals in Lake Coeur d'Alene Sediments

NASA Astrophysics Data System (ADS)

Sengor, S. S.; Spycher, N.; Belding, E.; Curthoys, K.; Ginn, T. R.

2005-12-01

Mining of precious metals since the late 1800's have left Lake Coeur d'Alene (LCdA) sediments heavily enriched with toxic metals, including Cd, Cu, Pb, and Zn. Indigenous microbes however are capable of catalyzing reactions that detoxify the benthic and aqueous lake environments, and thus constitute an important driving component in the biogeochemical cycles of these metals. Here we report on the development of a quantitative model of transport, fate, exposure and effects of toxic compounds on benthic microbial communities at LCdA. First, chemical data from the LCdA area have been compiled from multiple sources to investigate trends in chemical occurrence, as well as to define model boundary conditions. The model is structured as 1-D diffusive reactive transport model to simulate spatial and temporal distribution of metals through the benthic sediments. Inorganic reaction processes included in the model are aqueous speciation, surface complexation, mineral precipitation/dissolution and abiotic redox reactions. Simulations with and without surface complexation are carried out to evaluate the effect of sorption and the conservative behaviour of metals within the benthic sediments under abiotic and purely diffusive transport. The 1-D inorganic diffusive transport model is then coupled to a biotic reaction network including consortium biodegradation kinetics with multiple electron acceptors, product toxicity, and energy partitioning. Multiyear simulations are performed, with water column chemistry established as a boundary condition from extant data, to explore the role of biogeochemical dynamics on benthic fluxes of metals in the long term.

Field Validation of Toxicity Tests to Evaluate the Potential for Beneficial Use of Produced Water

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

Joseph Bidwell; Jonathan Fisher; Naomi Cooper

2008-03-31

This study investigated potential biological effects of produced water contamination derived from occasional surface overflow and possible subsurface intrusion at an oil production site along the shore of Skiatook Lake, Oklahoma. We monitored basic chemistry and acute toxicity to a suite of standard aquatic test species (fathead minnow-Pimephales promelas, Daphnia pulex, Daphnia magna, and Ceriodaphnia dubia) in produced water and in samples taken from shallow groundwater wells on the site. Toxicity identification evaluations and ion toxicity modeling were used to identify toxic constituents in the samples. Lake sediment at the oil production site and at a reference site were alsomore » analyzed for brine intrusion chemically and by testing sediment toxicity using the benthic invertebrates, Chironomus dilutus, and Hyallela azteca. Sediment quality was also assessed with in situ survival and growth studies with H. azteca and the Asian clam, Corbicula fluminea, and by benthic macroinvertebrate community sampling. The produced water was acutely toxic to the aquatic test organisms at concentrations ranging from 1% to 10% of the whole produced water sample. Toxicity identification evaluation and ion toxicity modeling indicated major ion salts and hydrocarbons were the primary mixture toxicants. The standardized test species used in the laboratory bioassays exhibited differences in sensitivity to these two general classes of contaminants, which underscores the importance of using multiple species when evaluating produced water toxicity. Toxicity of groundwater was greater in samples from wells near a produced water injection well and an evaporation pond. Principle component analyses (PCA) of chemical data derived from the groundwater wells indicated dilution by lake water and possible biogeochemical reactions as factors that ameliorated groundwater toxicity. Elevated concentrations of major ions were found in pore water from lake sediments, but toxicity from these ions was limited to sediment depths of 10 cm or greater, which is outside of the primary zone of biological activity. Further, exposure to site sediments did not have any effects on test organisms, and macroinvertebrate communities did not indicate impairment at the oil production site as compared to a reference site. In situ experiments with H. azteca and C. fluminea, indicated a sublethal site effect (on growth of both species), but these could not be definitively linked with produced water infiltration. Severe weather conditions (drought followed by flooding) negatively influenced the intensity of lake sampling aimed at delineating produced water infiltration. Due to the lack of clear evidence of produced water infiltration into the sub-littoral zone of the lake, it was not possible to assess whether the laboratory bioassays of produced water effectively indicate risk in the receiving system. However, the acutely toxic nature of the produced water and general lack of biological effects in the lake at the oil production site suggest minimal to no produced water infiltration into surficial lake sediments and the near-shore water column. This study was able to demonstrate the utility of ion toxicity modeling to support data from toxicity identification evaluations aimed at identifying key toxic constituents in produced water. This information could be used to prioritize options for treating produced water in order to reduce toxic constituents and enhance options for reuse. The study also demonstrated how geographic information systems, toxicity modeling, and toxicity assessment could be used to facilitate future site assessments.« less

Multiple system atrophy following chronic carbon disulfide exposure.

PubMed Central

Frumkin, H

1998-01-01

Carbon disulfide toxicity is well characterized. The principal target organ is the nervous system, although cardiovascular, reproductive, ophthalmologic, and other effects are also recognized. The neurotoxicity manifests in three ways: encephalopathy, peripheral and cranial nerve dysfunction, and movement abnormalities. This report describes a case of olivopontocerebellar atrophy, a form of multiple system atrophy, developing in an adult after over 30 years of occupational exposure to carbon disulfide. The patient presented with the insidious onset of balance problems, impotence, and irritability, without tremor, cogwheel rigidity, bradykinesia, or changes in facial expression. Over the next few years severe ataxia developed, and the clinical diagnosis was confirmed with computed tomography and magnetic resonance imaging scans. The patient experienced multiple medical complications and died approximately 9 years after diagnosis. This case is consistent with a large body of clinical and experimental literature, much of it 50 years old, showing that carbon disulfide can cause movement disorders. It also serves as a reminder that movement disorders, ranging from parkinsonism to dystonia, are associated with a variety of toxic exposures such as manganese, carbon monoxide, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and medications. Images Figure 1 PMID:9721261

Immuno-therapy of Acute Radiation Syndromes : Extracorporeal Immuno-Lympho-Plasmo-Sorption.

NASA Astrophysics Data System (ADS)

Popov, Dmitri; Maliev, Slava

Methods Results Summary and conclusions Introduction: Existing Medical Management of the Acute Radiation Syndromes (ARS) does not include methods of specific immunotherapy and active detoxication. Though the Acute Radiation Syndromes were defined as an acute toxic poisonous with development of pathological processes: Systemic Inflammatory Response Syndrome (SIRS), Toxic Multiple Organ Injury (TMOI), Toxic Multiple Organ Dysfunction Syndrome(TMODS), Toxic Multiple Organ Failure (TMOF). Radiation Toxins of SRD Group play an important role as the trigger mechanisms in development of the ARS clinical symptoms. Methods: Immuno-Lympho-Plasmo-Sorption is a type of Immuno-therapy which includes prin-ciples of immunochromato-graphy, plasmopheresis, and hemodialysis. Specific Antiradiation Antitoxic Antibodies are the active pharmacological agents of immunotherapy . Antiradia-tion Antitoxic Antibodies bind selectively to Radiation Neurotoxins, Cytotoxins, Hematotox-ins and neutralize their toxic activity. We have developed the highly sensitive method and system for extracorporeal-immune-lypmh-plasmo-sorption with antigen-specific IgG which is clinically important for treatment of the toxic and immunologic phases of the ARS. The method of extracorporeal-immune-lypmh-plasmo-sorption includes Antiradiation Antitoxic Antibodies (AAA) immobilized on microporous polymeric membranes with a pore size that is capable to provide diffusion of blood-lymph plasma. Plasma of blood or lymph of irradiated mammals contains Radiation Toxins (RT) that have toxic and antigenic properties. Radiation Toxins are Antigen-specific to Antitoxic blocking antibodies (Immunoglobulin G). Plasma diffuses through membranes with immobilized AAA and AA-antibodies bind to the polysaccharide chain of tox-ins molecules and complexes of AAA-RT that are captured on membrane surfaces. RT were removed from plasma. Re-transfusion of plasma of blood and lymph had been provided. We show a statistical significant reduction in postradiation lethality.

[Subcutaneous bortezomib as a new promising way to successful maintenance therapy in multiple myeloma].

PubMed

Grosicki, Sebastian

2012-01-01

Multiple myeloma (MM) despite the introduction to clinical practice of a new drugs in the last years, and still searching of new points of the handle for targeting treatment, remaining incurable disease. Even most intensive and most modern induction-consolidation regimens is not in the state to eradicate of the clone of myeloma, and even complete remission in immunofixation the most often after some time ends progression. Optimal way of maintenance treatment is still searching, which would be maximally effective near acceptable toxicity. Now hypothesis about possible successful maintenance therapy, which may prolong survival of MM patients became more actual in the face of the introduction to the studies with maintenance of a new drugs as: thalidomide, lenalidomide and bortesomib. The expectations on the essential progress to establish the optimal bortesomib-based regimen of the maintenance treatment in MM cause the results of the studies with its subcutaneous administration, which proved comparable efficacy with advantage in toxicity profile, especially neurological in comparison to classic intravenous way.

Birds and flame retardants: A review of the toxic effects on birds of historical and novel flame retardants.

PubMed

Guigueno, Mélanie F; Fernie, Kim J

2017-04-01

Flame retardants (FRs) are a diverse group of chemicals, many of which persist in the environment and bioaccumulate in biota. Although some FRs have been withdrawn from manufacturing and commerce (e.g., legacy FRs), many continue to be detected in the environment; moreover, their replacements and/or other novel FRs are also detected in biota. Here, we review and summarize the literature on the toxic effects of various FRs on birds. Birds integrate chemical information (exposure, effects) across space and time, making them ideal sentinels of environmental contamination. Following an adverse outcome pathway (AOP) approach, we synthesized information on 8 of the most commonly reported endpoints in avian FR toxicity research: molecular measures, thyroid-related measures, steroids, retinol, brain anatomy, behaviour, growth and development, and reproduction. We then identified which of these endpoints appear more/most sensitive to FR exposure, as determined by the frequency of significant effects across avian studies. The avian thyroid system, largely characterized by inconsistent changes in circulating thyroid hormones that were the only measure in many such studies, appears to be moderately sensitive to FR exposure relative to the other endpoints; circulating thyroid hormones, after reproductive measures, being the most frequently examined endpoint. A more comprehensive examination with concurrent measurements of multiple thyroid endpoints (e.g., thyroid gland, deiodinase enzymes) is recommended for future studies to more fully understand potential avian thyroid toxicity of FRs. More research is required to determine the effects of various FRs on avian retinol concentrations, inconsistently sensitive across species, and to concurrently assess multiple steroid hormones. Behaviour related to courtship and reproduction was the most sensitive of all selected endpoints, with significant effects recorded in every study. Among domesticated species (Galliformes), raptors (Accipitriformes and Falconiformes), songbirds (Passeriformes), and other species of birds (e.g. gulls), raptors seem to be the most sensitive to FR exposure across these measurements. We recommend that future avian research connect biochemical disruptions and changes in the brain to ecologically relevant endpoints, such as behaviour and reproduction. Moreover, connecting in vivo endpoints with molecular endpoints for non-domesticated avian species is also highly important, and essential to linking FR exposure with reduced fitness and population-level effects. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

Thalidomide plus oral melphalan compared with thalidomide alone for advanced multiple myeloma.

PubMed

Offidani, Massimo; Corvatta, Laura; Marconi, Monica; Olivieri, Attilio; Catarini, Massimo; Mele, Anna; Brunori, Marino; Candela, Marco; Malerba, Lara; Capelli, Debora; Montanari, Mauro; Leoni, Pietro

2004-01-01

Thalidomide, the prototype of a new class of agents active against multiple myeloma (MM), exerts synergistic/additive effects when combined with other drugs. The aim of this study was to compare the toxicity and efficacy of thalidomide alone and in combination with oral melphalan. Patients with advanced MM received 100 mg/day oral thalidomide escalated weekly up to 600 mg/day (n=23; T group), alone or with 0.20 oral mg/kg/die melphalan administered monthly for four consecutive days (n=27; TM group). A>/=50% paraprotein reduction was observed in 59% of TM compared with 26% of T patients (P=0.009); three TM patients were found to have an absence of paraprotein by immunofixation. After a median follow-up of 13 months (range 6-32), progression-free survival (PFS) at 2 years was significantly longer in the TM group (61 versus 45%; P=0.0376), whereas overall survival did not differ significantly. Toxicity was not significantly greater with the combination therapy; although DVT was more frequent (11 versus 4%), as was grade 3 leukopenia (30 versus 13%; P=0.073), there were no cases of severe infection. Thalidomide administered with oral melphalan improved response rates and PFS in patients with advanced MM without significantly increasing severe toxicity.

Multilevel Empirical Bayes Modeling for Improved Estimation of Toxicant Formulations to Suppress Parasitic Sea Lamprey in the Upper Great Lakes

USGS Publications Warehouse

Hatfield, L.A.; Gutreuter, S.; Boogaard, M.A.; Carlin, B.P.

2011-01-01

Estimation of extreme quantal-response statistics, such as the concentration required to kill 99.9% of test subjects (LC99.9), remains a challenge in the presence of multiple covariates and complex study designs. Accurate and precise estimates of the LC99.9 for mixtures of toxicants are critical to ongoing control of a parasitic invasive species, the sea lamprey, in the Laurentian Great Lakes of North America. The toxicity of those chemicals is affected by local and temporal variations in water chemistry, which must be incorporated into the modeling. We develop multilevel empirical Bayes models for data from multiple laboratory studies. Our approach yields more accurate and precise estimation of the LC99.9 compared to alternative models considered. This study demonstrates that properly incorporating hierarchical structure in laboratory data yields better estimates of LC99.9 stream treatment values that are critical to larvae control in the field. In addition, out-of-sample prediction of the results of in situ tests reveals the presence of a latent seasonal effect not manifest in the laboratory studies, suggesting avenues for future study and illustrating the importance of dual consideration of both experimental and observational data. ?? 2011, The International Biometric Society.

Chemical interaction: enhancement and inhibition of clastogenicity.

PubMed Central

Anwar, W A

1993-01-01

Most environmental exposures involve concurrent or sequential exposure to multiple chemicals in air, water, and food. Interactive effects in carcinogenesis have been described for certain combinations of agents. They are described in terms of enhancement or inhibition of carcinogenesis. Enhancement effects have been documented for cigarette smoking in combination with exposure to asbestos, radon, alcohol, or other exposures. A variety of inhibitors of carcinogenesis have also been described. They are classified into agents preventing formation of carcinogens; blocking agents; and suppressing agents. Assessment of risk from exposure to multiple agents can be derived either from epidemiological studies in relation to actual exposure or from laboratory studies after controlled exposure to different agents. Prediction of how toxic components of mixtures will interact should be based on an understanding of the mechanisms of such interactions. Compounds may interact chemically, yielding new toxic components or causing a change in the biological availability of the existing components or metabolites. In humans, great individual variability in response is to be expected because of genetic heterogeneity or acquired host susceptibility factors. Interaction is thus a key component in the risk assessment process. In this paper, the definition of interaction and the theoretical basis for different types of interaction in cancer causation are reviewed. Epidemiological and experimental studies showing interactive effects of two chemical carcinogens are also presented. PMID:8143617

Do Biopesticides Affect the Demographic Traits of a Parasitoid Wasp and Its Biocontrol Services through Sublethal Effects?

PubMed Central

Biondi, Antonio; Zappalà, Lucia; Stark, John D.; Desneux, Nicolas

2013-01-01

Pesticide risk assessments are usually based on short-term acute toxicity tests, while longer-term population dynamic related traits, critical to the success of biological control and Integrated Pest Management (IPM) programs, are often overlooked. This is increasingly important with respect to new biopesticides that frequently cause no short-term acute effects, but that can induce multiple physiological and behavioral sublethal effects, leading to a decrease in population growth and ecosystem services. In this study we assessed the lethal and sublethal effects of six biopesticides [abamectin, azadirachtin, Bacillus thuringiensis, borax plus citrus oil (Prev-Am®), emamectin benzoate, and spinosad], used in tomato crops to control the invasive pest Tuta absoluta (Lepidoptera: Gelechiidae), on adults and pupae of the parasitoid Bracon nigricans (Hymenoptera: Braconidae). Data on female survival and production of female offspring were used to calculate population growth indexes as a measure of population recovery after pesticide exposure. Spinosad caused 100% and 80% mortality in exposed adults (even 10 d after the treatment) and pupae, respectively. Although most of the biopesticides had low levels of acute toxicity, multiple sublethal effects were observed. The biocontrol activity of both females that survived 1-h and 10-d old residues, and females that emerged from topically treated pupae was significantly affected by the application of the neurotoxic insecticides emamectin benzoate and abamectin. Furthermore, very low B. nigricans demographic growth indices were estimated for these two insecticides, indicating potential local extinction of the wasp populations. Among the tested products, Bt proved to be the safest for B. nigricans adults and pupae. Our findings emphasize that acute toxicity assessment alone cannot fully predict the actual impact of pesticides on non-target parasitoids. Thus, sublethal effects related to the species specific life-history variables must be carefully considered in order to assess pesticide risks and to incorporate new pesticides, including biopesticides, into IPM programmes. PMID:24098793

Biological activity of selenium: Revisited.

PubMed

Wrobel, Jagoda K; Power, Ronan; Toborek, Michal

2016-02-01

Selenium (Se) is an essential micronutrient that exerts multiple and complex effects on human health. Se is essential for human well-being largely due to its potent antioxidant, anti-inflammatory, and antiviral properties. The physiological functions of Se are carried out by selenoproteins, in which Se is specifically incorporated as the amino acid, selenocysteine. Importantly, both beneficial and toxic effects of Se have been reported suggesting that the mode of action of Se is strictly chemical form and concentration dependent. Additionally, there is a relatively narrow window between Se deficiency and toxicity and growing evidence suggests that Se health effects depend greatly on the baseline level of this micronutrient. Thus, Se supplementation is not an easy task and requires an individualized approach. It is essential that we continue to explore and better characterize Se containing compounds and mechanisms of action, which could be crucial for disease prevention and treatment. © 2015 International Union of Biochemistry and Molecular Biology.

Comparative Developmental Toxicity and Stress Protein Responses of Dimethyl Sulfoxide to Rare Minnow and Zebrafish Embryos/Larvae.

PubMed

Xiong, Xiaoqin; Luo, Si; Wu, Benli; Wang, Jianwei

2017-02-01

Dimethyl sulfoxide (DMSO), a widely used carrier solvent, can be toxic to test organisms and has species-specific sensitivity. In this study, the developmental toxicity and stress protein responses of DMSO to rare minnow (Gobiocypris rarus) and zebrafish (Danio rerio) with two tests were compared in the early life stage. In the first test, fertilized eggs were exposed to 0%, 0.0001%, 0.001%, 0.01%, 0.1%, 1.0%, 1.5%, and 2.0% v/v of DMSO until 3 days post hatching. In the second test, larvae from 0 to 8 d were exposed to 2% DMSO until 4 days. Our results showed that DMSO was toxic to rare minnow and zebrafish on multiple indexes, and the no-observed-effect concentrations of DMSO in both species were 1.0% and 0.001% for developmental toxicity analysis and stress protein analysis, respectively. Furthermore, rare minnow larvae were more sensitive than zebrafish to DMSO for spinal malformation. The sensitive period for induction of spinal malformation by DMSO was 0-7 d after hatch (dah) for rare minnow and 0-4 dah for zebrafish. Together, these results will provide support to the use of DMSO in ecotoxicological studies using rare minnow and will contribute to a better understanding of the toxicity of DMSO.

Development and evaluation of consensus-based sediment quality guidelines for freshwater ecosystems

USGS Publications Warehouse

MacDonald, D.D.; Ingersoll, C.G.; Berger, T.A.

2000-01-01

Numerical sediment quality guidelines (SQGs) for freshwater ecosystems have previously been developed using a variety of approaches. Each approach has certain advantages and limitations which influence their application in the sediment quality assessment process. In an effort to focus on the agreement among these various published SQGs, consensus-based SQGs were developed for 28 chemicals of concern in freshwater sediments (i.e., metals, polycyclic aromatic hydrocarbons, polychlorinated biphenyls, and pesticides). For each contaminant of concern, two SQGs were developed from the published SQGs, including a threshold effect concentration (TEC) and a probable effect concentration (PEC). The resultant SQGs for each chemical were evaluated for reliability using matching sediment chemistry and toxicity data from field studies conducted throughout the United States. The results of this evaluation indicated that most of the TECs (i.e., 21 of 28) provide an accurate basis for predicting the absence of sediment toxicity. Similarly, most of the PECs (i.e., 16 of 28) provide an accurate basis for predicting sediment toxicity. Mean PEC quotients were calculated to evaluate the combined effects of multiple contaminants in sediment. Results of the evaluation indicate that the incidence of toxicity is highly correlated to the mean PEC quotient (R2= 0.98 for 347 samples). It was concluded that the consensus-based SQGs provide a reliable basis for assessing sediment quality conditions in freshwater ecosystems.

Comparative Developmental Toxicity of Flavonoids Using an Integrative Zebrafish System

PubMed Central

Bugel, Sean M.; Bonventre, Josephine A.; Tanguay, Robert L.

2016-01-01

Flavonoids are a large, structurally diverse class of bioactive naturally occurring chemicals commonly detected in breast milk, soy based infant formulas, amniotic fluid, and fetal cord blood. The potential for pervasive early life stage exposures raises concerns for perturbation of embryogenesis, though developmental toxicity and bioactivity information is limited for many flavonoids. Therefore, we evaluated a suite of 24 flavonoid and flavonoid-like chemicals using a zebrafish embryo-larval toxicity bioassay—an alternative model for investigating developmental toxicity of environmentally relevant chemicals. Embryos were exposed to 1–50 µM of each chemical from 6 to 120 h postfertilization (hpf), and assessed for 26 adverse developmental endpoints at 24, 72, and 120 hpf. Behavioral changes were evaluated in morphologically normal animals at 24 and 72 hpf, at 120 hpf using a larval photomotor response (LPR) assay. Gene expression was comparatively evaluated for all compounds for effects on biomarker transcripts indicative of AHR (cyp1a) and ER (cyp19a1b, esr1, lhb, vtg) pathway bioactivity. Overall, 15 of 24 flavonoids elicited adverse effects on one or more of the developmental or behavioral endpoints. Hierarchical clustering and principle component analyses compared toxicity profiles and identified 3 distinct groups of bioactive flavonoids. Despite robust induction of multiple estrogen-responsive biomarkers, co-exposure with ER and GPER antagonists did not ameliorate toxicity, suggesting ER-independence and alternative modes of action. Taken together, these studies demonstrate that development is sensitive to perturbation by bioactive flavonoids in zebrafish that are not related to traditional estrogen receptor mode of action pathways. This integrative zebrafish platform provides a useful framework for evaluating flavonoid developmental toxicity and hazard prioritization. PMID:27492224

Toxicity induced by chemical warfare agents: insights on the protective role of melatonin.

PubMed

Pita, René; Marco-Contelles, José; Ramos, Eva; Del Pino, Javier; Romero, Alejandro

2013-11-25

Chemical Warfare Agents (CWAs) are substances that can be used to kill, injure or incapacitate an enemy in warfare, but also against civilian population in terrorist attacks. Many chemical agents are able to generate free radicals and derived reactants, excitotoxicity process, or inflammation, and as consequence they can cause neurological symptoms and damage in different organs. Nowadays, taking into account that total immediate decontamination after exposure is difficult to achieve and there are not completely effective antidotes and treatments against all CWAs, we advance and propose that medical countermeasures against CWAs poisoning would benefit from a broad-spectrum multipotent molecule. Melatonin, a versatile and ubiquitous antioxidant molecule, originally discovered as a hormone synthesized mainly in the pineal gland, has low toxicity and high efficacy in reducing oxidative damage, anti-inflammatory effects by regulation of multiple cellular pathways and properties to prevent excitotoxicity, among others. The purpose of this review is to show the multiple and diverse properties of melatonin, as a pleiotropic indole derivative, and its marked potential for improving human health against the most widely used chemical weapons. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Interactions between cadmium and decabrominated diphenyl ether on blood cells count in rats-Multiple factorial regression analysis.

PubMed

Curcic, Marijana; Buha, Aleksandra; Stankovic, Sanja; Milovanovic, Vesna; Bulat, Zorica; Đukić-Ćosić, Danijela; Antonijević, Evica; Vučinić, Slavica; Matović, Vesna; Antonijevic, Biljana

2017-02-01

The objective of this study was to assess toxicity of Cd and BDE-209 mixture on haematological parameters in subacutely exposed rats and to determine the presence and type of interactions between these two chemicals using multiple factorial regression analysis. Furthermore, for the assessment of interaction type, an isobologram based methodology was applied and compared with multiple factorial regression analysis. Chemicals were given by oral gavage to the male Wistar rats weighing 200-240g for 28days. Animals were divided in 16 groups (8/group): control vehiculum group, three groups of rats were treated with 2.5, 7.5 or 15mg Cd/kg/day. These doses were chosen on the bases of literature data and reflect relatively high Cd environmental exposure, three groups of rats were treated with 1000, 2000 or 4000mg BDE-209/kg/bw/day, doses proved to induce toxic effects in rats. Furthermore, nine groups of animals were treated with different mixtures of Cd and BDE-209 containing doses of Cd and BDE-209 stated above. Blood samples were taken at the end of experiment and red blood cells, white blood cells and platelets counts were determined. For interaction assessment multiple factorial regression analysis and fitted isobologram approach were used. In this study, we focused on multiple factorial regression analysis as a method for interaction assessment. We also investigated the interactions between Cd and BDE-209 by the derived model for the description of the obtained fitted isobologram curves. Current study indicated that co-exposure to Cd and BDE-209 can result in significant decrease in RBC count, increase in WBC count and decrease in PLT count, when compared with controls. Multiple factorial regression analysis used for the assessment of interactions type between Cd and BDE-209 indicated synergism for the effect on RBC count and no interactions i.e. additivity for the effects on WBC and PLT counts. On the other hand, isobologram based approach showed slight antagonism for the effects on RBC and WBC while no interactions were proved for the joint effect on PLT count. These results confirm that the assessment of interactions between chemicals in the mixture greatly depends on the concept or method used for this evaluation. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Proteomic analysis of Arabidopsis thaliana leaves in response to acute boron deficiency and toxicity reveals effects on photosynthesis, carbohydrate metabolism, and protein synthesis.

PubMed

Chen, Mei; Mishra, Sasmita; Heckathorn, Scott A; Frantz, Jonathan M; Krause, Charles

2014-02-15

Boron (B) stress (deficiency and toxicity) is common in plants, but as the functions of this essential micronutrient are incompletely understood, so too are the effects of B stress. To investigate mechanisms underlying B stress, we examined protein profiles in leaves of Arabidopsis thaliana plants grown under normal B (30 μM), compared to plants transferred for 60 and 84 h (i.e., before and after initial visible symptoms) in deficient (0 μM) or toxic (3 mM) levels of B. B-responsive polypeptides were sequenced by mass spectrometry, following 2D gel electrophoresis, and 1D gels and immunoblotting were used to confirm the B-responsiveness of some of these proteins. Fourteen B-responsive proteins were identified, including: 9 chloroplast proteins, 6 proteins of photosynthetic/carbohydrate metabolism (rubisco activase, OEC23, photosystem I reaction center subunit II-1, ATPase δ-subunit, glycolate oxidase, fructose bisphosphate aldolase), 6 stress proteins, and 3 proteins involved in protein synthesis (note that the 14 proteins may fall into multiple categories). Most (8) of the B-responsive proteins decreased under both B deficiency and toxicity; only 3 increased with B stress. Boron stress decreased, or had no effect on, 3 of 4 oxidative stress proteins examined, and did not affect total protein. Hence, our results indicate relatively early specific effects of B stress on chloroplasts and protein synthesis. Copyright © 2013 Elsevier GmbH. All rights reserved.

Cytotoxicity and Physiological Effects of Silver Nanoparticles on Marine Invertebrates.

PubMed

Magesky, Adriano; Pelletier, Émilien

2018-01-01

Silver nanoparticles (AgNPs) incorporation in commercial products is increasing due to their remarkable physical and chemical properties and their low cost on the market. Silver has been known for a long time to be highly toxic to bacterial communities, aquatic organisms, and particularly to marine biota. Strong chloro-complexes dominate Ag speciation in seawater and facilitate its persistence in dissolved form. It has a great impact on marine organisms because low concentration of silver can lead to strong bioaccumulation, partly because the neutral silver chloro complex (AgCl 0 ) is highly bioavailable. Owing to the fact that estuaries and coastal areas are considered as the ultimate fate for AgNPs, the study of their toxic effects on marine invertebrates can reveal some environmental risks related to nanosilver exposure. In an attempt to reach this goal, many invertebrate taxa including mollusks, crustaceans, echinoderms and polychaetes have been used as biological models. The main findings related to AgNP toxicity and marine invertebrates are summarized hereafter. Some cellular mechanisms involving nano-internalization (cellular uptake, distribution and elimination), DNA damaging, antioxidant cellular defenses and protein expression are discussed. Physiological effects on early stage development, silver metabolic speciation, immune response, tissue damaging, anti-oxidant effects and nano-depuration are also described. Finally, we paid attention to some recent interesting findings using sea urchin developmental stages and their cells as models for nanotoxicity investigation. Cellular and physiological processes characterizing sea urchin development revealed new and multiple toxicity mechanisms of both soluble and nano forms of silver.

Developmental and reproductive toxicity of inorganic arsenic: animal studies and human concerns.

PubMed

Golub, M S; Macintosh, M S; Baumrind, N

1998-01-01

Information on the reproductive and developmental toxicity of inorganic arsenic is available primarily from studies in animals using arsenite and arsenate salts and arsenic trioxide. Inorganic arsenic has been extensively studied as a teratogen in animals. Data from animal studies demonstrate that arsenic can produce developmental toxicity, including malformation, death, and growth retardation, in four species (hamsters, mice, rats, rabbits). A characteristic pattern of malformations is produced, and the developmental toxicity effects are dependent on dose, route, and the day of gestation when exposure occurs. Studies with gavage and diet administration indicate that death and growth retardation are produced by oral arsenic exposure. Arsenic is readily transferred to the fetus and produces developmental toxicity in embryo culture. Animal studies have not identified an effect of arsenic on fertility in males or females. When females were dosed chronically for periods that included pregnancy, the primary effect of arsenic on reproduction was a dose-dependent increase in conceptus mortality and in postnatal growth retardation. Human data are limited to a few studies of populations exposed to arsenic from drinking water or from working at or living near smelters. Associations with spontaneous abortion and stillbirth have been reported in more than one of these studies, but interpretation of these studies is complicated because study populations were exposed to multiple chemicals. Thus, animal studies suggest that environmental arsenic exposures are primarily a risk to the developing fetus. In order to understand the implications for humans, attention must be given to comparative pharmacokinetics and metabolism, likely exposure scenarios, possible mechanisms of action, and the potential role of arsenic as an essential nutrient.

Synergistic hepatoprotective potential of ethanolic extract of Solanum xanthocarpum and Juniperus communis against paracetamol and azithromycin induced liver injury in rats.

PubMed

Singh, Hem; Prakash, Atish; Kalia, A N; Majeed, Abu Bakar Abdul

2016-10-01

Previously explored combination therapies mostly involved the use of bioactive molecules. It is believed that herbal compounds containing multiple plant products have synergistic hepatoprotective effects and could enhance the desired actions. To investigate the combination of ethanolic fruits extract of Solanum xanthocarpum (SX) and Juniperus communis (JC) against Paracetamol (PCM) and Azithromycin (AZM) induced liver toxicity in rats. Liver toxicity was induced by combine oral administration of PCM (250 mg/kg) and AZM (200 mg/kg) for 7 days in Wistar rats. Fruit extract of SX (200 and 400 mg/kg) and JC (200 and 400 mg/kg) were administered daily for 14 days. The hepatoprotective activity was assessed using liver functional test, oxidative parameters and histopathological examination. The results demonstrated that combine administration of AZM and PCM significantly produced liver toxicity by increasing the serum level of hepatic enzymes and oxidative parameters in liver of rats. Histopathological examination also indicated that AZM and PCM produced liver damage in rats. Chronic treatment of SX and JC extract significantly and dose-dependently attenuated the liver toxicity by normalizing the biochemical factors and no gross histopathological changes were observed in liver of rats. Furthermore, combine administration of lower dose of SX and JC significantly potentiated their hepatoprotective effect which was significant as compared to their effect per se. The results clearly indicated that SX and JC extract has hepatoprotective potential against AZM and PCM induced liver toxicity due to their synergistic anti-oxidant properties.

Meeting report: Estimating the benefits of reducing hazardous air pollutants--summary of 2009 workshop and future considerations.

PubMed

Gwinn, Maureen R; Craig, Jeneva; Axelrad, Daniel A; Cook, Rich; Dockins, Chris; Fann, Neal; Fegley, Robert; Guinnup, David E; Helfand, Gloria; Hubbell, Bryan; Mazur, Sarah L; Palma, Ted; Smith, Roy L; Vandenberg, John; Sonawane, Babasaheb

2011-01-01

Quantifying the benefits of reducing hazardous air pollutants (HAPs, or air toxics) has been limited by gaps in toxicological data, uncertainties in extrapolating results from high-dose animal experiments to estimate human effects at lower doses, limited ambient and personal exposure monitoring data, and insufficient economic research to support valuation of the health impacts often associated with exposure to individual air toxics. To address some of these issues, the U.S. Environmental Protection Agency held the Workshop on Estimating the Benefits of Reducing Hazardous Air Pollutants (HAPs) in Washington, DC, from 30 April to 1 May 2009. Experts from multiple disciplines discussed how best to move forward on air toxics benefits assessment, with a focus on developing near-term capability to conduct quantitative benefits assessment. Proposed methodologies involved analysis of data-rich pollutants and application of this analysis to other pollutants, using dose-response modeling of animal data for estimating benefits to humans, determining dose-equivalence relationships for different chemicals with similar health effects, and analysis similar to that used for criteria pollutants. Limitations and uncertainties in economic valuation of benefits assessment for HAPS were discussed as well. These discussions highlighted the complexities in estimating the benefits of reducing air toxics, and participants agreed that alternative methods for benefits assessment of HAPs are needed. Recommendations included clearly defining the key priorities of the Clean Air Act air toxics program to identify the most effective approaches for HAPs benefits analysis, focusing on susceptible and vulnerable populations, and improving dose-response estimation for quantification of benefits.

Stability of Spinal Bone Lesions in Patients With Multiple Myeloma After Radiotherapy-A Retrospective Analysis of 130 Cases.

PubMed

Lang, Kristin; König, Laila; Bruckner, Thomas; Förster, Robert; Sprave, Tanja; Schlampp, Ingmar; Bostel, Tilman; Welte, Stefan; Nicolay, Nils H; Debus, Jürgen; Rief, Harald

2017-12-01

The objective of the present retrospective analysis was the response evaluation regarding bone density and stability of patients with osteolytic spinal bone lesions due to multiple myeloma after palliative radiotherapy (RT). Patients with multiple myeloma who had undergone spinal RT from March 2003 to May 2016 were analyzed before and 3 and 6 months after RT. Assessment of spinal stability and bone density was performed using the internationally recognized Taneichi scoring system and measurement of bone density using computed tomography imaging-based Hounsfield units. For statistical analysis, we used the Bowker test, McNemar test, and κ statistics to detect possible asymmetries in the distribution of the Taneichi score over time. We used the Student t test for comparison of the density values (Hounsfield units) before and after treatment. Toxicity was evaluated using the Common Terminology Criteria for Adverse Events, version 4.0. Additionally, overall survival was calculated using the Kaplan-Meier method. We evaluated 130 patients (69% male; 31% female) with multiple myeloma and a median age of 58 years. The median follow-up period was 41 months. Before treatment, 51% of the lesions were classified as unstable. At 3 and 6 months after RT, this rate had decreased to 41% (P = .0047) and 24% (P = .2393), respectively. The computed tomography measurements showed a significant increase in bone density at 3 and 6 months after RT. Acute RT-related grade 1 and 2 complications were detected in 34% of patients. Late side effects (grade 1-2) were detected in 23% of the patients. No severe grade 3 or 4 acute or late toxicities were identified. The median overall survival was 19.7 months for all patients and 6.6 months for patients with a Karnofsky performance score of ≤ 70%. To the best of our knowledge, ours is the first report to analyze the bone density and stability in patients with multiple myeloma after RT using a validated scoring system and computed tomography imaging. Palliative RT is an effective method resulting in a significant increase in bone density for local response and stability without severe RT-related toxicity. Furthermore, recalcification could already be detected at 3 months after treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

Effectivity of advanced wastewater treatment: reduction of in vitro endocrine activity and mutagenicity but not of in vivo reproductive toxicity.

PubMed

Giebner, Sabrina; Ostermann, Sina; Straskraba, Susanne; Oetken, Matthias; Oehlmann, Jörg; Wagner, Martin

2018-02-01

Conventional wastewater treatment plants (WWTPs) have a limited capacity to eliminate micropollutants. One option to improve this is tertiary treatment. Accordingly, the WWTP Eriskirch at the German river Schussen has been upgraded with different combinations of ozonation, sand, and granulated activated carbon filtration. In this study, the removal of endocrine and genotoxic effects in vitro and reproductive toxicity in vivo was assessed in a 2-year long-term monitoring. All experiments were performed with aqueous and solid-phase extracted water samples. Untreated wastewater affected several endocrine endpoints in reporter gene assays. The conventional treatment removed the estrogenic and androgenic activity by 77 and 95 %, respectively. Nevertheless, high anti-estrogenic activities and reproductive toxicity persisted. All advanced treatment technologies further reduced the estrogenic activities by additional 69-86 % compared to conventional treatment, resulting in a complete removal of up to 97 %. In the Ames assay, we detected an ozone-induced mutagenicity, which was removed by subsequent filtration. This demonstrates that a post treatment to ozonation is needed to minimize toxic oxidative transformation products. In the reproduction test with the mudsnail Potamopyrgus antipodarum, a decreased number of embryos was observed for all wastewater samples. This indicates that reproductive toxicants were eliminated by neither the conventional nor the advanced treatment. Furthermore, aqueous samples showed higher anti-estrogenic and reproductive toxicity than extracted samples, indicating that the causative compounds are not extractable or were lost during extraction. This underlines the importance of the adequate handling of wastewater samples. Taken together, this study demonstrates that combinations of multiple advanced technologies reduce endocrine effects in vitro. However, they did not remove in vitro anti-estrogenicity and in vivo reproductive toxicity. This implies that a further optimization of advanced wastewater treatment is needed that goes beyond combining available technologies.

The acute and chronic toxicity of major geochemical ions to Hyalella azteca Ion interactions and comparisons to other species

EPA Science Inventory

We have previously reported that the acute and chronic toxicities of major geochemical ions (Na, K, Ca, Mg, Cl, SO4, HCO3) to Ceriodaphnia dubia can involve multiple, independent mechanisms. The toxicities of K, Mg, and Ca salts were best related to the chemical activity of the c...

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

A systems-level approach for investigating organophosphorus pesticide toxicity.

PubMed

Zhu, Jingbo; Wang, Jing; Ding, Yan; Liu, Baoyue; Xiao, Wei

2018-03-01

The full understanding of the single and joint toxicity of a variety of organophosphorus (OP) pesticides is still unavailable, because of the extreme complex mechanism of action. This study established a systems-level approach based on systems toxicology to investigate OP pesticide toxicity by incorporating ADME/T properties, protein prediction, and network and pathway analysis. The results showed that most OP pesticides are highly toxic according to the ADME/T parameters, and can interact with significant receptor proteins to cooperatively lead to various diseases by the established OP pesticide -protein and protein-disease networks. Furthermore, the studies that multiple OP pesticides potentially act on the same receptor proteins and/or the functionally diverse proteins explained that multiple OP pesticides could mutually enhance toxicological synergy or additive on a molecular/systematic level. To the end, the integrated pathways revealed the mechanism of toxicity of the interaction of OP pesticides and elucidated the pathogenesis induced by OP pesticides. This study demonstrates a systems-level approach for investigating OP pesticide toxicity that can be further applied to risk assessments of various toxins, which is of significant interest to food security and environmental protection. Copyright © 2017 Elsevier Inc. All rights reserved.

Multiple stressor effects in relation to declining amphibian populations

USGS Publications Warehouse

Linder, Greg L.; Krest, Sherry K.; Sparling, Donald; Little, E.

2003-01-01

Original research discusses the protocols and approaches to studying the effects of multiple environmental stressors on amphibian populations and gives new perspectives on this complicated subject. This new publication integrates a variety of stressors that can act in concert and may ultimately cause a decline in amphibian populations.Sixteen peer-reviewed papers cover:Toxicity Assessment examines methods, which range from long-established laboratory approaches for evaluating adverse chemical effects to amphibians, to methods that link chemicals in surface waters, sediments, and soils with adverse effects observed among amphibians in the field.Field and Laboratory Studies illustrates studies in the evaluation of multiple stressor effects that may lead to declining amphibian populations. A range of laboratory and field studies of chemicals, such as herbicides, insecticides, chlorinated organic compounds, metals, and complex mixtures are also included.Causal Analysis demonstrates the range of tools currently available for evaluating "cause-effect" relationships between environmental stressors and declining amphibian populations.Audience: This new publication is a must-have for scientists and resource management professionals from diverse fields, including ecotoxicology, chemistry, ecology, field biology, conservation biology, and natural resource management.

Fourth Indo-US Workshop on Mathematical Chemistry Held in Pune, Maharastra, India on 8-12 January 2005

DTIC Science & Technology

2005-01-12

Designing of less toxic to non target organophosphorus pesticide through multiple correlation analysis (MRA), a part of QSAR Rini Roy, Aditi Nag...of Organophosphorus Pesticide (OPs) in biological system and environment have implicated wide use of these types of pesticides in agriculture in...having minimal effect on any part of mammalian brain. In our study, we have dealt with the effects of phosphorothionate pesticides like methyl parathion

Food-chain contamination evaluations in ecological risk assessments

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

Linder, G.

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

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.

Protective effects of 27- and 24-hydroxycholesterol against staurosporine-induced cell death in undifferentiated neuroblastoma SH-SY5Y cells.

PubMed

Emanuelsson, Ida; Norlin, Maria

2012-09-06

Alterations in cholesterol metabolism have been linked to several neurodegenerative disorders, including Alzheimer's disease, multiple sclerosis and Parkinson's disease. Brain cholesterol is metabolized to the oxysterols 24-hydroxycholesterol and 27-hydroxycholesterol. Disturbed levels of these oxysterols are found in neurodegenerative conditions. In the current study we examined the effects of 27- and 24-hydroxycholesterol on viability of human neuroblastoma SH-SY5Y cells treated with staurosporine, a toxic substance that induces apoptosis. Analyses using MTT assay and measurement of lactate dehydrogenase release showed that presence of 27-hydroxycholesterol counteracted the toxic effects of staurosporine on these cells. Also, 27-hydroxycholesterol significantly decreased the staurosporine-mediated induction of caspase-3 and -7, known to be important in apoptotic events. 24-Hydroxycholesterol had similar effects on viability as 27-hydroxycholesterol in low concentrations, although in higher concentrations this oxysterol exacerbated the toxic effects of staurosporine. From these findings it may be concluded that effects of oxysterols on cellular viability are strongly dependent on the concentration and on the type of oxysterol. Previous studies on oxysterols have reported that these compounds are pro-apoptotic or trigger pathological changes that result in neurodegeneration. The present data indicate that, during some conditions, oxysterols may have neuroprotective effects. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Protective effects of a by-product of the pecan nut industry (Carya illinoensis) on the toxicity induced by cyclophosphamide in rats Carya illinoensis protects against cyclophosphamide-induced toxicity.

PubMed

Benvegnú, D; Barcelos, R C S; Boufleur, N; Reckziegel, P; Pase, C S; Müller, L G; Martins, N M B; Vareli, C; Bürger, M E

2010-01-01

This study investigated the antioxidant effects of pecan nut (Carya illinoensis) shell aqueous extract (AE) on toxicity induced by cyclophosphamide (CP) in the heart, kidney, liver, bladder, plasma and erythrocytes of rats. Rats were treated with water or pecan shell AE (5%) ad libitum, replacing drinking water for 37 days up to the end of the experiment. On day 30, half of each group received a single administration of vehicle or CP 200 mg/kg-ip. After 7 days, the organs were removed. Rats treated with CP showed an increase in lipid peroxidation (LP) and decrease in reduced glutathione (GSH) levels in all structures. Catalase (CAT) activity was increased in the heart and decreased in liver and kidney. Besides, CP treatment decreased plasmatic vitamin C (VIT C) levels and induced bladder macroscopical and microscopical damages. In contrast, co-treatment with pecan shell AE prevented the LP development and the GSH depletion in all structures, except in the heart and plasma, respectively. CAT activity in the heart and liver as well as the plasmatic VIT C levels remained unchanged. Finally, AE prevented CP-induced bladder injury. These findings revealed the protective role of pecan shell AE in CP-induced multiple organ toxicity.

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.

Quantitative Predictive Models for Systemic Toxicity (SOT)

EPA Science Inventory

Models to identify systemic and specific target organ toxicity were developed to help transition the field of toxicology towards computational models. By leveraging multiple data sources to incorporate read-across and machine learning approaches, a quantitative model of systemic ...

Causes of toxicity to Hyalella azteca in a stormwater management facility receiving highway runoff and snowmelt. Part II: salts, nutrients, and water quality.

PubMed

Bartlett, A J; Rochfort, Q; Brown, L R; Marsalek, J

2012-01-01

The Terraview-Willowfield Stormwater Management Facility (TWSMF) features a tandem of stormwater management ponds, which receive inputs of multiple contaminants from highway and residential runoff. Previous research determined that benthic communities in the ponds were impacted by poor habitat quality, due to elevated sediment concentrations of metals and polycyclic aromatic hydrocarbons (PAHS), and salinity in the overlying water, but did not address seasonal changes, including those caused by the influx of contaminants with the snowmelt. In order to address this issue, water and sediment samples were collected from the TWSMF during the fall and spring, and four-week sediment toxicity tests were conducted with Hyalella azteca. The effects of metals and PAHs are discussed in a companion paper; the effects of road salt, nutrients, and water quality are discussed here. After exposure to fall samples, survival of Hyalella was reduced (64-74% of controls) at three out of four sites, but growth was not negatively affected. After exposure to spring samples, survival was 0-75% of controls at the two sites furthest downstream, and growth was significantly lower in four out of five sites when comparing Hyalella exposed to site water overlying site sediment versus control water overlying site sediment. Toxicity appeared to be related to chloride concentrations: little or no toxicity occurred in fall samples (200 mg Cl(-)/L), and significant effects on survival and growth occurred in spring samples above 1550 mg Cl(-)/L and 380 mg Cl(-)/L, respectively. Sodium chloride toxicity tests showed similar results: four-week LC50s and EC25s (growth) were 1200 and 420 mg Cl(-)/L, respectively. Although water quality and nutrients were associated with effects observed in the TWSMF, chloride from road salt was the primary cause of toxicity in this study. Chloride persists during much of the year at concentrations representing a significant threat to benthic communities in the TWSMF. Copyright © 2011. Published by Elsevier B.V.

TOXICITY TESTING OF RESTORATIVE DENTAL MATERIALS USING BRINE SHRIMP LARVAE (ARTEMIA SALINA)

PubMed Central

Milhem, Manar M.; Al-Hiyasat, Ahmad S.; Darmani, Homa

2008-01-01

This study investigated the effect of extracts of different composites, glass ionomer cement (GIC)s and compomers on the viability of brine shrimp larvae. Ethanolic extracts of four dental composites (Z-100; Solitaire 2; Filtek P60 and Synergy), a conventional GIC (Ketac-Fil), a resin-modified glass ionomer cement (Vitremer), two compomers (F2000; Dyract AP), and a flowable compomer (Dyract Flow) were prepared from each material. Following evaporation of the ethanol, the extracts were resuspended in distilled water, which was then used to test the effects on the viability of brine shrimp larvae. For the composites, the extract of Synergy was the least toxic (88% viability) followed by the extracts of Solitaire 2, Z100 and P60 (75%, 67.5% and 50% viability, respectively). One-way ANOVA revealed highly significant differences between the resin composite materials (p<0.001). Follow-up comparison between the composite groups by Tukey's pairwise multiple-comparison test (α =0.05) showed that the extract of Synergy was significantly less toxic than the extracts of all the other materials except that of Solitaire 2. The compomers showed 100% lethality, while the percentage of viable larvae for the extracts of Ketac-Fil, and Vitremer were 32.3%, and 37.0%, respectively. One-way ANOVA revealed highly significant differences between the groups of materials (p<0.001). Follow-up comparison between the groups by Tukey's test (α = 0.05) showed that the toxic effect of the extracts of the compomers were significantly greater than that of Ketac-Fil, and Vitremer. The differences in the toxic effects of Vitremer and Ketac-Fil were not statistically significant. In conclusion, the toxicity of composite materials varied according to their chemical composition. Compomers were the most lethal materials to brine shrimp larvae followed by GICs and then composites. PMID:19089264

Clopidogrel-Induced Neutropenia after Coronary Stenting: Is Cilostazol a Good Alternative?

PubMed Central

Montalto, Massimo; Porto, Italo; Gallo, Antonella; Camaioni, Claudia; Della Bona, Roberta; Grieco, Antonio; Crea, Filippo; Landolfi, Raffaele

2011-01-01

Dual antiplatelet therapy with aspirin plus thienopyridines has become the standard treatment of patients undergoing coronary stenting. Clopidogrel has mostly replaced the use of ticlopidine due to its more favourable adverse event profile. However, also the use of clopidogrel is not without side effects. Clopidogrel major adverse events are represented by marrow suppression, manifesting with aplastic anaemia, thrombocytopenia and neutropenia. When clopidogrel toxicity occurs, there are few and unsubstantiated alternative treatments and thus, in these cases, medical decisions may be very difficult. We report a case of clopidogrel-induced bone marrow toxicity manifesting with severe neutropenia in a patient treated with multiple coronary stents and provide suggestions for an alternative treatment. PMID:21860799

Dose-rate effects of ethylene oxide exposure on developmental toxicity.

PubMed

Weller, E; Long, N; Smith, A; Williams, P; Ravi, S; Gill, J; Henessey, R; Skornik, W; Brain, J; Kimmel, C; Kimmel, G; Holmes, L; Ryan, L

1999-08-01

In risk assessment, evaluating a health effect at a duration of exposure that is untested involves assuming that equivalent multiples of concentration (C) and duration (T) of exposure have the same effect. The limitations of this approach (attributed to F. Haber, Zur Geschichte des Gaskrieges [On the history of gas warfare], in Funf Vortrage aus den Jahren 1920-1923 [Five lectures from the years 1920-1923], 1924, Springer, Berlin, pp. 76-92), have been noted in several studies. The study presented in this paper was designed to specifically look at dose-rate (C x T) effects, and it forms an ideal case study to implement statistical models and to examine the statistical issues in risk assessment. Pregnant female C57BL/6J mice were exposed, on gestational day 7, to ethylene oxide (EtO) via inhalation for 1.5, 3, or 6 h at exposures that result in C x T multiples of 2100 or 2700 ppm-h. EtO was selected because of its short half-life, documented developmental toxicity, and relevance to exposures that occur in occupational settings. Concurrent experiments were run with animals exposed to air for similar periods. Statistical analysis using models developed to assess dose-rate effects revealed significant effects with respect to fetal death and resorptions, malformations, crown-to-rump length, and fetal weight. Animals exposed to short, high exposures of EtO on day 7 of gestation were found to have more adverse effects than animals exposed to the same C x T multiple but at longer, lower exposures. The implication for risk assessment is that applying Haber's Law could potentially lead to an underestimation of risk at a shorter duration of exposure and an overestimation of risk at a longer duration of exposure. Further research, toxicological and statistical, are required to understand the mechanism of the dose-rate effects, and how to incorporate the mechanistic information into the risk assessment decision process.

Effects of deoxynivalenol on content of chloroplast pigments in barley leaf tissues.

PubMed

Bushnell, W R; Perkins-Veazie, P; Russo, V M; Collins, J; Seeland, T M

2010-01-01

To understand further the role of deoxynivalenol (DON) in development of Fusarium head blight (FHB), we investigated effects of the toxin on uninfected barley tissues. Leaf segments, 1 to 1.2 cm long, partially stripped of epidermis were floated with exposed mesophyll in contact with DON solutions. In initial experiments with the leaf segments incubated in light, DON at 30 to 90 ppm turned portions of stripped tissues white after 48 to 96 h. The bleaching effect was greatly enhanced by addition of 1 to 10 mM Ca(2+), so that DON at 10 to 30 ppm turned virtually all stripped tissues white within 48 h. Content of chlorophylls a and b and of total carotenoid pigment was reduced. Loss of electrolytes and uptake of Evans blue indicated that DON had a toxic effect, damaging plasmalemmas in treated tissues before chloroplasts began to lose pigment. When incubated in the dark, leaf segments also lost electrolytes, indicating DON was toxic although the tissues remained green. Thus, loss of chlorophyll in light was due to photobleaching and was a secondary effect of DON, not required for toxicity. In contrast to bleaching effects, some DON treatments that were not toxic kept tissues green without bleaching or other signs of injury, indicating senescence was delayed compared with slow yellowing of untreated leaf segments. Cycloheximide, which like DON, inhibits protein synthesis, also bleached some tissues and delayed senescence of others. Thus, the effects of DON probably relate to its ability to inhibit protein synthesis. With respect to FHB, the results suggest DON may have multiple roles in host cells of infected head tissues, including delayed senescence in early stages of infection and contributing to bleaching and death of cells in later stages.

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).

Fatal serotonin toxicity caused by moclobemide and fluoxetine overdose.

PubMed

Wu, Ming-Ling; Deng, Jou-Fang

2011-01-01

Both moclobemide and fluoxetine are used in the treatment of depression, and have been shown to produce fewer side effects than conventional tricyclic antidepressants. A combination of moclobemide and fluoxetine has been used in refractory depression, however there is potential for severe serotonin toxicity. We describe a lethal case of serotonin toxicity in a 36 year-old woman after she ingested multiple drugs, including moclobemide 4500 mg, fluoxetine 200 mg, propranolol 300 mg and several benzodiazepines. The clinical features included coma, mydriasis, hyperthermia, tremor, hyperreflexia, rhabdomyolysis, renal failure and respiratory insufficiency. Eventually, the patient died of disseminated intravascular coagulation and circulatory collapse at 22.5 h postingestion. Toxicological analysis of the patient's blood confirmed high levels of moclobemide 150 μg/mL (therapeutic 1-3 μg/mL), fluoxetine 3750 ng/mL (therapeutic 47-469 ng/mL) and several benzodiazepines. In conclusion, a combination of moclobemide and fluoxetine should be avoided in depressed patients with high suicidal tendencies. Moreover, early recognition and aggressive intervention are the mainstays in the management of potentially life-threatening serotonin toxicity.

Pore-Water Carbonate and Phosphate As Predictors of Arsenate Toxicity in Soil.

PubMed

Lamb, Dane T; Kader, Mohammed; Wang, Liang; Choppala, Girish; Rahman, Mohammad Mahmudur; Megharaj, Mallavarapu; Naidu, Ravi

2016-12-06

Phytotoxicity of inorganic contaminants is influenced by the presence of competing ions at the site of uptake. In this study, interaction of soil pore-water constituents with arsenate toxicity was investigated in cucumber (Cucumis sativa L) using 10 contrasting soils. Arsenate phytotoxicity was shown to be related to soluble carbonate and phosphate. The data indicated that dissolved phosphate and carbonate had an antagonistic impact on arsenate toxicity to cucumber. To predict arsenate phytotoxicity in soils with a diverse range of soil solution properties, both carbonate and phosphate were required. The relationship between arsenic and pore-water toxicity parameters was established initially using multiple regression. In addition, based on the relationship with carbonate and phosphate we successively applied a terrestrial biotic ligand-like model (BLM) including carbonate and phosphate. Estimated effective concentrations from the BLM-like parametrization were strongly correlated to measured arsenate values in pore-water (R 2 = 0.76, P < 0.001). The data indicates that an ion interaction model similar to the BLM for arsenate is possible, potentially improving current risk assessments at arsenic and co-contaminated soils.

Exposure to metals mixtures: Genomic alterations of infectious ...

EPA Pesticide Factsheets

Exposure to toxic metals can have harmful health effects, particularly in children. Although studies have investigated the individual effects toxic metals have on gene expression and health outcomes, there are no studies assessing the effect of metal mixtures on gene expression profiles. Here, we assessed the mixture effect of six toxic metals (arsenic, beryllium, cadmium, chromium, mercury, and lead) on gene expression profiles in children in Detroit, Michigan. As part of the Mechanistic Indicators of Childhood Asthma (MICA) cross sectional study, we assessed metal exposure in 131 children in Detroit using fingernail metals levels. A metals mixture score was calculated and compared to gene expression profiles across the population adjusting for age and race. There were 145 unique genes that were significantly differentially expressed when comparing children exposed to low and high levels of the metals mixture. Of the genes differentially expressed, 107 (74%) had increased expression while 38 (26%) had decreased expression. The main biological function associated with multiple metals was infectious disease. Within that group, genes were associated with infection of respiratory tract (P < 10-6) severe acute respiratory syndrome (P < 10-5), and sepsis (P < 10-3). Taken together, these data demonstrate that exposure to metals mixtures may activate gene networks related to infectious disease response. This abstract does not necessarily reflect the views or policie

Organotins in Neuronal Damage, Brain Function, and Behavior: A Short Review

PubMed Central

Ferraz da Silva, Igor; Freitas-Lima, Leandro Ceotto; Graceli, Jones Bernardes; Rodrigues, Lívia Carla de Melo

2018-01-01

The consequences of exposure to environmental contaminants have shown significant effects on brain function and behavior in different experimental models. The endocrine-disrupting chemicals (EDC) present various classes of pollutants with potential neurotoxic actions, such as organotins (OTs). OTs have received special attention due to their toxic effects on the central nervous system, leading to abnormal mammalian neuroendocrine axis function. OTs are organometallic pollutants with a tin atom bound to one or more carbon atoms. OT exposure may occur through the food chain and/or contaminated water, since they have multiple applications in industry and agriculture. In addition, OTs have been used with few legal restrictions in the last decades, despite being highly toxic. In addition to their action as EDC, OTs can also cross the blood–brain barrier and show relevant neurotoxic effects, as observed in several animal model studies specifically involving the development of neurodegenerative processes, neuroinflammation, and oxidative stress. Thus, the aim of this short review is to summarize the toxic effects of the most common OT compounds, such as trimethyltin, tributyltin, triethyltin, and triphenyltin, on the brain with a focus on neuronal damage as a result of oxidative stress and neuroinflammation. We also aim to present evidence for the disruption of behavioral functions, neurotransmitters, and neuroendocrine pathways caused by OTs. PMID:29358929

Low-dose AgNPs reduce lung mechanical function and innate immune defense in the absence of cellular toxicity.

PubMed

Botelho, Danielle J; Leo, Bey Fen; Massa, Christopher B; Sarkar, Srijata; Tetley, Terry D; Chung, Kian Fan; Chen, Shu; Ryan, Mary P; Porter, Alexandra E; Zhang, Junfeng; Schwander, Stephan K; Gow, Andrew J

2016-01-01

Multiple studies have examined the direct cellular toxicity of silver nanoparticles (AgNPs). However, the lung is a complex biological system with multiple cell types and a lipid-rich surface fluid; therefore, organ level responses may not depend on direct cellular toxicity. We hypothesized that interaction with the lung lining is a critical determinant of organ level responses. Here, we have examined the effects of low dose intratracheal instillation of AgNPs (0.05 μg/g body weight) 20 and 110 nm diameter in size, and functionalized with citrate or polyvinylpyrrolidone. Both size and functionalization were significant factors in particle aggregation and lipid interaction in vitro. One day post-intratracheal instillation lung function was assessed, and bronchoalveolar lavage (BAL) and lung tissue collected. There were no signs of overt inflammation. There was no change in surfactant protein-B content in the BAL but there was loss of surfactant protein-D with polyvinylpyrrolidone (PVP)-stabilized particles. Mechanical impedance data demonstrated a significant increase in pulmonary elastance as compared to control, greatest with 110 nm PVP-stabilized particles. Seven days post-instillation of PVP-stabilized particles increased BAL cell counts, and reduced lung function was observed. These changes resolved by 21 days. Hence, AgNP-mediated alterations in the lung lining and mechanical function resolve by 21 days. Larger particles and PVP stabilization produce the largest disruptions. These studies demonstrate that low dose AgNPs elicit deficits in both mechanical and innate immune defense function, suggesting that organ level toxicity should be considered.

Multiple organ failure with the adult respiratory distress syndrome in homicidal arsenic poisoning.

PubMed

Bolliger, C T; van Zijl, P; Louw, J A

1992-01-01

A 30-year-old man and a 39-year-old woman, who was 28 weeks pregnant, were simultaneously poisoned by eating chocolate containing arsenic trioxide. They developed a picture of multiple organ failure peaking around the 8th to 10th day after ingestion, with the development of life-threatening adult respiratory distress syndrome (ARDS) in both patients. This rarely reported complication of arsenic poisoning was managed successfully by intubation and mechanical ventilation with positive end expiratory pressure in both patients. Hemodynamic and laboratory data are presented supporting the clinical course. Arsenic toxicity further resulted in intrauterine fetal death. The effects of severe arsenic poisoning leading to early multiple organ failure with ARDS as well as to protracted, debilitating polyneuropathy are discussed.

Contrasting effects of hypoxia on copper toxicity during development in the three-spined stickleback (Gasterosteus aculeatus).

PubMed

Fitzgerald, Jennifer A; Katsiadaki, Ioanna; Santos, Eduarda M

2017-03-01

Hypoxia is a global problem in aquatic systems and often co-occurs with pollutants. Despite this, little is known about the combined effects of these stressors on aquatic organisms. The objective of this study was to investigate the combined effects of hypoxia and copper, a toxic metal widespread in the aquatic environment. We used the three-spined stickleback (Gasterosteus aculeatus) as a model because of its environmental relevance and amenability for environmental toxicology studies. We focused on embryonic development as this is considered to be a sensitive life stage to environmental pollution. We first investigated the effects of hypoxia alone on stickleback development to generate the information required to design subsequent studies. Our data showed that exposure to low oxygen concentrations (24.7 ± 0.9% air saturation; AS) resulted in strong developmental delays and increased mortalities, whereas a small decrease in oxygen (75.0 ± 0.5%AS) resulted in premature hatching. Stickleback embryos were then exposed to a range of copper concentrations under hypoxia (56.1 ± 0.2%AS) or normoxia (97.6 ± 0.1%AS), continuously, from fertilisation to free swimming larvae. Hypoxia caused significant changes in copper toxicity throughout embryonic development. Prior to hatching, hypoxia suppressed the occurrence of mortalities, but after hatching hypoxia significantly increased copper toxicity. Interestingly, when exposures were conducted only after hatching, the onset of copper-induced mortalities was delayed under hypoxia compared to normoxia, but after 48 h, copper was more toxic to hatched embryos under hypoxia. This is the second species for which the protective effect of hypoxia on copper toxicity prior to hatching, followed by its exacerbating effect after hatching is demonstrated, suggesting the hypothesis that this pattern may be common for teleost species. Our research highlights the importance of considering the interactions between multiple stressors, as understanding these interactions is essential to facilitate the accurate prediction of the consequences of exposure to complex stressors in a rapidly changing environment. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Executive Order 12898 and Social, Economic, and Sociopolitical Factors Influencing Toxic Release Inventory Facility Location in EPA Region 6: A Multi-Scale Spatial Assessment of Environmental Justice

ERIC Educational Resources Information Center

Moore, Andrea Lisa

2013-01-01

Toxic Release Inventory facilities are among the many environmental hazards shown to create environmental inequities in the United States. This project examined four factors associated with Toxic Release Inventory, specifically, manufacturing facility location at multiple spatial scales using spatial analysis techniques (i.e., O-ring statistic and…

Nrf2 and Nrf2-Related Proteins in Development and Developmental Toxicity: Insights from studies in Zebrafish (Danio rerio)

PubMed Central

Hahn, Mark E.; Timme-Laragy, Alicia R.; Karchner, Sibel I.; Stegeman, John J.

2015-01-01

Oxidative stress is an important mechanism of chemical toxicity, contributing to developmental toxicity and teratogenesis as well as to cardiovascular and neurodegenerative diseases and diabetic embryopathy. Developing animals are especially sensitive to effects of chemicals that disrupt the balance of processes generating reactive species and oxidative stress, and those anti-oxidant defenses that protect against oxidative stress. The expression and inducibility of anti-oxidant defenses through activation of NFE2-related factor 2 (Nrf2) and related proteins is an essential process affecting the susceptibility to oxidants, but the complex interactions of Nrf2 in determining embryonic response to oxidants and oxidative stress are only beginning to be understood. The zebrafish (Danio rerio) is an established model in developmental biology and now also in developmental toxicology and redox signaling. Here we review the regulation of genes involved in protection against oxidative stress in developing vertebrates, with a focus on Nrf2 and related cap’n’collar (CNC)-basic-leucine zipper (bZIP) transcription factors. Vertebrate animals including zebrafish share Nfe2, Nrf1, Nrf2, and Nrf3 as well as a core set of genes that respond to oxidative stress, contributing to the value of zebrafish as a model system with which to investigate the mechanisms involved in regulation of redox signaling and the response to oxidative stress during embryolarval development. Moreover, studies in zebrafish have revealed nrf and keap1 gene duplications that provide an opportunity to dissect multiple functions of vertebrate NRF genes, including multiple sensing mechanisms involved in chemical-specific effects. PMID:26130508

Dodecyltriphenylphosphonium inhibits multiple drug resistance in the yeast Saccharomyces cerevisiae.

PubMed

Knorre, Dmitry A; Markova, Olga V; Smirnova, Ekaterina A; Karavaeva, Iuliia E; Sokolov, Svyatoslav S; Severin, Fedor F

2014-08-08

Multiple drug resistance pumps are potential drug targets. Here we asked whether the lipophilic cation dodecyltriphenylphosphonium (C12TPP) can interfere with their functioning. First, we found that suppression of ABC transporter gene PDR5 increases the toxicity of C12TPP in yeast. Second, C12TPP appeared to prevent the efflux of rhodamine 6G - a fluorescent substrate of Pdr5p. Moreover, C12TPP increased the cytostatic effects of some other known Pdr5p substrates. The chemical nature of C12TPP suggests that after Pdr5p-driven extrusion the molecules return to the plasma membrane and then into the cytosol, thus effectively competing with other substrates of the pump. Copyright © 2014 Elsevier Inc. All rights reserved.

Development of Novel Models for Describing Multiple Toxicity Effects

DTIC Science & Technology

1994-10-12

Cimetidine and Thiopropazate Hydrochloride in the Prevention of Stress Ulcer Formation in Rats The Journal of Pharmacology and Experimental Therapeutics , 210...Synergism and Antagonism of GA and Growth Inhibitors on Growth and Sex Expression in Cucumber Journal of the American Society of Horticultural Science...for Synergism and Antagonism The Journal of Pharmacology and Experimental Therapeutics , 259, 1 286-294 (1991). compounds studied: APEC, CHA, NECA

Modeling adverse environmental impacts on the reproductive system.

PubMed

Sussman, N B; Mazumdar, S; Mattison, D R

1999-03-01

When priority topics are being established for the study of women's health, it is generally agreed that one important area on which to focus research is reproduction. For example, increasing attention has been directed to environmental exposures that disrupt the endocrine system and alter reproduction. These concerns also suggest the need to give greater attention to the use of animal toxicologic testing to draw inferences about human reproductive risks. Successful reproduction requires multiple simultaneous and sequential processes in both the male and female, and the effect of toxicity on reproduction-related processes is time dependent. Currently, however, the risk assessment approach does not allow for the use of multiple processes or for considering the reproductive process response as a function of time. We discuss several issues in modeling exposure effects on reproductive function for risk assessment and present an overview of approaches for reproductive risk assessment. Recommendations are provided for an effective animal study design for determining reproductive risk that addresses optimization of the duration of dosing, observation of the effects of exposure on validated biomarkers, analysis of several biomarkers for complete characterization of the exposure on the underlying biologic processes, the need for longitudinally observed exposure effects, and a procedure for estimating human reproductive risk from the animal findings. An approach to characterizing reproductive toxicity to estimate the increased fertility risks in a dibromochloropropane (DBCP)-exposed human population is illustrated, using several reproductive biomarkers simultaneously from a longitudinal rabbit inhalation study of DBCP and an interspecies extrapolation method.

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.

Chemical Analysis of Plants that Poison Livestock: Successes, Challenges, and Opportunities.

PubMed

Welch, Kevin D; Lee, Stephen T; Cook, Daniel; Gardner, Dale R; Pfister, James A

2018-04-04

Poisonous plants have a devastating impact on the livestock industry as well as human health. To fully understand the effects of poisonous plants, multiple scientific disciplines are required. Chemical analysis of plant secondary compounds is key to identifying the responsible toxins, characterizing their metabolism, and understanding their effects on animals and humans. In this review, we highlight some of the successes in studying poisonous plants and mitigating their toxic effects. We also highlight some of the remaining challenges and opportunities with regards to the chemical analysis of poisonous plants.

Ecotoxicological bioassays of sediment leachates in a river bed flanked by decommissioned pesticide plants in Nantong City, East China.

PubMed

Zhou, Yan; Wang, Fenghe; Wan, Jinzhong; He, Jian; Li, Qun; Qiang Chen; Gao, Jay; Lin, Yusuo; Zhang, Shengtian

2017-03-01

Traditionally, the toxicity of river contaminants is analyzed chemically or physically through river bed sediments. The biotoxicity of polluted sediment leachates has not caught our attention. This study aims to overcome this deficiency through a battery of biotests which were conducted to monitor comprehensive toxicity of sediment leachates for the Yaogang River in East Jiangsu Province of China, which is in close proximity to former pesticide plants. The general physical and chemical parameters of major pollutants were analyzed from river bed sediments collected at five strategic locations. The ecotoxicity analyses undertaken include overall fish (adult zebrafish) acute toxicity, luminescent bacteria (Vibrio fischeri) bioassay, and zebrafish embryo toxicity assay. Compared with the control group, sediment leachates increased the lethality, inhibited the embryos hatching and induced development abnormalities of zebrafish embryos, and inhibited the luminescence of V. fischeri. The results show that sediment leachates may assume various toxic effects, depending on the test organism. This diverse toxicity to aquatic organisms reflects their different sensitivity to sediment leachates. It is found clearly that V. fischeri was the organism which was characterized by the highest sensitivity to the sediment leachates. The complicated toxicity of leachates was not caused by one single factor but by multiple pollutants together. This indicates the need of estimations of sediment leachate not only taking into account chemical detection but also of applying the biotests to the problem. Thus, multigroup bioassays are necessary to realistically evaluate river ecological risks imposed by leachates.

Toxics Use Reduction in the Home: Lessons Learned from Household Exposure Studies

PubMed Central

Dunagan, Sarah C.; Dodson, Robin E.; Rudel, Ruthann A.; Brody, Julia G.

2010-01-01

Workers and fence-line communities have been the first to benefit from the substantial reductions in toxic chemical use and byproducts in industrial production resulting from the Massachusetts Toxics Use Reduction Act (TURA). As TURA motivates reformulation of products as well as retooling of production processes, benefits could extend more broadly to large-scale reductions in everyday exposures for the general population. Household exposure studies, including those conducted by Silent Spring Institute, show that people are exposed to complex mixtures of indoor toxics from building materials and a myriad of consumer products. Pollutants in homes are likely to have multiple health effects because many are classified as endocrine disrupting compounds (EDCs), with the ability to interfere with the body's hormone system. Product-related EDCs measured in homes include phthalates, halogenated flame retardants, and alkylphenols. Silent Spring Institute's chemical analysis of personal care and cleaning products confirms many are potential sources of EDCs, highlighting the need for a more comprehensive toxics use reduction (TUR) approach to reduce those exposures. Toxics use reduction targeted at EDCs in consumer products has the potential to substantially reduce occupational and residential exposures. The lessons that have emerged from household exposure research can inform improved chemicals management policies at the state and national levels, leading to safer products and widespread health and environmental benefits. PMID:21516227

Toxicity of medicinal plants used in traditional medicine in Northern Peru

PubMed Central

Bussmann, R.W.; Malca, G.; Glenn, A.; Sharon, D.; Nilsen, B.; Parris, B.; Dubose, D; Ruiz, D.; Saleda, J.; Martinez, M.; Carillo, L.; Walker, K.; Kuhlman, A.; Townesmith, A.

2011-01-01

Aim The plant species reported here are traditionally used in Northern Peru for a wide range of illnesses. Most remedies are prepared as ethanol or aqueous extracts and then ingested. The aim of this study was to evaluate the potential toxicity of these extracts. Materials and methods The toxicity of ethanolic and water extracts of 341 plant species was determined using a Brine-Shrimp assay. Results Overall 24% of the species in water extract and 76% of the species in alcoholic extract showed elevated toxicity levels to brine-shrimp. Although in most cases multiple extracts of the same species showed very similar toxicity values, in some cases the toxicity of different extracts of the same species varied from non-toxic to highly toxic. Conclusions Traditional preparation methods take different toxicity levels in aqueous and ethanol extracts into account when choosing the appropriate solvent for the preparation of a remedy. PMID:21575699

The protective effects of ascorbic acid, cimetidine, and nifedipine on diethyldithiocarbamate-induced hepatic toxicity in albino rats.

PubMed

Gaafa, Khadiga Mohammed; Badawy, Mohammed M; Hamza, Alaaeldin A

2011-10-01

The aim of the present work was to clarify the involvement of free radicals, cytochrome P450 toxic metabolites, and deregulation of calcium homeostasis in the mechanism of diethyldithiocarbamate (DDC) hepatotoxicity. This was elucidated through the preadministration of ascorbic acid (a free radical scavenger), cimetidine (an inhibitor of cytochrome P450 enzymes), or nifedipine (a calcium-blocking agent) before DDC treatment to male albino rats. DDC was administered either as a single dose [800 mg/kg body weight (b.w.), subcutaneously, s.c.] or daily repeated doses for 30 days (400 mg/kg b.w., s.c.). Oxidative stress indicators [e.g., malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase enzyme (SOD)] showed that single or repeated DDC doses induce an increase in MDA level and a decrease in SOD activity in the liver, whereas it causes depletion in hepatic GSH after a single dose and an elevation in its value after repeated doses. Severe histopathological changes were also observed in the livers of rats treated with single or repeated DDC doses. Ascorbic acid, cimetidine, and nifedipine pretreatments were found to induce highly protective effects against the evinced DDC hepatotoxicity, manifesting that free radical, cytochrome P450, and calcium-dependent processes contribute to DDC liver toxicity. Finally, although multiple mechanisms may be involved in the hepatotoxic changes induced by DDC, calcium disarrangement and free radical formation play a more critical role than cytochrome P450 in metabolic events leading to toxic effects of DDC.

Plant water relations as affected by heavy metal stress: A review

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

Barcelo, J.; Poschenrieder, C.

1990-01-01

Metal toxicity causes multiple direct and indirect effects in plants which concern practically all physiological functions. In this review the effects of excess heavy metals and aluminum on those functions which will alter plant water relations are considered. After a brief comment on the metal effects in cell walls and plasma-lemma, and their consequences for cell expansion growth, the influences of high meal availability on the factors which regulate water entry and water exit in plants are considered. Emphasis is placed on the importance of distinguishing between low water availability in mine and serpentine soils and toxicity effects in plantsmore » which may impair the ability of a plant to regulate water uptake. Examples on water relations of both plants grown on metalliferous soil and hydroponics are presented, and the effects of metal toxicity on root growth, water transport and transpiration are considered. It is concluded that future research has to focus on the mechanisms of metal-induced inhibition of both root elongation and morphogenetic processes within roots. In order to understand the relation between metal tolerance and drought resistance better, further studies into metal tolerance mechanisms at the cell wall, membrane and vacuolar level, as well as into the mechanisms of drought resistance of plants adapted to metalliferous soils are required. 135 refs., 7 figs., 6 tabs.« less

Differential toxic effects of azathioprine, 6-mercaptopurine and 6-thioguanine on human hepatocytes.

PubMed

Petit, Elise; Langouet, Sophie; Akhdar, Hanane; Nicolas-Nicolaz, Christophe; Guillouzo, André; Morel, Fabrice

2008-04-01

Thiopurines (azathioprine, 6-mercaptopurine and 6-thioguanine) are therapeutic compounds widely administered in the clinic for their multiple uses (autoimmune diseases, post-transplant immunosuppression and cancer). Despite these advantages, their therapeutic potential is limited by occasional adverse effects (myelotoxicity and hepatotoxicity) and by a relatively frequent lack of efficacy. Previous studies have demonstrated that azathioprine decreased the viability of rat hepatocytes. In order to investigate cytotoxic effects of thiopurines in human liver, we used primary human hepatocytes and a highly differentiated human hepatoma cell line, HepaRG, treated or not with azathioprine, 6-mercaptopurine and 6-thioguanine. In parallel, expression of the genes involved in the metabolism of thiopurines, glutathione synthesis and antioxidant defences was measured by quantitative PCR. We clearly demonstrate that human liver parenchymal cells were much less sensitive than rat hepatocytes to thiopurine treatments. The toxic effects appeared after 96 h of treatment while ATP depletion was observed after a 24 h incubation with azathioprine and 6-mercaptopurine. Toxic effects were more pronounced for azathioprine and 6-mercaptopurine, when compared to 6-thioguanine, and might explain glutathione synthesis and antioxidant enzyme induction only by these two drugs. Finally, we also demonstrate for the first time an up-regulation by azathioprine and 6-mercaptopurine of inosine monophosphate dehydrogenase which might have consequences on the de novo biosynthesis of guanine nucleotides and thiopurines metabolism.

Individual and combined effects of Aflatoxin B1, Deoxynivalenol and Zearalenone on HepG2 and RAW 264.7 cell lines.

PubMed

Zhou, Hongyuan; George, Saji; Hay, Crystal; Lee, Joel; Qian, He; Sun, Xiulan

2017-05-01

To understand the combinatorial toxicity of mycotoxins, we measured the effects of individual, binary and tertiary combinations of Aflatoxin B 1 (AFB 1 ), Deoxynivalenol (DON) and Zearalenone (ZEN) on the cell viability and cellular perturbations of HepG2 and RAW 264.7 cells. The nature of mycotoxins interactions was assessed using mathematical modeling (Chou-Talalay). Mechanisms of cytotoxicity were studied using high content screening (HCS) that probed cytotoxicity responses, such as changes in intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), intracellular calcium ([Ca 2+ ] i ) flux, and cell membrane damage. Our results showed that individual cytotoxicity of mycotoxins in a decreasing order was DON>AFB 1 >ZEN. Varying combinations of mycotoxins at differing concentrations showed different types of interactions. Most of the mixtures showed increasing toxic effects-synergism and/or addition while antagonistic effects were observed with combination of AFB 1 +ZEN. Generally, combination of mycotoxins showed significantly increased intracellular ROS production and [Ca 2+ ] i flux, and decreased MMP in both cell lines, showing that the synergistic and additive effects of mycotoxin combination originate from perturbations of multiple cellular functions. Additionally, this study demonstrated the applicability of HCS for gaining mechanistic understanding on the toxicity of individual as well as combinatorial mycotoxins, and also provided scientific bases for formulating regulatory policies. Copyright © 2017. Published by Elsevier Ltd.

Modifying Effects of Vitamin E on Chlorpyrifos Toxicity in Atlantic Salmon

PubMed Central

Olsvik, Pål A.; Berntssen, Marc H. G.; Søfteland, Liv

2015-01-01

The aim of this study was to elucidate how vitamin E (alpha tocopherol) may ameliorate the toxicity of the pesticide chlorpyrifos in Atlantic salmon. Freshly isolated hepatocytes were exposed to vitamin E, chlorpyrifos or a combination of vitamin E and chlorpyrifos (all 100 μM). Transcriptomics (RNA-seq) and metabolomics were used to screen for effects of vitamin E and chlorpyrifos. By introducing vitamin E, the number of upregulated transcripts induced by chlorpyrifos exposure was reduced from 941 to 626, while the number of downregulated transcripts was reduced from 901 to 742 compared to the control. Adding only vitamin E had no effect on the transcriptome. Jak-STAT signaling was the most significantly affected pathway by chlorpyrifos treatment according to the transcriptomics data. The metabolomics data showed that accumulation of multiple long chain fatty acids and dipeptides and amino acids in chlorpyrifos treated cells was partially alleviated by vitamin E treatment. Significant interaction effects between chlorpyrifos and vitamin E were seen for 15 metabolites, including 12 dipeptides. The antioxidant had relatively modest effects on chlorpyrifos-induced oxidative stress. By combining the two data sets, the study suggests that vitamin E supplementation prevents uptake and accumulation of fatty acids, and counteracts inhibited carbohydrate metabolism. Overall, this study shows that vitamin E only to a moderate degree modifies chlorpyrifos toxicity in Atlantic salmon liver cells. PMID:25774794

Interlaboratory evaluation of Hyalella azteca and Chironomus tentans short-term and long-term sediment toxicity tests

USGS Publications Warehouse

Norberg-King, T. J.; Sibley, P.K.; Burton, G.A.; Ingersoll, C.G.; Kemble, N.E.; Ireland, S.; Mount, D.R.; Rowland, C.D.

2006-01-01

Methods for assessing the long-term toxicity of sediments to Hyalella azteca and Chironomus tentans can significantly enhance the capacity to assess sublethal effects of contaminated sediments through multiple endpoints. Sublethal tests allow us to begin to understand the relationship between short-term and long-term effects for toxic sediments. We present an interlaboratory evaluation with long-term and 10-d tests using control and contaminated sediments in which we assess whether proposed and existing performance criteria (test acceptability criteria [TAC]) could be achieved. Laboratories became familiar with newly developed, long-term protocols by testing two control sediments in phase 1. In phase 2, the 10-d and long-term tests were examined with several sediments. Laboratories met the TACs, but results varied depending on the test organism, test duration, and endpoints. For the long-term tests in phase 1, 66 to 100% of the laboratories consistently met the TACs for survival, growth, or reproduction using H. azteca, and 70 to 100% of the laboratories met the TACs for survival and growth, emergence, reproduction, and hatchability using C. tentans. In phase 2, fewer laboratories participated in long-term tests: 71 to 88% of the laboratories met the TAC for H. azteca, whereas 50 to 67% met the TAC for C. tentans. In the 10-d tests with H. azteca, and C. tentans, 82 and 88% of the laboratories met the TAC for survival, respectively, and 80% met the TAC for C. tentans growth. For the 10-d and long-term tests, laboratories predicted similar toxicity. Overall, the interlaboratory evaluation showed good precision of the methods, appropriate endpoints were incorporated into the test protocols, and tests effectively predicted the toxicity of sediments.

Evaluation of ecotoxicological effects of benzophenone UV filters: Luminescent bacteria toxicity, genotoxicity and hormonal activity.

PubMed

Zhang, Qiuya; Ma, Xiaoyan; Dzakpasu, Mawuli; Wang, Xiaochang C

2017-08-01

The widespread use of organic ultraviolet (UV) filters in personal care products raises concerns about their potentially hazardous effects on human and ecosystem health. In this study, the toxicities of four commonly used benzophenones (BPs) UV filters including benzophenone (BP), 2-Hydroxybenzophenone (2HB), 2-Hydroxy-4-methoxybenzophenone (BP3), and 2-Hydroxy-4-methoxybenzophenone-5-sulfonicacid (BP4) in water were assayed in vitro using Vibrio fischeri, SOS/umu assay, and yeast estrogen screen (YES) assay, as well as in vivo using zebrafish larvae. The results showed that the luminescent bacteria toxicity, expressed as logEC 50 , increased with the lipophilicity (logKow) of BPs UV filters. Especially, since 2HB, BP3 and BP4 had different substituent groups, namely -OH, -OCH 3 and -SO 3 H, respectively, these substituent functional groups had a major contribution to the lipophilicity and acute toxicity of these BPs. Similar tendency was observed for the genotoxicity, expressed as the value of induction ratio=1.5. Moreover, all the target BPs UV filters showed estrogenic activity, but no significant influences of lipophilicity on the estrogenicity were observed, with BP3 having the weakest estrogenic efficiency in vitro. Although BP3 displayed no noticeable adverse effects in any in vitro assays, multiple hormonal activities were observed in zebrafish larvae including estrogenicity, anti-estrogenicity and anti-androgenicity by regulating the expression of target genes. The results indicated potential hazardous effects of BPs UV filters and the importance of the combination of toxicological evaluation methods including in vitro and in vivo assays. Copyright © 2017 Elsevier Inc. All rights reserved.

Toxicity of Gamma Knife Radiosurgery in the Treatment of Intracranial Tumors in Patients With Collagen Vascular Diseases or Multiple Sclerosis

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

Lowell, Dot; Tatter, Stephen B.; Bourland, J. Daniel

Purpose: To assess toxicity in patients with either a collagen vascular disease (CVD) or multiple sclerosis (MS) treated with intracranial radiosurgery. Methods and Materials: Between January 2004 and April 2009, 6 patients with MS and 14 patients with a CVD were treated with Gamma Knife radiosurgery (GKRS) for intracranial tumors. Treated lesions included 15 total brain metastases in 7 patients, 11 benign brain tumors, 1 low grade glioma, and 1 cavernous malformation. Toxicities were graded by the Radiation Therapy Oncology Group Acute/Late Radiation Morbidity Scoring Criteria. 'Rare toxicities' were characterized as those reported in the scientific literature at an incidencemore » of <5%. Results: Median follow-up time was 16 months. Median dose to the tumor margin was 13.0 Gy (range, 12-21 Gy). Median size of tumor was 5.0 cm{sup 3} (range, 0.14-7.8 cm{sup 3}). Of the 14 patients with CVD, none experienced a Grade 3 or 4 toxicity or a toxicity characterized as rare. Of the 6 patients with MS, 3 experienced rare toxicities, and two of these were Grade 3 toxicities. Rare complications included a patient experiencing both communicating hydrocephalus and facial nerve palsy, as well as 2 additional patients with motor cranial nerve palsy. High-grade toxicities included the patient with an acoustic neuroma requiring ventriculoperitoneal shunt placement for obstructive hydrocephalus, and 1 patient with a facial nerve schwannoma who experienced permanent facial nerve palsy. Interval between radiosurgery and high-grade toxicities ranged from 1 week to 4 months. Conclusions: Our series suggests that patients with MS who receive GKRS may be at increased risk of rare and high-grade treatment-related toxicity. Given the time course of toxicity, treatment-related edema or demyelination represent potential mechanisms.« less

DOSE-DEPENDENT TRANSITIONS IN MECHANISMS OF TOXICITY: CASE STUDIES

EPA Science Inventory

Experience with dose response and mechanisms of toxicity has shown that multiple mechanisms may exist for a single agent along the continuum of the full dose-response curve. It is highly likely that critical, limiting steps in any given mechanistic pathway may become overwhelmed ...

Assessment of the individual and mixture toxicity of cadmium, copper and oxytetracycline, on the embryo-larval development of the sea urchin Paracentrotus lividus.

PubMed

Gharred, Tahar; Jebali, Jamel; Belgacem, Mariem; Mannai, Rabeb; Achour, Sami

2016-09-01

Multiple pollutions by trace metals and pharmaceuticals have become one of the most important problems in marine coastal areas because of its excessive toxicity on organisms living in this area. This study aimed to assess the individual and mixture toxicity of Cu, Cd, and oxytetracycline frequently existing in the contaminated marine areas and the embryo-larval development of the sea urchin Paracentrotus lividus. The individual contamination of the spermatozoid for 1 h with the increasing concentrations of Cd, Cu, and OTC decreases the fertility rate and increases larvae anomalies in the order Cu > Cd > OTC. Moreover, the normal larva frequency and the length of spicules were more sensitive than the fertilization rate and normal gastrula frequency endpoints. The mixture toxicity assessed by multiple experimental designs showed clearly that concentrations of Cd, Cu, and OTC superior to 338 μg/L, 0.56 μg/L, and 0.83 mg/L, respectively, cause significant larva malformations.

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.

Stress and Coping with War: The Experience of Deployment and Reunion for Mortuary Affairs Units, Reserve Units, and First-Term Army Wives

DTIC Science & Technology

1992-08-01

presented with multiple somatic complaints and fears of having been exposwd to toxic substances or infectious diseases (123rd ARCOM). The final...soldiers who presented with multiple somatic complaints and fears of having been exposed to toxic substances or infectious diseases while in the Gulf (the...lazy people." "Our CO complicated things by involving himself in business that he had no business being involved in." "To try to get supply was a real

Toxicity profiles and solvent-toxicant interference in the planarian Schmidtea mediterranea after dimethylsulfoxide (DMSO) exposure.

PubMed

Stevens, An-Sofie; Pirotte, Nicky; Plusquin, Michelle; Willems, Maxime; Neyens, Thomas; Artois, Tom; Smeets, Karen

2015-03-01

To investigate hydrophobic test compounds in toxicological studies, solvents like dimethylsulfoxide (DMSO) are inevitable. However, using these solvents, the interpretation of test compound-induced responses can be biased. DMSO concentration guidelines are available, but are mostly based on acute exposures involving one specific toxicity endpoint. Hence, to avoid solvent-toxicant interference, we use multiple chronic test endpoints for additional interpretation of DMSO concentrations and propose a statistical model to assess possible synergistic, antagonistic or additive effects of test compounds and their solvents. In this study, the effects of both short- (1 day) and long-term (2 weeks) exposures to low DMSO concentrations (up to 1000 µl l(-1) ) were studied in the planarian Schmidtea mediterranea. We measured different biological levels in both fully developed and developing animals. In a long-term exposure set-up, a concentration of 500 µl l(-1) DMSO interfered with processes on different biological levels, e.g. behaviour, stem cell proliferation and gene expression profiles. After short exposure times, 500 µl l(-1) DMSO only affected motility, whereas the most significant changes on different parameters were observed at a concentration of 1000 µl l(-1) DMSO. As small sensitivity differences exist between biological levels and developmental stages, we advise the use of this solvent in concentrations below 500 µl l(-1) in this organism. In the second part of our study, we propose a statistical approach to account for solvent-toxicant interactions and discuss full-scale solvent toxicity studies. In conclusion, we reassessed DMSO concentration limits for different experimental endpoints in the planarian S. mediterranea. Copyright © 2014 John Wiley & Sons, Ltd.

ToxCast Phase I

EPA Pesticide Factsheets

Background: Chemical toxicity testing is being transformed by advances in biology and computer modeling, concerns over animal use and the thousands of environmental chemicals lacking toxicity data. EPA's ToxCast program aims to address these concerns by screening and prioritizing chemicals for potential human toxicity using in vitro assays and in silico approaches. Objectives: This project aims to evaluate the use of in vitro assays for understanding the types of molecular and pathway perturbations caused by environmental chemicals and to build initial prioritization models of in vivo toxicity. Methods: We tested 309 mostly pesticide active chemicals in 467 assays across 9 technologies, including high-throughput cell-free assays and cell-based assays in multiple human primary cells and cell lines, plus rat primary hepatocytes. Both individual and composite scores for effects on genes and pathways were analyzed. Results: Chemicals display a broad spectrum of activity at the molecular and pathway levels. Many expected interactions are seen, including endocrine and xenobiotic metabolism enzyme activity. Chemicals range in promiscuity across pathways, from no activity to affecting dozens of pathways. We find a statistically significant inverse association between the number of pathways perturbed by a chemical at low in vitro concentrations and the lowest in vivo dose at which a chemical causes toxicity. We also find associations between a small set in vitro ass

Repurposing cephalosporin antibiotics as pro-senescent radiosensitizers.

PubMed

Labay, Edwardine; Mauceri, Helena J; Efimova, Elena V; Flor, Amy C; Sutton, Harold G; Kron, Stephen J; Weichselbaum, Ralph R

2016-06-07

Radiation therapy remains a significant therapeutic modality in the treatment of cancer. An attractive strategy would be to enhance the benefits of ionizing radiation (IR)with radiosensitizers. A high-content drug repurposing screen of approved and investigational agents, natural products and other small molecules has identified multiple candidates that blocked repair of IR damage in vitro. Here, we validated a subset of these hits in vitro and then examined effects on tumor growth after IR in a murine tumor model. Based on robust radiosensitization in vivo and other favorable properties of cephalexin, we conducted additional studies with other beta-lactam antibiotics. When combined with IR, each cephalosporin tested increased DNA damage and slowed tumor growth without affecting normal tissue toxicity. Our data implicate reactive oxygen species in the mechanism by which cephalosporins augment the effects of IR. This work provides a rationale for using commonly prescribed beta-lactam antibiotics as non-toxic radiosensitizers to enhance the therapeutic ratio of radiotherapy.

The effect of uranium on bacterial viability and cell surface morphology using atomic force microscopy in the presence of bicarbonate ions

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

Sepulveda-Medina, Paola; Katsenovich, Yelena; Musaramthota, Vishal

Nuclear production facilities during the Cold War have caused liquid waste to leak and soak into the ground creating multiple radionuclide plumes. The Arthrobacter bacteria are one of the most common groups in soils and are found in large numbers in subsurface environments contaminated with radionuclides. This study experimentally analyzed changes on the bacteria surface after uranium exposure and evaluated the effect of bicarbonate ions on U(VI) toxicity of a less uranium tolerant Arthrobacter strain, G968, by investigating changes in adhesion forces and cells dimensions via atomic force microscopy (AFM). AFM and viability studies showed that samples containing bicarbonate aremore » able to acclimate and withstand uranium toxicity. Samples containing no bicarbonate exhibited deformed surfaces and a low height profile, which might be an indication that the cells are not alive.« less

Regulation of DNA Alkylation Damage Repair: Lessons and Therapeutic Opportunities

PubMed Central

Soll, Jennifer M.; Sobol, Robert W.; Mosammaparast, Nima

2016-01-01

Alkylation chemotherapy is one of the most widely used systemic therapies for cancer. While somewhat effective, clinical responses and toxicities of these agents are highly variable. A major contributing factor for this variability is the numerous distinct lesions that are created upon alkylation damage. These adducts activate multiple repair pathways. There is mounting evidence that the individual pathways function cooperatively, suggesting that coordinated regulation of alkylation repair is critical to prevent toxicity. Furthermore, some alkylating agents produce adducts that overlap with newly discovered methylation marks, making it difficult to distinguish between bona fide damaged bases and so called ‘epigenetic’ adducts. We discuss new efforts aimed at deciphering the mechanisms that regulate these repair pathways, emphasizing their implications for cancer chemotherapy. PMID:27816326

Quality-of-Life Impairments Persist Six Months After Treatment of Graves' Hyperthyroidism and Toxic Nodular Goiter: A Prospective Cohort Study.

PubMed

Cramon, Per; Winther, Kristian Hillert; Watt, Torquil; Bonnema, Steen Joop; Bjorner, Jakob Bue; Ekholm, Ola; Groenvold, Mogens; Hegedüs, Laszlo; Feldt-Rasmussen, Ulla; Rasmussen, Åse Krogh

2016-08-01

The treatment of hyperthyroidism is aimed at improving health-related quality of life (HRQoL) and reducing morbidity and mortality. However, few studies have used validated questionnaires to assess HRQoL prospectively in such patients. The purpose of this study was to assess the impact of hyperthyroidism and its treatment on HRQoL using validated disease-specific and generic questionnaires. This prospective cohort study enrolled 88 patients with Graves' hyperthyroidism and 68 with toxic nodular goiter from endocrine outpatient clinics at two Danish university hospitals. The patients were treated with antithyroid drugs, radioactive iodine, or surgery. Disease-specific and generic HRQoL were assessed using the thyroid-related patient-reported outcome (ThyPRO) and the Medical Outcomes Study 36-item Short Form (SF-36), respectively, evaluated at baseline and six-month follow-up. The scores were compared with those from two general population samples who completed ThyPRO (n = 739) and SF-36 (n = 6638). Baseline scores for patients with Graves' hyperthyroidism and toxic nodular goiter were significantly worse than those for the general population scores on all comparable ThyPRO scales and all SF-36 scales and component summaries. ThyPRO scores improved significantly with treatment on all scales in Graves' hyperthyroidism and four scales in toxic nodular goiter, while SF-36 scores improved on five scales and both component summaries in Graves' hyperthyroidism and only one scale in toxic nodular goiter. In Graves' hyperthyroidism, large treatment effects were observed on three ThyPRO scales (Hyperthyroid Symptoms, Tiredness, Overall HRQoL) and moderate effects on three scales (Anxiety, Emotional Susceptibility, Impaired Daily Life), while moderate effects were seen in two ThyPRO scales in toxic nodular goiter (Anxiety, Overall HRQoL). However, significant disease-specific and generic HRQoL deficits persisted on multiple domains across both patient groups. Graves' hyperthyroidism and toxic nodular goiter cause severe disease-specific and generic HRQoL impairments, and HRQoL deficits persist in both patient groups six months after treatment. These data have the potential to improve communication between physicians and patients by offering realistic estimates of expected HRQoL impairments and treatment effects. Future studies should identify risk factors for persistent HRQoL deficits, compare HRQoL effects of the various therapies, and thereby aid in determining the optimal treatment strategies.

Copper toxicity and organic matter: Resiliency of watersheds in the Duluth Complex, Minnesota, USA

USGS Publications Warehouse

Piatak, Nadine; Seal, Robert; Jones, Perry M.; Woodruff, Laurel G.

2015-01-01

We estimated copper (Cu) toxicity in surface water with high dissolved organic matter (DOM) for unmined mineralized watersheds of the Duluth Complex using the Biotic Ligand Model (BLM), which evaluates the effect of DOM, cation competition for biologic binding sites, and metal speciation. A sediment-based BLM was used to estimate stream-sediment toxicity; this approach factors in the cumulative effects of multiple metals, incorporation of metals into less bioavailable sulfides, and complexation of metals with organic carbon. For surface water, the formation of Cu-DOM complexes significantly reduces the amount of Cu available to aquatic organisms. The protective effects of cations, such as calcium (Ca) and magnesium (Mg), competing with Cu to complex with the biotic ligand is likely not as important as DOM in water with high DOM and low hardness. Standard hardness-based water quality criteria (WQC) are probably inadequate for describing Cu toxicity in such waters and a BLM approach may yield more accurate results. Nevertheless, assumptions about relative proportions of humic acid (HA) and fulvic acid (FA) in DOM significantly influence BLM results; the higher the HA fraction, the higher calculated resiliency of the water to Cu toxicity. Another important factor is seasonal variation in water chemistry, with greater resiliency to Cu toxicity during low flow compared to high flow.Based on generally low total organic carbon and sulfur content, and equivalent metal ratios from total and weak partial extractions, much of the total metal concentration in clastic streambedsediments may be in bioavailable forms, sorbed on clays or hydroxide phases. However, organicrich fine-grained sediment in the numerous wetlands may sequester significant amount of metals, limiting their bioavailability. A high proportion of organic matter in waters and some sediments will play a key role in the resiliency of these watersheds to potential additional metal loads associated with future mining operations.

Effect of Cytotoxic Therapy on Sexuality and Gonadal Function

DTIC Science & Technology

1981-01-01

have produced toxicities involving multiple organ and testosterone levels fall. systems. Drug induced azoospermia and amenor- In women FSH stimulates ...Additionally, several men complained that Summary although their libido was satisfactory, orgasm The dose of a cytotoxic agent that produces was not...some of the men enced irritability and some became physically PATIENTS LIBIDO RATING: MALES 10 9 8 SEXUAL ACTIVITY 5 Fig. 1. Correlation of WEEKLY 4

Effect of time to infusion of autologous stem cells (24 vs. 48 h) after high-dose melphalan in patients with multiple myeloma.

PubMed

Talamo, Giampaolo; Rakszawski, Kevin L; Rybka, Witold B; Dolloff, Nathan G; Malysz, Jozef; Berno, Tamara; Zangari, Maurizio

2012-08-01

High-dose melphalan (HD-Mel) is considered the current standard of care among the preparative regimens used in autologous peripheral blood stem cell transplantation (SCT) for multiple myeloma (MM), but optimal time and schedule of administration is not defined. We retrospectively analyzed outcomes and toxicities of HD-Mel administered on day -2 vs. day -1 before autologous stem cells infusion. A total of 138 consecutive MM patients treated at Penn State Hershey Cancer Institute between 2007 and 2010 were included in this study. No difference in time to hematopoietic recovery, common SCT-related toxicities, and clinical outcomes was seen between patients who received HD-Mel on day -2 (group A, n = 47), and those who received it on day -1 (group B, n = 91). Prompt and full hematopoietic recovery occurred even when stem cells were infused between 8 and 24 h after completion of chemotherapy. In the absence of prospective and randomized data, we conclude that a single I.V. infusion of HD-Mel on day -1 is a safe and effective practice, and the so-called 'day of rest' before the transplant appears not to be necessary. © 2012 John Wiley & Sons A/S.

Pre-Clinical Evaluation of a Novel RXR Agonist for the Treatment of Neuroblastoma

PubMed Central

Waters, Alicia M.; Stewart, Jerry E.; Atigadda, Venkatram R.; Mroczek-Musulman, Elizabeth; Muccio, Donald D.; Grubbs, Clinton J.; Beierle, Elizabeth A.

2015-01-01

Neuroblastoma remains a common cause of pediatric cancer deaths, especially for children who present with advanced stage or recurrent disease. Currently, retinoic acid therapy is used as maintenance treatment to induce differentiation and reduce tumor recurrence following induction therapy for neuroblastoma, but unavoidable side effects are seen. A novel retinoid, UAB30, has been shown to generate negligible toxicities. In the current study, we hypothesized that UAB30 would have a significant impact on multiple neuroblastoma cell lines in vitro and in vivo. Cellular survival, cell cycle analysis, migration, and invasion were studied using alamarBlue® assays, FACS, and Transwell® assays, respectively, in multiple cell lines following treatment with UAB30. In addition, an in vivo murine model of human neuroblastoma was utilized to study the effects of UAB30 upon tumor xenograft growth and animal survival. We successfully demonstrated decreased cellular survival, invasion and migration, cell cycle arrest and increased apoptosis after treatment with UAB30. Furthermore, inhibition of tumor growth and increased survival was observed in a murine neuroblastoma xenograft model. The results of these in vitro and in vivo studies suggest a potential therapeutic role for the low toxicity synthetic retinoid X receptor selective agonist, UAB30, in neuroblastoma treatment. PMID:25944918

In vitro toxicity of different-sized ZnO nanoparticles in Caco-2 cells

NASA Astrophysics Data System (ADS)

Kang, Tianshu; Guan, Rongfa; Chen, Xiaoqiang; Song, Yijuan; Jiang, Han; Zhao, Jin

2013-11-01

There has been rapid growth in nanotechnology in both the public and private sectors worldwide, but concern about nanosafety exists. To assess size-dependent cytotoxicity on human cancer cells, we studied the cytotoxic effect of three kinds of zinc oxide nanoparticles (ZnO NPs) on human epithelial colorectal adenocarcinoma (Caco-2) cells. Nanoparticles were first characterized by size, distribution, and intensity. Multiple assays have been adopted to measure the cell activity and oxidative stress. The cytotoxicity of ZnO NPs was time dependent and dose dependent. The 24-h exposure was chosen to confirm the viability and accessibility of the cells and taken as the appropriate time for the following test system. The IC50 value was found at a low concentration. The oxidative stress elicited a significant reduction in glutathione with increase in reactive oxygen species and lactate dehydrogenase. The toxicity resulted in a deletion of cells in the G1 phase and an accumulation of cells in the S and G2/M phases. One type of metallic oxide (ZnO) exerted different cytotoxic effects according to different particle sizes. Data from the previous experiments showed that 26-nm ZnO NPs appeared to have the highest toxicity to Caco-2 cells. The study demonstrated the toxicity of ZnO NPs to Caco-2 cells and the impact of particle size, which could be useful in the medical applications.

Nitrite addition to acidified sludge significantly improves digestibility, toxic metal removal, dewaterability and pathogen reduction

NASA Astrophysics Data System (ADS)

Du, Fangzhou; Keller, Jürg; Yuan, Zhiguo; Batstone, Damien J.; Freguia, Stefano; Pikaar, Ilje

2016-12-01

Sludge management is a major issue for water utilities globally. Poor digestibility and dewaterability are the main factors determining the cost for sludge management, whereas pathogen and toxic metal concentrations limit beneficial reuse. In this study, the effects of low level nitrite addition to acidified sludge to simultaneously enhance digestibility, toxic metal removal, dewaterability and pathogen reduction were investigated. Waste activated sludge (WAS) from a full-scale waste water treatment plant was treated at pH 2 with 10 mg NO2--N/L for 5 h. Biochemical methane potential tests showed an increase in the methane production of 28%, corresponding to an improvement from 247 ± 8 L CH4/kg VS to 317 ± 1 L CH4/kg VS. The enhanced removal of toxic metals further increased the methane production by another 18% to 360 ± 6 L CH4/kg VS (a total increase of 46%). The solids content of dewatered sludge increased from 14.6 ± 1.4% in the control to 18.2 ± 0.8%. A 4-log reduction for both total coliforms and E. coli was achieved. Overall, this study highlights the potential of acidification with low level nitrite addition as an effective and simple method achieving multiple improvements in terms of sludge management.

Nitrite addition to acidified sludge significantly improves digestibility, toxic metal removal, dewaterability and pathogen reduction

PubMed Central

Du, Fangzhou; Keller, Jürg; Yuan, Zhiguo; Batstone, Damien J.; Freguia, Stefano; Pikaar, Ilje

2016-01-01

Sludge management is a major issue for water utilities globally. Poor digestibility and dewaterability are the main factors determining the cost for sludge management, whereas pathogen and toxic metal concentrations limit beneficial reuse. In this study, the effects of low level nitrite addition to acidified sludge to simultaneously enhance digestibility, toxic metal removal, dewaterability and pathogen reduction were investigated. Waste activated sludge (WAS) from a full-scale waste water treatment plant was treated at pH 2 with 10 mg NO2−-N/L for 5 h. Biochemical methane potential tests showed an increase in the methane production of 28%, corresponding to an improvement from 247 ± 8 L CH4/kg VS to 317 ± 1 L CH4/kg VS. The enhanced removal of toxic metals further increased the methane production by another 18% to 360 ± 6 L CH4/kg VS (a total increase of 46%). The solids content of dewatered sludge increased from 14.6 ± 1.4% in the control to 18.2 ± 0.8%. A 4-log reduction for both total coliforms and E. coli was achieved. Overall, this study highlights the potential of acidification with low level nitrite addition as an effective and simple method achieving multiple improvements in terms of sludge management. PMID:28004811

The marijuana component cannabidiol inhibits beta-amyloid-induced tau protein hyperphosphorylation through Wnt/beta-catenin pathway rescue in PC12 cells.

PubMed

Esposito, Giuseppe; De Filippis, Daniele; Carnuccio, Rosa; Izzo, Angelo A; Iuvone, Teresa

2006-03-01

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. A massive accumulation of beta-amyloid (Abeta) peptide aggregates has been proposed as pivotal event in AD. Abeta-induced toxicity is accompanied by a variegated combination of events including oxidative stress. The Wnt pathway has multiple actions in the cascade of events triggered by Abeta, and drugs that rescue Wnt activity may be considered as novel therapeutics for AD treatment. Cannabidiol, a non-psychoactive marijuana component, has been recently proposed as an antioxidant neuroprotective agent in neurodegenerative diseases. Moreover, it has been shown to rescue PC12 cells from toxicity induced by Abeta peptide. However, the molecular mechanism of cannabidiol-induced neuroprotective effect is still unknown. Here, we report that cannabidiol inhibits hyperphosphorylation of tau protein in Abeta-stimulated PC12 neuronal cells, which is one of the most representative hallmarks in AD. The effect of cannabidiol is mediated through the Wnt/beta-catenin pathway rescue in Abeta-stimulated PC12 cells. These results provide new molecular insight regarding the neuroprotective effect of cannabidiol and suggest its possible role in the pharmacological management of AD, especially in view of its low toxicity in humans.

Acute and chronic nephrotoxicity of platinum nanoparticles in mice

NASA Astrophysics Data System (ADS)

Yamagishi, Yoshiaki; Watari, Akihiro; Hayata, Yuya; Li, Xiangru; Kondoh, Masuo; Yoshioka, Yasuo; Tsutsumi, Yasuo; Yagi, Kiyohito

2013-09-01

Platinum nanoparticles are being utilized in various industrial applications, including in catalysis, cosmetics, and dietary supplements. Although reducing the size of the nanoparticles improves the physicochemical properties and provides useful performance characteristics, the safety of the material remains a major concern. The aim of the present study was to evaluate the biological effects of platinum particles less than 1 nm in size (snPt1). In mice administered with a single intravenous dose of snPt1, histological analysis revealed necrosis of tubular epithelial cells and urinary casts in the kidney, without obvious toxic effects in the lung, spleen, and heart. These mice exhibited dose-dependent elevation of blood urea nitrogen, an indicator of kidney damage. Direct application of snPt1 to in vitro cultures of renal cells induced significant cytotoxicity. In mice administered for 4 weeks with twice-weekly intraperitoneal snPt1, histological analysis of the kidney revealed urinary casts, tubular atrophy, and inflammatory cell accumulation. Notably, these toxic effects were not observed in mice injected with 8-nm platinum particles, either by single- or multiple-dose administration. Our findings suggest that exposure to platinum particles of less than 1 nm in size may induce nephrotoxicity and disrupt some kidney functions. However, this toxicity may be reduced by increasing the nanoparticle size.

Dietary toxicity of field-contaminated invertebrates to marine fish: effects of metal doses and subcellular metal distribution.

PubMed

Dang, Fei; Rainbow, Philip S; Wang, Wen-Xiong

2012-09-15

There is growing awareness of the toxicological effects of metal-contaminated invertebrate diets on the health of fish populations in metal-contaminated habitats, yet the mechanisms underlying metal bioaccumulation and toxicity are complex. In the present study, marine fish Terapon jurbua terepon were fed a commercial diet supplemented with specimens of the polychaete Nereis diversicolor or the clam Scrobicularia plana, collected from four metal-impacted estuaries (Tavy, Restronguet Creek, West Looe, Gannel) in southwest England, as environmentally realistic metal sources. A comparative toxicological evaluation of both invertebrates showed that fish fed S. plana for 21 d exhibited evident mortality compared to those fed N. diversicolor. Furthermore, a spatial effect on mortality was observed. Differences in metal doses rather than subcellular metal distributions between N. diversicolor and S. plana appeared to be the cause of such different mortalities. Partial least squares regression was used to evaluate the statistical relationship between multiple-metal doses and fish mortality, revealing that Pb, Fe, Cd and Zn in field-collected invertebrates co-varied most strongly with the observed mortality. This study provides a step toward exploring the underlying mechanism of dietary toxicity and identifying the potential causality in complex metal mixture exposures in the field. Copyright © 2012 Elsevier B.V. All rights reserved.

Fundamental Flaws of Hormesis for Public Health Decisions

PubMed Central

Thayer, Kristina A.; Melnick, Ronald; Burns, Kathy; Davis, Devra; Huff, James

2005-01-01

Hormesis (defined operationally as low-dose stimulation, high-dose inhibition) is often used to promote the notion that while high-level exposures to toxic chemicals could be detrimental to human health, low-level exposures would be beneficial. Some proponents claim hormesis is an adaptive, generalizable phenomenon and argue that the default assumption for risk assessments should be that toxic chemicals induce stimulatory (i.e., “beneficial”) effects at low exposures. In many cases, nonmonotonic dose–response curves are called hormetic responses even in the absence of any mechanistic characterization of that response. Use of the term “hormesis,” with its associated descriptors, distracts from the broader and more important questions regarding the frequency and interpretation of nonmonotonic dose responses in biological systems. A better understanding of the biological basis and consequences of nonmonotonic dose–response curves is warranted for evaluating human health risks. The assumption that hormesis is generally adaptive is an oversimplification of complex biological processes. Even if certain low-dose effects were sometimes considered beneficial, this should not influence regulatory decisions to allow increased environmental exposures to toxic and carcinogenic agents, given factors such as interindividual differences in susceptibility and multiplicity in exposures. In this commentary we evaluate the hormesis hypothesis and potential adverse consequences of incorporating low-dose beneficial effects into public health decisions. PMID:16203233

Acute and chronic nephrotoxicity of platinum nanoparticles in mice

PubMed Central

2013-01-01

Platinum nanoparticles are being utilized in various industrial applications, including in catalysis, cosmetics, and dietary supplements. Although reducing the size of the nanoparticles improves the physicochemical properties and provides useful performance characteristics, the safety of the material remains a major concern. The aim of the present study was to evaluate the biological effects of platinum particles less than 1 nm in size (snPt1). In mice administered with a single intravenous dose of snPt1, histological analysis revealed necrosis of tubular epithelial cells and urinary casts in the kidney, without obvious toxic effects in the lung, spleen, and heart. These mice exhibited dose-dependent elevation of blood urea nitrogen, an indicator of kidney damage. Direct application of snPt1 to in vitro cultures of renal cells induced significant cytotoxicity. In mice administered for 4 weeks with twice-weekly intraperitoneal snPt1, histological analysis of the kidney revealed urinary casts, tubular atrophy, and inflammatory cell accumulation. Notably, these toxic effects were not observed in mice injected with 8-nm platinum particles, either by single- or multiple-dose administration. Our findings suggest that exposure to platinum particles of less than 1 nm in size may induce nephrotoxicity and disrupt some kidney functions. However, this toxicity may be reduced by increasing the nanoparticle size. PMID:24059288

Evaluation of e-liquid toxicity using an open-source high-throughput screening assay

PubMed Central

Keating, James E.; Zorn, Bryan T.; Kochar, Tavleen K.; Wolfgang, Matthew C.; Glish, Gary L.; Tarran, Robert

2018-01-01

The e-liquids used in electronic cigarettes (E-cigs) consist of propylene glycol (PG), vegetable glycerin (VG), nicotine, and chemical additives for flavoring. There are currently over 7,700 e-liquid flavors available, and while some have been tested for toxicity in the laboratory, most have not. Here, we developed a 3-phase, 384-well, plate-based, high-throughput screening (HTS) assay to rapidly triage and validate the toxicity of multiple e-liquids. Our data demonstrated that the PG/VG vehicle adversely affected cell viability and that a large number of e-liquids were more toxic than PG/VG. We also performed gas chromatography–mass spectrometry (GC-MS) analysis on all tested e-liquids. Subsequent nonmetric multidimensional scaling (NMDS) analysis revealed that e-liquids are an extremely heterogeneous group. Furthermore, these data indicated that (i) the more chemicals contained in an e-liquid, the more toxic it was likely to be and (ii) the presence of vanillin was associated with higher toxicity values. Further analysis of common constituents by electron ionization revealed that the concentration of cinnamaldehyde and vanillin, but not triacetin, correlated with toxicity. We have also developed a publicly available searchable website (www.eliquidinfo.org). Given the large numbers of available e-liquids, this website will serve as a resource to facilitate dissemination of this information. Our data suggest that an HTS approach to evaluate the toxicity of multiple e-liquids is feasible. Such an approach may serve as a roadmap to enable bodies such as the Food and Drug Administration (FDA) to better regulate e-liquid composition. PMID:29584716

Evaluating the Spatial Distribution of Toxic Air Contaminants in Multiple Ecosystem Indicators in the Sierra Nevada-Southern Cascades

NASA Astrophysics Data System (ADS)

Nanus, L.; Simonich, S. L.; Rocchio, J.; Flanagan, C.

2013-12-01

Toxic air contaminants originating from agricultural areas of the Central Valley in California threaten vulnerable sensitive receptors including surface water, vegetation, snow, sediments, fish, and amphibians in the Sierra Nevada-Southern Cascades region. The spatial distribution of toxic air contaminants in different ecosystem indicators depends on variation in atmospheric concentrations and deposition, and variation in air toxics accumulation in ecosystems. The spatial distribution of organic air toxics and mercury at over 330 unique sampling locations and sample types over two decades (1990-2009) in the Sierra Nevada-Southern Cascades region were compiled and maps were developed to further understand spatial patterns and linkages between air toxics deposition and ecological effects. Potential ecosystem impacts in the Sierra Nevada-Southern Cascades region include bioaccumulation of air toxics in both aquatic and terrestrial ecosystems, reproductive disruption, and immune suppression. The most sensitive ecological end points in the region that are affected by bioaccumulation of toxic air contaminants are fish. Mercury was detected in all fish and approximately 6% exceeded human consumption thresholds. Organic air toxics were also detected in fish yielding variable spatial patterns. For amphibians, which are sensitive to pesticide exposure and potential immune suppression, increasing trends in current and historic use pesticides are observed from north to south across the region. In other indicators, such as vegetation, pesticide concentrations in lichen increase with increasing elevation. Current and historic use pesticides and mercury were also observed in snowpack at high elevations in the study area. This study shows spatial patterns in toxic air contaminants, evaluates associated risks to sensitive receptors, and identifies data gaps. Future research on atmospheric modeling and information on sources is needed in order to predict which ecosystems are the most sensitive to toxic air contaminants in the Sierra Nevada-Southern Cascades region.

Effects of pesticides on songbird productivity in conjunction with pecan cultivation in southern Georgia: A multiple-exposure experimental design

USGS Publications Warehouse

Patnode, K.A.; White, D.H.

1991-01-01

A prototypic experimental design was used to assess sublethal effects of multiple and varied organophosphates and carbamates on reproduction in birds. The design allowed for classification of pesticide exposure according to toxicity of applied compounds and type and frequency of applications. Daily survival rates (DSRs) of nests, eggs, and nestlings were determined for northern mockingbirds (Mimus polyglottos), brown thrashers (Toxostoma rufum), and northern cardinals (Cardinalis cardinalis) nesting along edges of pecan orchards and row crops in southern Georgia [USA]. Egg and nestling DSRs for all species combined varied inversely (P 0.05) among three exposure levels. Brain cholinesterase activities were age-dependent and substantiated adult, but not nestling, exposure. Results suggest that increasing exposure to pesticides may reduce songbird productivity.

Cd²⁺-induced alteration of the global proteome of human skin fibroblast cells.

PubMed

Prins, John M; Fu, Lijuan; Guo, Lei; Wang, Yinsheng

2014-03-07

Cadmium (Cd(2+)) is a toxic heavy metal and a well-known human carcinogen. The toxic effects of Cd(2+) on biological systems are diverse and thought to be exerted through a complex array of mechanisms. Despite the large number of studies aimed to elucidate the toxic mechanisms of action of Cd(2+), few have been targeted toward investigating the ability of Cd(2+) to disrupt multiple cellular pathways simultaneously and the overall cellular responses toward Cd(2+) exposure. In this study, we employed a quantitative proteomic method, relying on stable isotope labeling by amino acids in cell culture (SILAC) and LC-MS/MS, to assess the Cd(2+)-induced simultaneous alterations of multiple cellular pathways in cultured human skin fibroblast cells. By using this approach, we were able to quantify 2931 proteins, and 400 of them displayed significantly changed expression following Cd(2+) exposure. Our results unveiled that Cd(2+) treatment led to the marked upregulation of several antioxidant enzymes (e.g., metallothionein-1G, superoxide dismutase, pyridoxal kinase, etc.), enzymes associated with glutathione biosynthesis and homeostasis (e.g., glutathione S-transferases, glutathione synthetase, glutathione peroxidase, etc.), and proteins involved in cellular energy metabolism (e.g., glycolysis, pentose phosphate pathway, and the citric acid cycle). Additionally, we found that Cd(2+) treatment resulted in the elevated expression of two isoforms of dimethylarginine dimethylaminohydrolase (DDAH I and II), enzymes known to play a key role in regulating nitric oxide biosynthesis. Consistent with these findings, we observed elevated formation of nitric oxide in human skin (GM00637) and lung (IMR-90) fibroblast cells following Cd(2+) exposure. The upregulation of DDAH I and II suggests a role of nitric oxide synthesis in Cd(2+)-induced toxicity in human cells.

Traffic and meteorological impacts on near-road air quality: summary of methods and trends from the Raleigh Near-Road Study.

PubMed

Baldauf, Richard; Thoma, Eben; Hays, Michael; Shores, Richard; Kinsey, John; Gullett, Brian; Kimbrough, Sue; Isakov, Vlad; Long, Thomas; Snow, Richard; Khlystov, Andrey; Weinstein, Jason; Chen, Fu-Lin; Seila, Robert; Olson, David; Gilmour, Ian; Cho, Seung-Hyun; Watkins, Nealson; Rowley, Patricia; Bang, John

2008-07-01

A growing number of epidemiological studies conducted worldwide suggest an increase in the occurrence of adverse health effects in populations living, working, or going to school near major roadways. A study was designed to assess traffic emissions impacts on air quality and particle toxicity near a heavily traveled highway. In an attempt to describe the complex mixture of pollutants and atmospheric transport mechanisms affecting pollutant dispersion in this near-highway environment, several real-time and time-integrated sampling devices measured air quality concentrations at multiple distances and heights from the road. Pollutants analyzed included U.S. Environmental Protection Agency (EPA)-regulated gases, particulate matter (coarse, fine, and ultrafine), and air toxics. Pollutant measurements were synchronized with real-time traffic and meteorological monitoring devices to provide continuous and integrated assessments of the variation of near-road air pollutant concentrations and particle toxicity with changing traffic and environmental conditions, as well as distance from the road. Measurement results demonstrated the temporal and spatial impact of traffic emissions on near-road air quality. The distribution of mobile source emitted gas and particulate pollutants under all wind and traffic conditions indicated a higher proportion of elevated concentrations near the road, suggesting elevated exposures for populations spending significant amounts of time in this microenvironment. Diurnal variations in pollutant concentrations also demonstrated the impact of traffic activity and meteorology on near-road air quality. Time-resolved measurements of multiple pollutants demonstrated that traffic emissions produced a complex mixture of criteria and air toxic pollutants in this microenvironment. These results provide a foundation for future assessments of these data to identify the relationship of traffic activity and meteorology on air quality concentrations and population exposures.

Retardation of biodegradation of linear alkyl benzene sulphonate by a sublethal concentration of mercuric chloride

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

Misra, V.; Pandey, S.D.; Viswanathan, P.N.

1991-10-01

Environmental xenobiotics are usually classified into persistent and biodegradable ones. However, this may not be universally true, since biochemical capacity of ecosystems species may vary with species diversity and versatility. This may differ in different locations decided by geoclimatic factors. Prolonged exposure of organisms causing primary degradation to the toxic xenobiotics may lead to metabolic adaptation to survive the chemical stress. Also under multiple toxicant stress, the normal biodegrading capacity may be impaired by the effect of one toxicant on the organisms per se or on the enzymes causing degradation. If such inhibition of biodegradation occurs in ecosystems, even normallymore » biodegradable chemicals may tend to accumulate. To test this view, model experiments were conducted with LAS (Linear alkyl benzene sulphonate) a biodegradable surfactant and mercuric chloride. Since the purpose of the study was to test the degradation under natural conditions, no attempt was made to identify the micro-organisms involved.« less

Bioactivation to an aldehyde metabolite--possible role in the onset of toxicity induced by the anti-HIV drug abacavir.

PubMed

Grilo, Nádia M; Charneira, Catarina; Pereira, Sofia A; Monteiro, Emília C; Marques, M Matilde; Antunes, Alexandra M M

2014-01-30

Aldehydes are highly reactive molecules, which can be generated during numerous physiological processes, including the biotransformation of drugs. Several non-P450 enzymes participate in their metabolism albeit alcohol dehydrogenase and aldehyde dehydrogenase are the ones most frequently involved in this process. Endogenous and exogenous aldehydes have been strongly implicated in multiple human pathologies. Their ability to react with biomacromolecules (e.g. proteins) yielding covalent adducts is suggested to be the common primary mechanism underlying the toxicity of these reactive species. Abacavir is one of the options for combined anti-HIV therapy. Although individual susceptibilities to adverse effects differ among patients, abacavir is associated with idiosyncratic hypersensitivity drug reactions and an increased risk of cardiac dysfunction. This review highlights the current knowledge on abacavir metabolism and discusses the potential role of bioactivation to an aldehyde metabolite, capable of forming protein adducts, in the onset of abacavir-induced toxic outcomes. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

A Review of Use of Enantiomers in Homeopathy

PubMed Central

Kuzeff, R. M.

2012-01-01

This paper reviews publications of laboratory experiments using pairs of enantiomers in homeopathy. Many molecules in nature have geometry which enables them to exist as nonsuperimposable mirror images or enantiomers. Modulation of toxicity of such molecules provides possibility for therapeutics, since they target multiple points in biochemical pathways. It was hypothesized that toxicity of a chemical agent could be counteracted by a homeopathic preparation of the enantiomer of the chemical agent (patents applied for: PCT/AU2003/000219-PCT/AU2008/001611). A diverse body of data, including controlled laboratory studies, supports the conclusion that toxicity of optical isomers may be inhibited by homeopathic enantiomer preparations. These data were obtained with minimal or no pretesting to determine optimal test solutions. Inhibition of the excitotoxic neurotransmitter L-glutamic acid with homeopathic preparations of D-glutamic acid indicates the latter may be of use for amelioration of symptoms of disturbances of mood. Similarly, homeopathic preparation of (+)-nicotine may be of use for inhibition of effects of nicotine in tobacco. PMID:23724294

New Antioxidant Drugs for Neonatal Brain Injury

PubMed Central

Tataranno, Maria Luisa; Longini, Mariangela; Buonocore, Giuseppe

2015-01-01

The brain injury concept covers a lot of heterogeneity in terms of aetiology involving multiple factors, genetic, hemodynamic, metabolic, nutritional, endocrinological, toxic, and infectious mechanisms, acting in antenatal or postnatal period. Increased vulnerability of the immature brain to oxidative stress is documented because of the limited capacity of antioxidant enzymes and the high free radicals (FRs) generation in rapidly growing tissue. FRs impair transmembrane enzyme Na+/K+-ATPase activity resulting in persistent membrane depolarization and excessive release of FR and excitatory aminoacid glutamate. Besides being neurotoxic, glutamate is also toxic to oligodendroglia, via FR effects. Neuronal cells die of oxidative stress. Excess of free iron and deficient iron/binding metabolising capacity are additional features favouring oxidative stress in newborn. Each step in the oxidative injury cascade has become a potential target for neuroprotective intervention. The administration of antioxidants for suspected or proven brain injury is still not accepted for clinical use due to uncertain beneficial effects when treatments are started after resuscitation of an asphyxiated newborn. The challenge for the future is the early identification of high-risk babies to target a safe and not toxic antioxidant therapy in combination with standard therapies to prevent brain injury and long-term neurodevelopmental impairment. PMID:25685254

A Drosophila model for toxicogenomics: Genetic variation in susceptibility to heavy metal exposure

PubMed Central

Luoma, Sarah E.; St. Armour, Genevieve E.; Thakkar, Esha

2017-01-01

The genetic factors that give rise to variation in susceptibility to environmental toxins remain largely unexplored. Studies on genetic variation in susceptibility to environmental toxins are challenging in human populations, due to the variety of clinical symptoms and difficulty in determining which symptoms causally result from toxic exposure; uncontrolled environments, often with exposure to multiple toxicants; and difficulty in relating phenotypic effect size to toxic dose, especially when symptoms become manifest with a substantial time lag. Drosophila melanogaster is a powerful model that enables genome-wide studies for the identification of allelic variants that contribute to variation in susceptibility to environmental toxins, since the genetic background, environmental rearing conditions and toxic exposure can be precisely controlled. Here, we used extreme QTL mapping in an outbred population derived from the D. melanogaster Genetic Reference Panel to identify alleles associated with resistance to lead and/or cadmium, two ubiquitous environmental toxins that present serious health risks. We identified single nucleotide polymorphisms (SNPs) associated with variation in resistance to both heavy metals as well as SNPs associated with resistance specific to each of them. The effects of these SNPs were largely sex-specific. We applied mutational and RNAi analyses to 33 candidate genes and functionally validated 28 of them. We constructed networks of candidate genes as blueprints for orthologous networks of human genes. The latter not only provided functional contexts for known human targets of heavy metal toxicity, but also implicated novel candidate susceptibility genes. These studies validate Drosophila as a translational toxicogenomics gene discovery system. PMID:28732062

Aerosolized 3-bromopyruvate inhibits lung tumorigenesis without causing liver toxicity.

PubMed

Zhang, Qi; Pan, Jing; North, Paula E; Yang, Shoua; Lubet, Ronald A; Wang, Yian; You, Ming

2012-05-01

3-Bromopyruvate, an alkylating agent and a well-known inhibitor of energy metabolism, has been proposed as a specific anticancer agent. However, the chemopreventive effect of 3-bromopyruvate in lung tumorigenesis has not been tested. In this study, we investigated the chemopreventive activity of 3-bromopyruvate in a mouse lung tumor model. Benzo(a)pyrene was used to induce lung tumors, and 3-bromopyruvate was administered by oral gavage to female A/J mice. We found that 3-bromopyruvate significantly decreased tumor multiplicity and tumor load by 58% and 83%, respectively, at a dose of 20 mg/kg body weight by gavage. Due to the known liver toxicity of 3-bromopyruvate in animal models given large doses of 3-bromopyruvate, confirmed in this study, we decided to test the chemopreventive activity of aerosolized 3-bromopyruvate in the same lung tumor model. As expected, aerosolized 3-bromopyruvate similarly significantly decreased tumor multiplicity and tumor load by 49% and 80%, respectively, at a dose of 10 mg/mL by inhalation. Interestingly, the efficacy of aerosolized 3-bromopyruvate did not accompany any liver toxicity indicating that it is a safer route of administering this compound. Treatment with 3-bromopyruvate increased immunohistochemical staining for cleaved caspase-3, suggesting that the lung tumor inhibitory effects of 3-bromopyruvate were through induction of apoptosis. 3-Bromopyruvate also dissociated hexokinase II from mitochondria, reduced hexokinase activity, and blocked energy metabolism in cancer cells, finally triggered cancer cell death and induced apoptosis through caspase-3, and PARP in human lung cancer cell line. The ability of 3-bromopyruvate to inhibit mouse lung tumorigenesis, in part through induction of apoptosis, merits further investigation of this compound as a chemopreventive agent for human lung cancer.

Nrf2 and Nrf2-related proteins in development and developmental toxicity: Insights from studies in zebrafish (Danio rerio).

PubMed

Hahn, Mark E; Timme-Laragy, Alicia R; Karchner, Sibel I; Stegeman, John J

2015-11-01

Oxidative stress is an important mechanism of chemical toxicity, contributing to developmental toxicity and teratogenesis as well as to cardiovascular and neurodegenerative diseases and diabetic embryopathy. Developing animals are especially sensitive to effects of chemicals that disrupt the balance of processes generating reactive species and oxidative stress, and those anti-oxidant defenses that protect against oxidative stress. The expression and inducibility of anti-oxidant defenses through activation of NFE2-related factor 2 (Nrf2) and related proteins is an essential process affecting the susceptibility to oxidants, but the complex interactions of Nrf2 in determining embryonic response to oxidants and oxidative stress are only beginning to be understood. The zebrafish (Danio rerio) is an established model in developmental biology and now also in developmental toxicology and redox signaling. Here we review the regulation of genes involved in protection against oxidative stress in developing vertebrates, with a focus on Nrf2 and related cap'n'collar (CNC)-basic-leucine zipper (bZIP) transcription factors. Vertebrate animals including zebrafish share Nfe2, Nrf1, Nrf2, and Nrf3 as well as a core set of genes that respond to oxidative stress, contributing to the value of zebrafish as a model system with which to investigate the mechanisms involved in regulation of redox signaling and the response to oxidative stress during embryolarval development. Moreover, studies in zebrafish have revealed nrf and keap1 gene duplications that provide an opportunity to dissect multiple functions of vertebrate NRF genes, including multiple sensing mechanisms involved in chemical-specific effects. Copyright © 2015. Published by Elsevier Inc.

Molecular markers of trichloroethylene-induced toxicity in human kidney cells

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

Lash, Lawrence H.; Putt, David A.; Hueni, Sarah E.

Difficulties in evaluation of trichloroethylene (TRI)-induced toxicity in humans and extrapolation of data from laboratory animals to humans are due to the existence of multiple target organs, multiple metabolic pathways, sex-, species-, and strain-dependent differences in both metabolism and susceptibility to toxicity, and the lack or minimal amount of human data for many target organs. The use of human tissue for mechanistic studies is thus distinctly advantageous. The kidneys are one target organ for TRI and metabolism by the glutathione (GSH) conjugation pathway is responsible for nephrotoxicity. The GSH conjugate is processed further to produce the cysteine conjugate, S-(1,2-dichlorovinyl)-L-cysteine (DCVC),more » which is the penultimate nephrotoxic species. Confluent, primary cultures of human proximal tubular (hPT) cells were used as the model system. Although cells in log-phase growth, which are undergoing more rapid DNA synthesis, would give lower LD{sub 50} values, confluent cells more closely mimic the in vivo proximal tubule. DCVC caused cellular necrosis only at relatively high doses (>100 {mu}M) and long incubation times (>24 h). In contrast, both apoptosis and enhanced cellular proliferation occurred at relatively low doses (10-100 {mu}M) and early incubation times (2-8 h). These responses were associated with prominent changes in expression of several proteins that regulate apoptosis (Bcl-2, Bax, Apaf-1, Caspase-9 cleavage, PARP cleavage) and cellular growth, differentiation and stress response (p53, Hsp27, NF-{kappa}B). Effects on p53 and Hsp27 implicate function of protein kinase C, the mitogen activated protein kinase pathway, and the cytoskeleton. The precise pattern of expression of these and other proteins can thus serve as molecular markers for TRI exposure and effect in human kidney.« less

Simultaneous Delivery of Multiple Antibacterial Agents from Additively Manufactured Porous Biomaterials to Fully Eradicate Planktonic and Adherent Staphylococcus aureus.

PubMed

Bakhshandeh, S; Gorgin Karaji, Z; Lietaert, K; Fluit, A C; Boel, C H E; Vogely, H C; Vermonden, T; Hennink, W E; Weinans, H; Zadpoor, A A; Amin Yavari, S

2017-08-09

Implant-associated infections are notoriously difficult to treat and may even result in amputation and death. The first few days after surgery are the most critical time to prevent those infections, preferably through full eradication of the micro-organisms entering the body perioperatively. That is particularly important for patients with a compromised immune system such as orthopedic oncology patients, as they are at higher risk for infection and complications. Full eradication of bacteria is, especially in a biofilm, extremely challenging due to the toxicity barrier that prevents delivery of high doses of antibacterial agents. This study aimed to use the potential synergistic effects of multiple antibacterial agents to prevent the use of toxic levels of these agents and achieve full eradication of planktonic and adherent bacteria. Silver ions and vancomycin were therefore simultaneously delivered from additively manufactured highly porous titanium implants with an extremely high surface area incorporating a bactericidal coating made from chitosan and gelatin applied by electrophoretic deposition (EPD). The presence of the chitosan/gelatin (Ch+Gel) coating, Ag, and vancomycin (Vanco) was confirmed by X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FTIR). The release of vancomycin and silver ions continued for at least 21 days as measured by inductively coupled plasma (ICP) and UV-spectroscopy. Antibacterial behavior against Staphylococcus aureus, both planktonic and in biofilm, was evaluated for up to 21 days. The Ch+Gel coating showed some bactericidal behavior on its own, while the loaded hydrogels (Ch+Gel+Ag and Ch+Gel+Vanco) achieved full eradication of both planktonic and adherent bacteria without causing significant levels of toxicity. Combining silver and vancomycin improved the release profiles of both agents and revealed a synergistic behavior that further increased the bactericidal effects.

Simultaneous Delivery of Multiple Antibacterial Agents from Additively Manufactured Porous Biomaterials to Fully Eradicate Planktonic and Adherent Staphylococcus aureus

PubMed Central

2017-01-01

Implant-associated infections are notoriously difficult to treat and may even result in amputation and death. The first few days after surgery are the most critical time to prevent those infections, preferably through full eradication of the micro-organisms entering the body perioperatively. That is particularly important for patients with a compromised immune system such as orthopedic oncology patients, as they are at higher risk for infection and complications. Full eradication of bacteria is, especially in a biofilm, extremely challenging due to the toxicity barrier that prevents delivery of high doses of antibacterial agents. This study aimed to use the potential synergistic effects of multiple antibacterial agents to prevent the use of toxic levels of these agents and achieve full eradication of planktonic and adherent bacteria. Silver ions and vancomycin were therefore simultaneously delivered from additively manufactured highly porous titanium implants with an extremely high surface area incorporating a bactericidal coating made from chitosan and gelatin applied by electrophoretic deposition (EPD). The presence of the chitosan/gelatin (Ch+Gel) coating, Ag, and vancomycin (Vanco) was confirmed by X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FTIR). The release of vancomycin and silver ions continued for at least 21 days as measured by inductively coupled plasma (ICP) and UV-spectroscopy. Antibacterial behavior against Staphylococcus aureus, both planktonic and in biofilm, was evaluated for up to 21 days. The Ch+Gel coating showed some bactericidal behavior on its own, while the loaded hydrogels (Ch+Gel+Ag and Ch+Gel+Vanco) achieved full eradication of both planktonic and adherent bacteria without causing significant levels of toxicity. Combining silver and vancomycin improved the release profiles of both agents and revealed a synergistic behavior that further increased the bactericidal effects. PMID:28696671

Effects of individual and combined toxicity of bisphenol A, dibutyl phthalate and cadmium on oxidative stress and genotoxicity in HepG 2 cells.

PubMed

Li, Xiaohui; Yin, Pinghe; Zhao, Ling

2017-07-01

Bisphenol A, dibutyl phthalate and cadmium can be found in environment simultaneously. Several studies suggested that they had genotoxic effect. In this study, mono-exposure and co-exposure treatments, designed by 3 × 3 full factorial, were established to determine the individual toxicity and binary mixtures' combined effects on the oxidative stress and genotoxicity in HepG 2 cells. The highest oxidative damage was observed in the Cd treatments groups. Compared with control groups, the maximum level of reactive oxygen species and malondialdehyde were ∼1.4 fold and ∼2.22 fold respectively. And a minimum level of superoxide dismutase activity was found with the decrease of 43%. The mechanism that excessive oxidative stress led to the DNA damage was inferred. However, cells treated with BPA showed the worst DNA damage rather than Cd, which may because Cd mainly damages DNA repairing mechanism. For the joint effect, different interactions can be found in different biological endpoints for different combinations since different mechanisms have been clarified in mixture toxicity studies. It is sure that the co-exposure groups enhanced cytotoxicity, oxidative stress and genotoxicity compared to the mono-exposures. Synergistic and additive interactions were considered, which means greater threat to organisms when exposed to multiple estrogenic endocrine disruptors. Copyright © 2017 Elsevier Ltd. All rights reserved.

Mitoxantrone is More Toxic than Doxorubicin in SH-SY5Y Human Cells: A 'Chemobrain' In Vitro Study.

PubMed

Almeida, Daniela; Pinho, Rita; Correia, Verónica; Soares, Jorge; Bastos, Maria de Lourdes; Carvalho, Félix; Capela, João Paulo; Costa, Vera Marisa

2018-05-05

The potential neurotoxic effects of anticancer drugs, like doxorubicin (DOX) and mitoxantrone (MTX; also used in multiple sclerosis), are presently important reasons for concern, following epidemiological data indicating that cancer survivors submitted to chemotherapy may suffer cognitive deficits. We evaluated the in vitro neurotoxicity of two commonly used chemotherapeutic drugs, DOX and MTX, and study their underlying mechanisms in the SH-SY5Y human neuronal cell model. Undifferentiated human SH-SY5Y cells were exposed to DOX or MTX (0.13, 0.2 and 0.5 μM) for 48 h and two cytotoxicity assays were performed, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) reduction and the neutral red (NR) incorporation assays. Phase contrast microphotographs, Hoechst, and acridine orange/ethidium bromide stains were performed. Mitochondrial membrane potential was also assessed. Moreover, putative protective drugs, namely the antioxidants N -acetyl-l-cysteine (NAC; 1 mM) and 100 μM tiron, the inhibitor of caspase-3/7, Ac-DEVD-CHO (100 μM), and a protein synthesis inhibitor, cycloheximide (CHX; 10 nM), were tested to prevent DOX- or MTX-induced toxicity. The MTT reduction assay was also done in differentiated SH-SY5Y cells following exposure to 0.2 μM DOX or MTX. MTX was more toxic than DOX in both cytotoxicity assays and according to the morphological analyses. MTX also evoked a higher number of apoptotic nuclei than DOX. Both drugs, at the 0.13 μM concentration, caused mitochondrial membrane potential depolarization after a 48-h exposure. Regarding the putative neuroprotectors, 1 mM NAC was not able to prevent the cytotoxicity caused by either drug. Notwithstanding, 100 μM tiron was capable of partially reverting MTX-induced cytotoxicity in the NR uptake assay. One hundred μM Ac-DEVD-CHO and 10 nM cycloheximide (CHX) also partially prevented the toxicity induced by DOX in the NR uptake assay. MTX was more toxic than DOX in differentiated SH-SY5Y cells, while MTX had similar toxicity in differentiated and undifferentiated SH-SY5Y cells. In fact, MTX was the most neurotoxic drug tested and the mechanisms involved seem dissimilar among drugs. Thus, its toxicity mechanisms need to be further investigated as to determine the putative neurotoxicity for multiple sclerosis and cancer patients.

Cadmium Handling, Toxicity and Molecular Targets Involved during Pregnancy: Lessons from Experimental Models.

PubMed

Jacobo-Estrada, Tania; Santoyo-Sánchez, Mitzi; Thévenod, Frank; Barbier, Olivier

2017-07-22

Even decades after the discovery of Cadmium (Cd) toxicity, research on this heavy metal is still a hot topic in scientific literature: as we wrote this review, more than 1440 scientific articles had been published and listed by the PubMed.gov website during 2017. Cadmium is one of the most common and harmful heavy metals present in our environment. Since pregnancy is a very particular physiological condition that could impact and modify essential pathways involved in the handling of Cd, the prenatal life is a critical stage for exposure to this non-essential element. To give the reader an overview of the possible mechanisms involved in the multiple organ toxic effects in fetuses after the exposure to Cd during pregnancy, we decided to compile some of the most relevant experimental studies performed in experimental models and to summarize the advances in this field such as the Cd distribution and the factors that could alter it (diet, binding-proteins and membrane transporters), the Cd-induced toxicity in dams (preeclampsia, fertility, kidney injury, alteration in essential element homeostasis and bone mineralization), in placenta and in fetus (teratogenicity, central nervous system, liver and kidney).

Cadmium Handling, Toxicity and Molecular Targets Involved during Pregnancy: Lessons from Experimental Models

PubMed Central

Santoyo-Sánchez, Mitzi; Thévenod, Frank; Barbier, Olivier

2017-01-01

Even decades after the discovery of Cadmium (Cd) toxicity, research on this heavy metal is still a hot topic in scientific literature: as we wrote this review, more than 1440 scientific articles had been published and listed by the PubMed.gov website during 2017. Cadmium is one of the most common and harmful heavy metals present in our environment. Since pregnancy is a very particular physiological condition that could impact and modify essential pathways involved in the handling of Cd, the prenatal life is a critical stage for exposure to this non-essential element. To give the reader an overview of the possible mechanisms involved in the multiple organ toxic effects in fetuses after the exposure to Cd during pregnancy, we decided to compile some of the most relevant experimental studies performed in experimental models and to summarize the advances in this field such as the Cd distribution and the factors that could alter it (diet, binding-proteins and membrane transporters), the Cd-induced toxicity in dams (preeclampsia, fertility, kidney injury, alteration in essential element homeostasis and bone mineralization), in placenta and in fetus (teratogenicity, central nervous system, liver and kidney). PMID:28737682

Human biology-based drug safety evaluation: scientific rationale, current status and future challenges.

PubMed

Kenna, J Gerry

2017-05-01

Animal toxicity studies used to assess the safety of new candidate pharmaceuticals prior to their progression into human clinical trials are unable to assess the risk of non-pharmacologically mediated idiosyncratic adverse drug reactions (ADRs), the most frequent of which are drug-induced liver injury and cardiotoxicity. Idiosyncratic ADRs occur only infrequently and in certain susceptible humans, but are caused by many hundreds of different drugs and may lead to serious illness. Areas covered: Idiosyncratic ADRs are initiated by drug-related chemical insults, which cause toxicity due to susceptibility factors that manifest only in certain patients. The chemical insults can be detected using in vitro assays. These enable useful discrimination between drugs that cause high versus low levels of idiosyncratic ADR concern. Especially promising assays, which have been described recently in peer-reviewed scientific literature, are highlighted. Expert opinion: Effective interpretation of in vitro toxicity data requires integration of endpoints from multiple assays, which each address different mechanisms, and must also take account of human systemic and tissue drug exposure in vivo. Widespread acceptance and use of such assays has been hampered by the lack of correlation between idiosyncratic human ADR risk and toxicities observed in vivo in animals.

Alcohol-antiretroviral interactive toxicity beliefs as a potential barrier to HIV pre-exposure prophylaxis among men who have sex with men.

PubMed

Kalichman, Seth C; Eaton, Lisa

2017-07-17

Pre-exposure prophylaxis (PrEP) offers as much as 90% protection against HIV transmission. However, the effectiveness of PrEP depends on uptake and adherence to even intermittent dosing. Along with intoxication leading to unintentional non-adherence, believing that alcohol mixed with pharmaceuticals is harmful (i.e., interactive toxicity beliefs) may lead to poor uptake and intentional non-adherence. HIV-negative sexually active men who have sex with men ( N  = 272) at a large Gay Pride event in Atlanta, GA, completed anonymous surveys of demographic characteristics, sexual behaviour, alcohol use and PrEP-related alcohol interactive toxicity beliefs. A total of 118 (43%) men surveyed had two or more male sex partners and condomless anal sex in the previous six months. Alcohol use was reported by over 90% of men and it was common for participants to believe that mixing alcohol and antiretrovirals is toxic; 75% endorsed at least one interactive toxicity belief. Among the 118 men who had engaged in condomless anal sex and had multiple sex partners, one in three stated that they were not interested in PrEP and men not interested in PrEP were significantly more likely to binge drink and hold interactive toxicity beliefs. These results mirror studies that find interactive toxicity beliefs are a potent predictor of intentional antiretroviral non-adherence among people living with HIV and suggest interactive toxicity beliefs may impede PrEP uptake and adherence. Messages to increase PrEP awareness and adherence may also take steps to counter erroneous beliefs about mixing alcohol with antiretrovirals in the context of PrEP.

Alcohol-antiretroviral interactive toxicity beliefs as a potential barrier to HIV pre-exposure prophylaxis among men who have sex with men

PubMed Central

Kalichman, Seth C; Eaton, Lisa

2017-01-01

Abstract Introduction: Pre-exposure prophylaxis (PrEP) offers as much as 90% protection against HIV transmission. However, the effectiveness of PrEP depends on uptake and adherence to even intermittent dosing. Along with intoxication leading to unintentional non-adherence, believing that alcohol mixed with pharmaceuticals is harmful (i.e., interactive toxicity beliefs) may lead to poor uptake and intentional non-adherence. Methods: HIV-negative sexually active men who have sex with men (N = 272) at a large Gay Pride event in Atlanta, GA, completed anonymous surveys of demographic characteristics, sexual behaviour, alcohol use and PrEP-related alcohol interactive toxicity beliefs. Results: A total of 118 (43%) men surveyed had two or more male sex partners and condomless anal sex in the previous six months. Alcohol use was reported by over 90% of men and it was common for participants to believe that mixing alcohol and antiretrovirals is toxic; 75% endorsed at least one interactive toxicity belief. Among the 118 men who had engaged in condomless anal sex and had multiple sex partners, one in three stated that they were not interested in PrEP and men not interested in PrEP were significantly more likely to binge drink and hold interactive toxicity beliefs. Conclusions: These results mirror studies that find interactive toxicity beliefs are a potent predictor of intentional antiretroviral non-adherence among people living with HIV and suggest interactive toxicity beliefs may impede PrEP uptake and adherence. Messages to increase PrEP awareness and adherence may also take steps to counter erroneous beliefs about mixing alcohol with antiretrovirals in the context of PrEP. PMID:28715159

Preliminary outcome and toxicity report of extended-field, intensity-modulated radiation therapy for gynecologic malignancies

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

Salama, Joseph K.; Mundt, Arno J.; Department of Radiation Oncology, University of Illinois, Chicago, IL

2006-07-15

Purpose: The aim of this article is to report a preliminary analysis of our initial clinical experience with extended-field intensity-modulated radiotherapy for gynecologic malignancies. Methods and Materials: Between November 2002 and May 2005, 13 women with gynecologic malignancies were treated with extended-field radiation therapy. Of the women, 7 had endometrial cancer, 4 cervical cancer, 1 recurrent endometrial cancer, and 1 suspected cervical cancer. All women underwent computed tomography planning, with the upper vagina, parametria, and uterus (if present) contoured within the CTV. In addition, the clinical target volume contained the pelvic and presacral lymph nodes as well as the para-aorticmore » lymph nodes. All acute toxicity was scored according to the Common Terminology Criteria for Adverse Events (CTCAE v 3.0). All late toxicity was scored using the Radiation Therapy Oncology Group late toxicity score. Results: The median follow-up was 11 months. Extended-field intensity-modulated radiation therapy (IMRT) for gynecologic malignancies was well tolerated. Two patients experienced Grade 3 or higher toxicity. Both patients were treated with concurrent cisplatin based chemotherapy. Neither patient was planned with bone marrow sparing. Eleven patients had no evidence of late toxicity. One patient with multiple previous surgeries experienced a bowel obstruction. One patient with bilateral grossly involved and unresectable common iliac nodes experienced bilateral lymphedema. Extended-field-IMRT achieved good local control with only 1 patient, who was metastatic at presentation, and 1 patient not able to complete treatment, experiencing in-field failure. Conclusions: Extended-field IMRT is safe and effective with a low incidence of acute toxicity. Longer follow-up is needed to assess chronic toxicity, although early results are promising.« less

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.

A Qualitative Analysis of Acute Skin Toxicity among Breast Cancer Radiotherapy Patients

PubMed Central

Schnur, Julie B.; Ouellette, Suzanne C.; DiLorenzo, Terry A.; Green, Sheryl; Montgomery, Guy H.

2013-01-01

Objectives One of the most common acute side effects of breast cancer radiotherapy is treatment induced skin changes, referred to as skin toxicity. Yet no research to date has focused expressly on skin toxicity-related quality of life in breast cancer radiotherapy patients. Therefore, our aim was to use qualitative approaches to better understand the impact of skin toxicity on quality of life. Methods Semi-structured interviews were conducted with 20 women (Stage 0-III breast cancer), during their last week of external beam radiotherapy. Each interview was transcribed verbatim, and thematic analysis was performed. Results Three themes were identified based on the interview responses: First, skin changes affect multiple dimensions of quality of life. They cause physical discomfort, body image disturbance, emotional distress, and impair both day-to-day functioning and satisfaction with radiation treatment. Second, individual differences affect women’s experiences. Generally African-American women, younger women, women who are not currently in a relationship, women who are being treated during the summer, and women who are more invested in their appearance are more distressed by skin toxicity. Third, women use a variety of symptom management strategies including self-medication, complementary/alternative medicine approaches, and psychological strategies. Conclusions Implications of results are: 1) Skin toxicity affects numerous dimensions of quality of life, and assessment approaches and psychosocial interventions should address this; 2) individual differences may affect the experience of skin toxicity, and should be considered in treatment and education approaches; and 3) participants’ own creativity and problem-solving should be used to improve the treatment experience. PMID:20238306

Biotoxicity assessment and toxicity mechanism on coal gasification wastewater (CGW): A comparative analysis of effluent from different treatment processes.

PubMed

Ma, Weiwei; Han, Yuxing; Xu, Chunyan; Han, Hongjun; Zhu, Hao; Li, Kun; Zheng, Mengqi

2018-05-04

Even though coal gasification wastewater (CGW) treated by various biochemical treatment processes generally met the national discharge standard, its potential biotoxicity was still unknown. Therefore, in this study, bioassay with Tetrahymena thermophila (T. thermophila) was conducted to comprehensively evaluate the variation of biotoxicity in raw CGW and the treated effluent from lab-scale micro-electrolysis integrated with biological reactor (MEBR), single iron-carbon micro-electrolysis (ICME) and conventional activated sludge (CAS) processes. The results illustrated that raw CGW presented intensive acute toxicity with 24 h EC 50 value of 8.401% and toxic unit (TU) value of 11.90. Moreover, it performed significant cell membrane destruction and DNA damage even at 10% dilution concentration. The toxicant identification results revealed that multiple toxic polar compounds such as phenolic, heterocyclic and polycyclic aromatic compounds were the main contributors for biotoxicity. Furthermore, these compounds could accelerate oxidative stress, thereby inducing oxidative damage of cell membrane and DNA. As for treated effluent, TU value was decreased by 90.58% in MEBR process. An effective biotoxicity reduction was achieved in MEBR process owing to high removal efficiency in polar organic toxicants. In contrast, effluent from ICME and CAS processes presented relatively high acute toxicity and genotoxicity, because various heterocyclic and polycyclic aromatic compounds were difficult to be degraded in these processes. Therefore, it was suggested that MEBR was a potential and feasible process for improving CGW treatment and minimizing ecological risk. Copyright © 2018. Published by Elsevier B.V.

Multiple sclerosis, brain radiotherapy, and risk of neurotoxicity: The Mayo Clinic experience

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

Miller, Robert C.; Lachance, Daniel H.; Lucchinetti, Claudia F.

2006-11-15

Purpose: The aim of this study was a retrospective assessment of neurotoxicity in patients with multiple sclerosis (MS) receiving external beam radiotherapy (EBRT) to the brain. Methods and Materials: We studied 15 consecutively treated patients with MS who received brain EBRT. Neurologic toxicity was assessed with the Common Toxicity Criteria v.3.0. Results: Median follow-up for the 5 living patients was 6.0 years (range, 3.3-27.4 years). No exacerbation of MS occurred in any patient during EBRT. Five patients had Grade 4 neurologic toxicity and 1 had possible Grade 5 toxicity. Kaplan-Meier estimated risk of neurotoxicity greater than Grade 4 at 5more » years was 57% (95% confidence interval, 27%-82%). Toxicity occurred at 37.5 to 54.0 Gy at a median of 1.0 year (range, 0.2-4.3 years) after EBRT. Univariate analysis showed an association between opposed-field irradiation of the temporal lobes, central white matter, and brainstem and increased risk of neurotoxicity (p < 0.04). Three of 6 cases of toxicity occurred in patients treated before 1986. Conclusions: External beam radiotherapy of the brain in patients with MS may be associated with an increased risk of neurotoxicity compared with patients without demyelinating illnesses. However, this risk is associated with treatment techniques that may not be comparable to modern, conformal radiotherapy.« less

Inhaled gene therapy in lung cancer: proof-of-concept for nano-oncology and nanobiotechnology in the management of lung cancer.

PubMed

Zarogoulidis, Paul; Darwiche, Kaid; Hohenforst-Schmidt, Wolfgang; Huang, Haidong; Li, Qiang; Freitag, Lutz; Zarogoulidis, Konstantinos

2013-08-01

Lung cancer still remains one of the leading causes of death among cancer patients. Although novel targeted therapies have been established in everyday treatment practice, and conventional platinum-based doublets have demonstrated effective results regarding overall and progression-free survival, we have still failed to achieve long-term survival. Therefore, several strategies of applying locoregional therapy are under investigation. Aerosol chemotherapy is already under investigation and, taking this a step further, aerosol gene therapies with multiple delivery systems are being developed. Several efforts have demonstrated its efficiency and effectiveness, but there are still multiple factors that have to be considered and combined to achieve an overall more effective multifunctional treatment. In the current review, we present data regarding aerosol delivery systems, transporters, carriers, vectors, genes, toxicity, efficiency, specificity, lung microenvironment and delivery gene therapy systems. Finally, we present current studies and future perspectives.

Classification and Dose-Response Characterization of ...

EPA Pesticide Factsheets

Thirty years and over a billion of today’s 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 U.S. Environmental Protection Agency’s (EPA) Toxicity Reference Database (ToxRefDB). The source toxicity data in ToxRefDB covers multiple study types, including subchronic, developmental, reproductive, chronic, and cancer studies, resulting in a diverse set of endpoints and toxicities. Novel approaches to chemical classification are performed as a model application of ToxRefDB and as an essential need for highly detailed chemical classifications within the EPA’s ToxCast™ research program. In order to develop predictive models and biological signatures utilizing high-throughput screening (HTS) and in vitro genomic data, endpoints and toxicities must first be identified and globally characterized for ToxCast Phase I chemicals. Secondarily, dose-response characterization within and across toxicity endpoints provide insight into key precursor toxicity events and overall endpoint relevance. Toxicity-based chemical classification and dose-response characterization utilizing ToxRefDB prioritized toxicity endpoints and differentiated toxicity outcomes across a large chemical set.

In silico quantitative structure-toxicity relationship study of aromatic nitro compounds.

PubMed

Pasha, Farhan Ahmad; Neaz, Mohammad Morshed; Cho, Seung Joo; Ansari, Mohiuddin; Mishra, Sunil Kumar; Tiwari, Sharvan

2009-05-01

Small molecules often have toxicities that are a function of molecular structural features. Minor variations in structural features can make large difference in such toxicity. Consequently, in silico techniques may be used to correlate such molecular toxicities with their structural features. Relative to nine different sets of aromatic nitro compounds having known observed toxicities against different targets, we developed ligand-based 2D quantitative structure-toxicity relationship models using 20 selected topological descriptors. The topological descriptors have several advantages such as conformational independency, facile and less time-consuming computation to yield good results. Multiple linear regression analysis was used to correlate variations of toxicity with molecular properties. The information index on molecular size, lopping centric index and Kier flexibility index were identified as fundamental descriptors for different kinds of toxicity, and further showed that molecular size, branching and molecular flexibility might be particularly important factors in quantitative structure-toxicity relationship analysis. This study revealed that topological descriptor-guided quantitative structure-toxicity relationship provided a very useful, cost and time-efficient, in silico tool for describing small-molecule toxicities.

Infliximab treatment in a patient with rheumatoid arthritis on hemodialysis.

PubMed

Singh, Ranju; Cuchacovich, Raquel; Huang, Wenqun; Espinoza, Luis R

2002-03-01

We describe a 60-year-old woman with active rheumatoid arthritis (RA) and endstage renal disease secondary to hypertensive nephrosclerosis undergoing hemodialysis. She had tried multiple antirheumatic medications; however, their usefulness was limited due to toxic side effects or lack of efficacy. She was then treated with chimeric antitumor necrosis factor monoclonal antibody (infliximab), which resulted in immediate improvement in clinical and laboratory measures. After about 2 years of therapy, no side effects have been observed. This report expands the spectrum of infliximab to include RA patients with renal insufficiency.

Intra- and interlaboratory variability in acute toxicity tests with glochidia and juveniles of freshwater mussels (Unionidae)

USGS Publications Warehouse

Wang, N.; Augspurger, T.; Barnhart, M.C.; Bidwell, Joseph R.; Cope, W.G.; Dwyer, F.J.; Geis, S.; Greer, I.E.; Ingersoll, C.G.; Kane, C.M.; May, T.W.; Neves, R.J.; Newton, T.J.; Roberts, A.D.; Whites, D.W.

2007-01-01

The present study evaluated the performance and variability in acute toxicity tests with glochidia and newly transformed juvenile mussels using the standard methods outlined in American Society for Testing and Materials (ASTM). Multiple 48-h toxicity tests with glochidia and 96-h tests with juvenile mussels were conducted within a single laboratory and among five laboratories. All tests met the test acceptability requirements (e.g., ???90% control survival). Intralaboratory tests were conducted over two consecutive mussel-spawning seasons with mucket (Actinonaias ligamentina) or fatmucket (Lampsilis siliquoidea) using copper, ammonia, or chlorine as a toxicant. For the glochidia of both species, the variability of intralaboratory median effective concentrations (EC50s) for the three toxicants, expressed as the coefficient of variation (CV), ranged from 14 to 27% in 24-h exposures and from 13 to 36% in 48-h exposures. The intralaboratory CV of copper EC50s for juvenile fatmucket was 24% in 48-h exposures and 13% in 96-h exposures. Interlaboratory tests were conducted with fatmucket glochidia and juveniles by five laboratories using copper as a toxicant. The interlaboratory CV of copper EC50s for glochidia was 13% in 24-h exposures and 24% in 48-h exposures, and the interlaboratory CV for juveniles was 22% in 48-h exposures and 42% in 96-h exposures. The high completion success and the overall low variability in test results indicate that the test methods have acceptable precision and can be performed routinely. ?? 2007 SETAC.

Strontium 89 in the treatment of pain due to diffuse osseous metastases: a university hospital experience.

PubMed Central

Ashayeri, Ebrahim; Omogbehin, Adedamola; Sridhar, Rajagopalan; Shankar, Ravi A.

2002-01-01

More than two-thirds of the patients with osseous metastases experience debilitating bone pain, requiring some form of pain relief. Analgesics are limited in their efficacy. Palliative application of hemi-body external beam radiation therapy in the treatment of multiple osseous metastases also is limited due to toxicity associated with large treatment ports. Intravenous injections of bone seeking radioisotopes are effective in the palliation of pain with fewer side effects. Forty-one patients with multiple osseous metastases due to prostate and breast cancer were treated with strontium chloride 89 (89Sr) at the department of radiation oncology, in a university hospital. A retrospective analysis of these patients indicated that all subjects had severe pain that diminished their quality of life. Most of these patients had multiple co-morbid factors. Many were on opioids leading to adverse effects such as nausea, constipation, and drowsiness that required additional medication. Objective findings and evaluation of the responses were not always available for all patients. Following treatmentwith 89Sr, over two-thirds of the patients responded favorably and required lower doses of opioids. PMID:12152927

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

PubMed

Shukla, G S; Singhal, R L

1984-08-01

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

Caenorhabditis elegans, a Biological Model for Research in Toxicology.

PubMed

Tejeda-Benitez, Lesly; Olivero-Verbel, Jesus

2016-01-01

Caenorhabditis elegans is a nematode of microscopic size which, due to its biological characteristics, has been used since the 1970s as a model for research in molecular biology, medicine, pharmacology, and toxicology. It was the first animal whose genome was completely sequenced and has played a key role in the understanding of apoptosis and RNA interference. The transparency of its body, short lifespan, ability to self-fertilize and ease of culture are advantages that make it ideal as a model in toxicology. Due to the fact that some of its biochemical pathways are similar to those of humans, it has been employed in research in several fields. C. elegans' use as a biological model in environmental toxicological assessments allows the determination of multiple endpoints. Some of these utilize the effects on the biological functions of the nematode and others use molecular markers. Endpoints such as lethality, growth, reproduction, and locomotion are the most studied, and usually employ the wild type Bristol N2 strain. Other endpoints use reporter genes, such as green fluorescence protein, driven by regulatory sequences from other genes related to different mechanisms of toxicity, such as heat shock, oxidative stress, CYP system, and metallothioneins among others, allowing the study of gene expression in a manner both rapid and easy. These transgenic strains of C. elegans represent a powerful tool to assess toxicity pathways for mixtures and environmental samples, and their numbers are growing in diversity and selectivity. However, other molecular biology techniques, including DNA microarrays and MicroRNAs have been explored to assess the effects of different toxicants and samples. C. elegans has allowed the assessment of neurotoxic effects for heavy metals and pesticides, among those more frequently studied, as the nematode has a very well defined nervous system. More recently, nanoparticles are emergent pollutants whose toxicity can be explored using this nematode. Overall, almost every type of known toxicant has been tested with this animal model. In the near future, the available knowledge on the life cycle of C. elegans should allow more studies on reproduction and transgenerational toxicity for newly developed chemicals and materials, facilitating their introduction in the market. The great diversity of endpoints and possibilities of this animal makes it an easy first-choice for rapid toxicity screening or to detail signaling pathways involved in mechanisms of toxicity.

Congenital skeletal malformations and cleft palate induced in goats by ingestion of Lupinus, Conium and Nicotiana species.

PubMed

Panter, K E; Keeler, R F; Bunch, T D; Callan, R J

1990-01-01

Three piperidine alkaloid containing plants, Conium maculatum (poison-hemlock), Nicotiana glauca (tree tobacco) and Lupinus formosus (lunara lupine), induced multiple congenital contractures (MCC) and palatoschisis in goat kids when their dams were gavaged with the plant during gestation days 30-60. The skeletal abnormalities included fixed extension or flexure of the carpal, tarsal, and fetlock joints, scoliosis, lordosis, torticollis and rib cage abnormalities. Clinical signs of toxicity included those reported in sheep, cattle and pigs--ataxia, incoordination, muscular weakness, prostration and death. One quinolizidine alkaloid containing plant, Lupinus caudatus (tailcup lupine), on the other hand, which is also known to cause MCC in cows, caused only slight signs of toxicity in pregnant goats and no teratogenic effects in their offspring.

Hydrogen gas alleviates oxygen toxicity by reducing hydroxyl radical levels in PC12 cells.

PubMed

Yu, Junchao; Yu, Qiuhong; Liu, Yaling; Zhang, Ruiyun; Xue, Lianbi

2017-01-01

Hyperbaric oxygen (HBO) therapy through breathing oxygen at the pressure of above 1 atmosphere absolute (ATA) is useful for varieties of clinical conditions, especially hypoxic-ischemic diseases. Because of generation of reactive oxygen species (ROS), breathing oxygen gas at high pressures can cause oxygen toxicity in the central nervous system, leading to multiple neurological dysfunction, which limits the use of HBO therapy. Studies have shown that Hydrogen gas (H2) can diminish oxidative stress and effectively reduce active ROS associated with diseases. However, the effect of H2 on ROS generated from HBO therapy remains unclear. In this study, we investigated the effect of H2 on ROS during HBO therapy using PC12 cells. PC12 cells cultured in medium were exposed to oxygen gas or mixed oxygen gas and H2 at 1 ATA or 5 ATA. Cells viability and oxidation products and ROS were determined. The data showed that H2 promoted the cell viability and inhibited the damage in the cell and mitochondria membrane, reduced the levels of lipid peroxidation and DNA oxidation, and selectively decreased the levels of •OH but not disturbing the levels of O2•-, H2O2, or NO• in PC12 cells during HBO therapy. These results indicated that H2 effectively reduced •OH, protected cells against oxygen toxicity resulting from HBO therapy, and had no effect on other ROS. Our data supported that H2 could be potentially used as an antioxidant during HBO therapy.

Dialium seed coprophagy in wild western gorillas: Multiple nutritional benefits and toxicity reduction hypotheses.

PubMed

Masi, Shelly; Breuer, Thomas

2018-04-01

Unraveling the relationship between the unusual feeding behaviors and the nutritional intake of endangered species may provide crucial information for understanding species response to habitat unpredictable changes. Primates occasionally re-ingest fruit seeds alongside ingestion of feces, a behavior called coprophagy. The nutritional benefit is one of the several non-mutual exclusive hypotheses proposed to explain this behavior. We investigated the ecological correlates of coprophagy in wild western gorillas. We tested whether coprophagy occurred during periods of lower fruit availability and whether it led to higher nutrient intake in comparison to the other food. Data integrated phenological, fecal and nutritional analyses of gorilla food with behavioral observations collected at two sites in Central Africa (Mbeli Bai: ad libitum observations on 15 groups/solitary males, October 2002-November 2005; Bai Hokou: 5-min scan on a habituated group, December 2004-December 2005). Coprophagy occurred at the end of the high-fruiting season in association of two Dialium species. Coprophagy correlated positively with the occurrence of Dialium spp. fruit in gorilla feces and in the feeding scans, and showed a positive trend with Dialium availability but not with total fruit availability. Nutritional comparison of Dialium seeds with other important gorilla food showed higher fat and mineral content, particularly of Mg, but also of phenols and tannins in Dialium seeds. We discuss how the effect of gut processing and gut heat via coprophagy may act as cooking-like effect: increasing the ability to maximize nutrient intake by concurrently softening fibers and decreasing the toxic effect of antifeedants, like in human traditional cooking. Our results support both the multiple nutritional benefit hypothesis and the toxicity reduction hypothesis. Since Dialium is precious timber, the importance of this tree for the critically endangered western gorillas should be taken with high consideration when planning controlled logging of degraded forests or in face of habitat changes. © 2018 Wiley Periodicals, Inc.

Quantitative structure-toxicity relationship (QSTR) studies on the organophosphate insecticides.

PubMed

Can, Alper

2014-11-04

Organophosphate insecticides are the most commonly used pesticides in the world. In this study, quantitative structure-toxicity relationship (QSTR) models were derived for estimating the acute oral toxicity of organophosphate insecticides to male rats. The 20 chemicals of the training set and the seven compounds of the external testing set were described by means of using descriptors. Descriptors for lipophilicity, polarity and molecular geometry, as well as quantum chemical descriptors for energy were calculated. Model development to predict toxicity of organophosphate insecticides in different matrices was carried out using multiple linear regression. The model was validated internally and externally. In the present study, QSTR model was used for the first time to understand the inherent relationships between the organophosphate insecticide molecules and their toxicity behavior. Such studies provide mechanistic insight about structure-toxicity relationship and help in the design of less toxic insecticides. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Hypofractionated radiation therapy for prostate cancer: biologic and technical considerations

PubMed Central

Sanfilippo, Nicholas J; Cooper, Benjamin T

2014-01-01

The optimal radiation schedule for the curative treatment of prostate cancer is not known. The dose-response of tumors and normal tissues to fractionated irradiation can be described according to a parameter called the alpha-beta ratio (α/β). In the past several years numerous reports have been published that suggest that the alpha-beta ratio for prostate cancer may be quite low; between 1 and 3. If this hypothesis is true, then a radiation therapy schedule that employs less frequent and larger fractions, termed hypofractionation, may be more efficacious. Multiple randomized trials have been conducted comparing moderate (less than 5 Gy/day) hypofractionated radiation therapy and standard radiation therapy in men with prostate cancer. In the majority of these studies the moderate hypofractionated arm had equivalent efficacy with a similar or improved side effect profile. One area to use caution may be in patients with compromised (IPSS > 12) urinary function at baseline due to an increase in urinary toxicity observed in patients treated with hypofractionated radiation in one study. Extreme hypofractionation (greater than or equal to 5 Gy/day), is currently being compared in a randomized trial. Early prospectively collected data from multiple institutions demonstrates efficacy and toxicity that compares favorably with historical controls. The cost savings from hypofractionation could be profound on a national level and only increases the necessity of testing hypofractionated treatment schedules. Long term data and future trials will help radiation oncologists determine the ideal fractionation scheme based on cost, efficacy, and toxicity. PMID:25606574

Disseminated viridians streptococcus (Streptococcus mitis) infection presenting with toxic shock-like syndrome.

PubMed

Intalapaporn, Poj; Wongcharoen, Sunee; Chinapha, Anongnart; Jariyasethpong, Tavatchai

2013-03-01

The authors report a case of a 35-year-old man with no known underlying disease who presented with fever, cellulitis with hemorrhagic blebs on the left leg, monoarthricular left knee arthritis, multiple organ failure and septic shock. His clinical syndrome was compatible with toxic shock syndrome and his blood grew alpha hemolytic (viridians) Streptococcus mitis. To our knowledge, there are few reported cases of toxic shock syndrome cause by Streptococcus mitis in immune-competent adults.

Efficacy of Stereotactic Radiosurgery in Patients with Multiple Metastases: Importance of Volume Rather Than Number of Lesions.

PubMed

Dahshan, Basem A; Mattes, Malcolm D; Bhatia, Sanjay; Palek, Mary Susan; Cifarelli, Christopher P; Hack, Joshua D; Vargo, John A

2017-12-19

The role of stereotactic radiosurgery (SRS) in the treatment of multiple brain metastases is controversial. While whole brain radiation therapy (WBRT) has historically been the mainstay of treatment, its value is increasingly being questioned as emerging data supports that SRS alone can provide comparable therapeutic outcomes for limited (one to three) intracranial metastases with fewer adverse effects, including neurocognitive decline. Multiple recent studies have also demonstrated that patients with multiple (> 3) intracranial metastases with a low overall tumor volume have a favorable therapeutic response to SRS, with no significant difference compared to patients with limited metastases. Herein, we present a patient with previously controlled breast cancer who presented with multiple recurrences of intracranial metastases but low total intracranial tumor volume each time. This patient underwent SRS alone for a total of 40 metastatic lesions over three separate procedures with good local control and without any significant cognitive toxicity. The patient eventually opted for enrollment in the NRG-CC001 clinical trial after multiple cranial recurrences. She received conventional WBRT with six months of memantine and developed significant neurocognitive side effects. This case highlights the growing body of literature supporting the role of SRS alone in the management of multiple brain metastases and the importance of maximizing neurocognition as advances in systemic therapies prolong survival in Stage IV cancer.

Efficacy of Stereotactic Radiosurgery in Patients with Multiple Metastases: Importance of Volume Rather Than Number of Lesions

PubMed Central

Mattes, Malcolm D; Bhatia, Sanjay; Palek, Mary Susan; Cifarelli, Christopher P; Hack, Joshua D; Vargo, John A

2017-01-01

The role of stereotactic radiosurgery (SRS) in the treatment of multiple brain metastases is controversial. While whole brain radiation therapy (WBRT) has historically been the mainstay of treatment, its value is increasingly being questioned as emerging data supports that SRS alone can provide comparable therapeutic outcomes for limited (one to three) intracranial metastases with fewer adverse effects, including neurocognitive decline. Multiple recent studies have also demonstrated that patients with multiple (> 3) intracranial metastases with a low overall tumor volume have a favorable therapeutic response to SRS, with no significant difference compared to patients with limited metastases. Herein, we present a patient with previously controlled breast cancer who presented with multiple recurrences of intracranial metastases but low total intracranial tumor volume each time. This patient underwent SRS alone for a total of 40 metastatic lesions over three separate procedures with good local control and without any significant cognitive toxicity. The patient eventually opted for enrollment in the NRG-CC001 clinical trial after multiple cranial recurrences. She received conventional WBRT with six months of memantine and developed significant neurocognitive side effects. This case highlights the growing body of literature supporting the role of SRS alone in the management of multiple brain metastases and the importance of maximizing neurocognition as advances in systemic therapies prolong survival in Stage IV cancer. PMID:29492355

Importance of dual delivery systems for bone tissue engineering.

PubMed

Farokhi, Mehdi; Mottaghitalab, Fatemeh; Shokrgozar, Mohammad Ali; Ou, Keng-Liang; Mao, Chuanbin; Hosseinkhani, Hossein

2016-03-10

Bone formation is a complex process that requires concerted function of multiple growth factors. For this, it is essential to design a delivery system with the ability to load multiple growth factors in order to mimic the natural microenvironment for bone tissue formation. However, the short half-lives of growth factors, their relatively large size, slow tissue penetration, and high toxicity suggest that conventional routes of administration are unlikely to be effective. Therefore, it seems that using multiple bioactive factors in different delivery systems can develop new strategies for improving bone tissue regeneration. Combination of these factors along with biomaterials that permit tunable release profiles would help to achieve truly spatiotemporal regulation during delivery. This review summarizes the various dual-control release systems that are used for bone tissue engineering. Copyright © 2015 Elsevier B.V. All rights reserved.

Development and application of the adverse outcome pathway framework for understanding and predicting chronic toxicity: I. Challenges and research needs in ecotoxicology.

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

To elucidate the effects of chemicals on populations of different species in the environment, efficient testing and modeling approaches are needed that consider multiple stressors and allow reliable extrapolation of responses across species. An adverse outcome pathway (AOP) is a concept that provides a framework for organizing knowledge about the progression of toxicity events across scales of biological organization that lead to adverse outcomes relevant for risk assessment. In this paper, we focus on exploring how the AOP concept can be used to guide research aimed at improving both our understanding of chronic toxicity, including delayed toxicity as well as epigenetic and transgenerational effects of chemicals, and our ability to predict adverse outcomes. A better understanding of the influence of subtle toxicity on individual and population fitness would support a broader integration of sublethal endpoints into risk assessment frameworks. Detailed mechanistic knowledge would facilitate the development of alternative testing methods as well as help prioritize higher tier toxicity testing. We argue that targeted development of AOPs supports both of these aspects by promoting the elucidation of molecular mechanisms and their contribution to relevant toxicity outcomes across biological scales. We further discuss information requirements and challenges in application of AOPs for chemical- and site-specific risk assessment and for extrapolation across species. We provide recommendations for potential extension of the AOP framework to incorporate information on exposure, toxicokinetics and situation-specific ecological contexts, and discuss common interfaces that can be employed to couple AOPs with computational modeling approaches and with evolutionary life history theory. The extended AOP framework can serve as a venue for integration of knowledge derived from various sources, including empirical data as well as molecular, quantitative and evolutionary-based models describing species responses to toxicants. This will allow a more efficient application of AOP knowledge for quantitative chemical- and site-specific risk assessment as well as for extrapolation across species in the future. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Metal mixture modeling evaluation project: 2. Comparison of four modeling approaches.

PubMed

Farley, Kevin J; Meyer, Joseph S; Balistrieri, Laurie S; De Schamphelaere, Karel A C; Iwasaki, Yuichi; Janssen, Colin R; Kamo, Masashi; Lofts, Stephen; Mebane, Christopher A; Naito, Wataru; Ryan, Adam C; Santore, Robert C; Tipping, Edward

2015-04-01

As part of the Metal Mixture Modeling Evaluation (MMME) project, models were developed by the National Institute of Advanced Industrial Science and Technology (Japan), the US Geological Survey (USA), HDR|HydroQual (USA), and the Centre for Ecology and Hydrology (United Kingdom) to address the effects of metal mixtures on biological responses of aquatic organisms. A comparison of the 4 models, as they were presented at the MMME workshop in Brussels, Belgium (May 2012), is provided in the present study. Overall, the models were found to be similar in structure (free ion activities computed by the Windermere humic aqueous model [WHAM]; specific or nonspecific binding of metals/cations in or on the organism; specification of metal potency factors or toxicity response functions to relate metal accumulation to biological response). Major differences in modeling approaches are attributed to various modeling assumptions (e.g., single vs multiple types of binding sites on the organism) and specific calibration strategies that affected the selection of model parameters. The models provided a reasonable description of additive (or nearly additive) toxicity for a number of individual toxicity test results. Less-than-additive toxicity was more difficult to describe with the available models. Because of limitations in the available datasets and the strong interrelationships among the model parameters (binding constants, potency factors, toxicity response parameters), further evaluation of specific model assumptions and calibration strategies is needed. © 2014 SETAC.

Metal Mixture Modeling Evaluation project: 2. Comparison of four modeling approaches

USGS Publications Warehouse

Farley, Kevin J.; Meyer, Joe; Balistrieri, Laurie S.; DeSchamphelaere, Karl; Iwasaki, Yuichi; Janssen, Colin; Kamo, Masashi; Lofts, Steve; Mebane, Christopher A.; Naito, Wataru; Ryan, Adam C.; Santore, Robert C.; Tipping, Edward

2015-01-01

As part of the Metal Mixture Modeling Evaluation (MMME) project, models were developed by the National Institute of Advanced Industrial Science and Technology (Japan), the U.S. Geological Survey (USA), HDR⎪HydroQual, Inc. (USA), and the Centre for Ecology and Hydrology (UK) to address the effects of metal mixtures on biological responses of aquatic organisms. A comparison of the 4 models, as they were presented at the MMME Workshop in Brussels, Belgium (May 2012), is provided herein. Overall, the models were found to be similar in structure (free ion activities computed by WHAM; specific or non-specific binding of metals/cations in or on the organism; specification of metal potency factors and/or toxicity response functions to relate metal accumulation to biological response). Major differences in modeling approaches are attributed to various modeling assumptions (e.g., single versus multiple types of binding site on the organism) and specific calibration strategies that affected the selection of model parameters. The models provided a reasonable description of additive (or nearly additive) toxicity for a number of individual toxicity test results. Less-than-additive toxicity was more difficult to describe with the available models. Because of limitations in the available datasets and the strong inter-relationships among the model parameters (log KM values, potency factors, toxicity response parameters), further evaluation of specific model assumptions and calibration strategies is needed.

Estimation of reliability of predictions and model applicability domain evaluation in the analysis of acute toxicity (LD50).

PubMed

Sazonovas, A; Japertas, P; Didziapetris, R

2010-01-01

This study presents a new type of acute toxicity (LD(50)) prediction that enables automated assessment of the reliability of predictions (which is synonymous with the assessment of the Model Applicability Domain as defined by the Organization for Economic Cooperation and Development). Analysis involved nearly 75,000 compounds from six animal systems (acute rat toxicity after oral and intraperitoneal administration; acute mouse toxicity after oral, intraperitoneal, intravenous, and subcutaneous administration). Fragmental Partial Least Squares (PLS) with 100 bootstraps yielded baseline predictions that were automatically corrected for non-linear effects in local chemical spaces--a combination called Global, Adjusted Locally According to Similarity (GALAS) modelling methodology. Each prediction obtained in this manner is provided with a reliability index value that depends on both compound's similarity to the training set (that accounts for similar trends in LD(50) variations within multiple bootstraps) and consistency of experimental results with regard to the baseline model in the local chemical environment. The actual performance of the Reliability Index (RI) was proven by its good (and uniform) correlations with Root Mean Square Error (RMSE) in all validation sets, thus providing quantitative assessment of the Model Applicability Domain. The obtained models can be used for compound screening in the early stages of drug development and prioritization for experimental in vitro testing or later in vivo animal acute toxicity studies.

Image-guided total-marrow irradiation using helical tomotherapy in patients with multiple myeloma and acute leukemia undergoing hematopoietic cell transplantation.

PubMed

Wong, Jeffrey Y C; Rosenthal, Joseph; Liu, An; Schultheiss, Timothy; Forman, Stephen; Somlo, George

2009-01-01

Total-body irradiation (TBI) has an important role in patients undergoing hematopoietic cell transplantation (HCT), but is associated with significant toxicities. Targeted TBI using helical tomotherapy results in reduced doses to normal organs, which predicts for reduced toxicities compared with standard TBI. Thirteen patients with multiple myeloma were treated in an autologous tandem transplantation Phase I trial with high-dose melphalan, followed 6 weeks later by total-marrow irradiation (TMI) to skeletal bone. Dose levels were 10, 12, 14, and 16 Gy at 2 Gy daily/twice daily. In a separate allogeneic HCT trial, 8 patients (5 with acute myelogenous leukemia, 1 with acute lymphoblastic leukemia, 1 with non-Hodgkin's lymphoma, and 1 with multiple myeloma) were treated with TMI plus total lymphoid irradiation plus splenic radiotherapy to 12 Gy (1.5 Gy twice daily) combined with fludarabine/melphalan. For the 13 patients in the tandem autologous HCT trial, median age was 54 years (range, 42-66 years). Median organ doses were 15-65% that of the gross target volume dose. Primarily Grades 1-2 acute toxicities were observed. Six patients reported no vomiting; 9 patients, no mucositis; 6 patients, no fatigue; and 8 patients, no diarrhea. For the 8 patients in the allogeneic HCT trial, median age was 52 years (range, 24-61 years). Grades 2-3 nausea, vomiting, mucositis, and diarrhea were observed. In both trials, no Grade 4 nonhematologic toxicity was observed, and all patients underwent successful engraftment. This study shows that TMI using helical tomotherapy is clinically feasible. The reduced acute toxicities observed compare favorably with those seen with standard TBI. Initial results are encouraging and warrant further evaluation as a method to dose escalate with acceptable toxicity or to offer TBI-containing regimens to patients unable to tolerate standard approaches.

Development of an assay to assess genotoxicity by particulate matter extract

PubMed Central

Priftis, Alexandros; Papikinos, Konstantinos; Koukoulanaki, Marina; Kerasioti, Efthalia; Stagos, Dimitrios; Konstantinopoulos, Konstantinos; Spandidos, Demetrios A.; Kermenidou, Marianthi; Karakitsios, Spyros; Sarigiannis, Dimosthenis; Tsatsakis, Aristides M.; Kouretas, Demetrios

2017-01-01

The current study describes a method for assessing the oxidative potential of common environmental stressors (ambient air particulate matter), using a plasmid relaxation assay where the extract caused single-strand breaks, easily visualised through electrophoresis. This assay utilises a miniscule amount (11 µg) of particulate matter (PM) extract compared to other, cell-based methods (~3,000 µg). The negative impact of air pollution on human health has been extensively recognised. Among the air pollutants, PM plays an eminent role, as reflected in the broad scientific interest. PM toxicity highly depends on its composition (metals and organic compounds), which in turn has been linked to multiple health effects (such as cardiorespiratory diseases and cancer) through multiple toxicity mechanisms; the induction of oxidative stress is considered a major mechanism among these. In this study, the PM levels, oxidative potential, cytotoxicity and genotoxicity of PM in the region of Larissa, Greece were examined using the plasmid relaxation assay. Finally, coffee extracts from different varieties, derived from both green and roasted seeds, were examined for their ability to inhibit PM-induced DNA damage. These extracts also exerted an inhibitory effect on xanthine oxidase and catalase, but had no effect against superoxide dismutase. Overall, this study highlights the importance of assays for assessing the oxidative potential of widespread environmental stressors (PM), as well as the antioxidant capacity of beverages and food items, with the highlight being the development of a plasmid relaxation assay to assess the genotoxicity caused by PM using only a miniscule amount. PMID:28260086

Exposure of mallards (Anas platyrhynchos) to the hepatotoxic cyanobacterium Nodularia spumigena

USGS Publications Warehouse

Sipia, V.O.; Franson, J. Christian; Sjovall, O.; Pflugmacher, S.; Shearn-Bochsler, Valerie I.; Rocke, Tonie E.; Meriluoto, J.A.O.

2008-01-01

Nodularin (NODLN) is a cyclic pentapeptide hepatotoxin produced by the cyanobacterium Nodularia spumigena, which forms extensive blooms during the summer in the Baltic Sea. Nodularin was detected in liver, muscle and/or feather samples of several common eiders (Somateria mollissima) from the Gulf of Finland (northern Baltic Sea) in 2002-2005. Published information on the adverse effects of NODLN in marine birds is scarce. The aim of this study was to evaluate the toxicity of NODLN, and determine the concentrations of NODLN in liver and muscle tissue in mallards (Anas platyrhynchos) exposed to N. spumigena. Mallards received a single or multiple exposure via oral gavage with an aqueous slurry containing toxic N. spumigena. Dosages ranged from 200 to 600 ??g NODLN per kg body weight (bw). There were minimal histopathological changes in liver tissue, and brain cholinesterase activity did not differ among treatment groups. Concentrations of NODLN measured by LC-MS in liver varied between approximately 3-120 ??g kg-1 dry weight (dw) and ducks receiving multiple exposures had significantly greater liver toxin levels than ducks receiving the two lowest single exposures. In muscle, NODLN concentrations were approximately 2-6 ??g kg-1 dw, but did not differ significantly among exposure groups. This is the first in vivo lab study examining the effects and bioaccumulation of NODLN from N. spumigena in birds. The mallards in this study were resistant to adverse effects and did not bioaccumulate substantial levels of NODLN at the doses given. ?? 2008 Taylor & Francis.

Chemical warfare agents. Classes and targets.

PubMed

Schwenk, Michael

2018-09-01

Synthetic toxic chemicals (toxicants) and biological poisons (toxins) have been developed as chemical warfare agents in the last century. At the time of their initial consideration as chemical weapon, only restricted knowledge existed about their mechanisms of action. There exist two different types of acute toxic action: nonspecific cytotoxic mechanisms with multiple chemo-biological interactions versus specific mechanisms that tend to have just a single or a few target biomolecules. TRPV1- and TRPA-receptors are often involved as chemosensors that induce neurogenic inflammation. The present work briefly surveys classes and toxicologically relevant features of chemical warfare agents and describes mechanisms of toxic action. Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical immobilization of Pb, Cu, and Cd by phosphate materials and calcium carbonate in contaminated soils.

PubMed

Huang, Guoyong; Su, Xiaojuan; Rizwan, Muhammad Shahid; Zhu, Yifei; Hu, Hongqing

2016-08-01

Soil contamination with toxic metals has increasingly become a global concern over the past few decades. Phosphate and carbonate compounds are good passivation materials for Pb immobilization, while the effect of phosphate and carbonate on the immobilization of multiple heavy metals (Pb, Cu, and Cd) in contaminated soils was seldom investigated. In this study, bone meal (BM), phosphate rock (PR), oxalic acid-activated phosphate rock (APR), super phosphate (SP), and calcium carbonate (CC) were added to the contaminated soils to evaluate the effect of phosphate materials and calcium carbonate on the immobilization of Pb, Cu, and Cd. The results showed that the pH of the treated soils increased 1.3-2.7, except SP which decreased 0.5 at most. Compared to the control treatment, all phosphates and calcium carbonate added to the polluted soils increased the fraction of residual metals, and the application of APR, PR, BM, and CC significantly reduced exchangeable and carbonate-bound fraction metals. PR and APR were the most effective for the immobilization of Pb, Cu, and Cd in the soils among these materials. Moreover, the concentrations of all metals in the toxicity characteristic leaching procedure (TCLP) leachate decreased with increasing amounts of amendments, and the concentrations of Pb in the TCLP leachate for soils treated with PR and APR were below the nonhazardous regulatory limit of 5 mg L(-1) (US Environmental Protection Agency). Based on our results, phosphate rock and oxalic acid-activated phosphate rock are effective in the immobilization of multiple metals by reducing their mobility in the co-contaminated soils.

Comparison of conventional and lipid emulsion formulations of amphotericin B: Pharmacokinetics and toxicokinetics in dogs.

PubMed

Nieto, J; Alvar, J; Rodríguez, C; San Andrés, M I; San Andrés, M D; González, F

2018-04-01

The major limiting factor in the use of amphotericin B (AmB) is cumulative nephrotoxicity. In previous studies, AmB mixed with Intralipid® 20% (AmB-IL), a parenteral fat emulsion, reduces its toxicity, increases its efficacy and is less expensive than other commercial amphotericin B lipid formulations. The pharmacokinetics and toxicity of the conventional deoxycholate AmB formulation (Fungizone®) and AmB-IL were compared in dogs. The pharmacokinetic of AmB was significantly modified and renal toxicity and infusion-related side effects were reduced when the drug was prepared in fat emulsion. In addition, pharmacokinetics and toxicity were evaluated after the administration of multiple doses of AmB-IL with the purpose of determining an optimal treatment protocol in dogs. When using a consecutive day administration regime, there was a significant drug accumulation together with an increase in creatinine values after each dose. However, when using three doses per week administration regime, similar maximum and minimum plasma concentrations were maintained. During the four weeks of treatment a moderate increase in the creatinine values was observed but none of the treatments were ended prematurely. All these data suggest that Intralipid®, similar to that seen previously in humans, favors AmB distribution to the organs, decreasing drug toxicity and increasing its therapeutic index in the dogs. The dose protocol evaluated (25mg/m 2 /48h/three times per week) produces maintenance of AmB plasma levels that were close to that obtained by others authors after administration of liposomal formulations of AmB and that have been demonstrated to be clinically effective. Copyright © 2018 Elsevier Ltd. All rights reserved.

Imatinib and polypharmacy in very old patients with chronic myeloid leukemia: effects on response rate, toxicity and outcome.

PubMed

Iurlo, Alessandra; Nobili, Alessandro; Latagliata, Roberto; Bucelli, Cristina; Castagnetti, Fausto; Breccia, Massimo; Abruzzese, Elisabetta; Cattaneo, Daniele; Fava, Carmen; Ferrero, Dario; Gozzini, Antonella; Bonifacio, Massimiliano; Tiribelli, Mario; Pregno, Patrizia; Stagno, Fabio; Vigneri, Paolo; Annunziata, Mario; Cavazzini, Francesco; Binotto, Gianni; Mansueto, Giovanna; Russo, Sabina; Falzetti, Franca; Montefusco, Enrico; Gugliotta, Gabriele; Storti, Sergio; D'Addosio, Ada M; Scaffidi, Luigi; Cortesi, Laura; Cedrone, Michele; Rossi, Antonella Russo; Avanzini, Paolo; Mauro, Endri; Spadea, Antonio; Celesti, Francesca; Giglio, Gianfranco; Isidori, Alessandro; Crugnola, Monica; Calistri, Elisabetta; Sorà, Federica; Rege-Cambrin, Giovanna; Sica, Simona; Luciano, Luigiana; Galimberti, Sara; Orlandi, Ester M; Bocchia, Monica; Tettamanti, Mauro; Alimena, Giuliana; Saglio, Giuseppe; Rosti, Gianantonio; Mannucci, Pier Mannuccio; Cortelezzi, Agostino

2016-11-29

About 40% of all patients with chronic myeloid leukemia are currently old or very old. They are effectively treated with imatinib, even though underrepresented in clinical studies. Furthermore, as it happens in the general population, they often receive multiple drugs for associated chronic illnesses. Aim of this study was to assess whether or not in imatinib-treated patients aged >75 years the exposure to polypharmacy (5 drugs or more) had an impact on cytogenetic and molecular response rates, event-free and overall survival, as well as on hematological or extra-hematological toxicity. 296 patients at 35 Italian hematological institutions were evaluated. Polypharmacy was reported in 107 patients (36.1%), and drugs more frequently used were antiplatelets, diuretics, proton pump inhibitors, ACE-inhibitors, beta-blockers, calcium channel blockers, angiotensin II receptors blockers, statins, oral hypoglycemic drugs and alpha blockers. Complete cytogenetic response was obtained in 174 patients (58.8%), 78 (26.4%) within 6 month, 63 (21.3%) between 7 and 12 months. Major molecular response was obtained in 153 patients (51.7%), 64 (21.6%) within the 12 month. One hundred and twenty-eight cases (43.2%) of hematological toxicity were recorded, together with 167 cases (56.4%) of extra-hematological toxicity. Comparing patients exposed to polypharmacy to those without, no difference was observed pertaining to the dosage of imatinib, cytogenetic and molecular responses and hematological and extra-hematological toxicity. Notwithstanding the several interactions reported in the literature between imatinib and some of the medications considered herewith, this fact does not seem to have a clinical impact on response rate and outcome.

Hybrid Modeling Approach to Estimate Exposures of Hazardous Air Pollutants (HAPs) for the National Air Toxics Assessment (NATA).

PubMed

Scheffe, Richard D; Strum, Madeleine; Phillips, Sharon B; Thurman, James; Eyth, Alison; Fudge, Steve; Morris, Mark; Palma, Ted; Cook, Richard

2016-11-15

A hybrid air quality model has been developed and applied to estimate annual concentrations of 40 hazardous air pollutants (HAPs) across the continental United States (CONUS) to support the 2011 calendar year National Air Toxics Assessment (NATA). By combining a chemical transport model (CTM) with a Gaussian dispersion model, both reactive and nonreactive HAPs are accommodated across local to regional spatial scales, through a multiplicative technique designed to improve mass conservation relative to previous additive methods. The broad scope of multiple pollutants capturing regional to local spatial scale patterns across a vast spatial domain is precedent setting within the air toxics community. The hybrid design exhibits improved performance relative to the stand alone CTM and dispersion model. However, model performance varies widely across pollutant categories and quantifiably definitive performance assessments are hampered by a limited observation base and challenged by the multiple physical and chemical attributes of HAPs. Formaldehyde and acetaldehyde are the dominant HAP concentration and cancer risk drivers, characterized by strong regional signals associated with naturally emitted carbonyl precursors enhanced in urban transport corridors with strong mobile source sector emissions. The multiple pollutant emission characteristics of combustion dominated source sectors creates largely similar concentration patterns across the majority of HAPs. However, reactive carbonyls exhibit significantly less spatial variability relative to nonreactive HAPs across the CONUS.

The effects of PCBs and dioxins on child health.

PubMed

Lundqvist, Christofer; Zuurbier, Moniek; Leijs, Marike; Johansson, Carolina; Ceccatelli, Sandra; Saunders, Margaret; Schoeters, Greet; ten Tusscher, Gavin; Koppe, Janna G

2006-10-01

BACKGROUND/EXPOSURE: Dioxins and PCBs are highly persistent and highly toxic environmental pollutants which at present are derived mainly from waste incineration and food contamination. They are widespread in nature and pollute human food, including breast milk so that basically all children in Europe are exposed to measurable levels. RESULTS/TOXICITY IN CHILDREN: The toxicity of dioxins and PCBs are well described both from animal studies and from a number of human epidemiological studies including several large cohort studies. Especially developmental exposure has been shown to affect endocrine and cognitive systems negatively. Measurable outcomes include reduced IQ and changed behaviour. Foetotoxic effects with reduced birth weight and increased congenital anomalies such as cleft lip have also been described. Exposure to PCBs and dioxins must be considered also in the context of multiple exposure to several toxins simultaneously or sequentially. CONCLUSION/SUGGESTED ACTION: Some measures aimed at reducing exposure to dioxins have been partly successful in that the dioxin content of breast milk is going down. However, further steps to reduce exposure must be taken. We suggest legislative measures for reducing the re-entry of especially PCBs from waste into the environment. Individual pre-conception counselling is recommended in order to reduce developmental exposure and its consequences. Biomonitoring of the substances themselves in breast milk and foods is recommended as well as monitoring possible endocrine effects.

Sex-Specific Effects of Combined Exposure to Chemical and Non-chemical Stressors on Neuroendocrine Development: a Review of Recent Findings and Putative Mechanisms.

PubMed

Cowell, Whitney J; Wright, Rosalind J

2017-12-01

Environmental toxicants and psychosocial stressors share many biological substrates and influence overlapping physiological pathways. Increasing evidence indicates stress-induced changes to the maternal milieu may prime rapidly developing physiological systems for disruption by concurrent or subsequent exposure to environmental chemicals. In this review, we highlight putative mechanisms underlying sex-specific susceptibility of the developing neuroendocrine system to the joint effects of stress or stress correlates and environmental toxicants (bisphenol A, alcohol, phthalates, lead, chlorpyrifos, and traffic-related air pollution). We provide evidence indicating that concurrent or tandem exposure to chemical and non-chemical stressors during windows of rapid development is associated with sex-specific synergistic, potentiated and reversed effects on several neuroendocrine endpoints related to hypothalamic-pituitary-adrenal axis function, sex steroid levels, neurotransmitter circuits, and innate immune function. We additionally identify gaps, such as the role that the endocrine-active placenta plays, in our understanding of these complex interactions. Finally, we discuss future research needs, including the investigation of non-hormonal biomarkers of stress. We demonstrate multiple physiologic systems are impacted by joint exposure to chemical and non-chemical stressors differentially among males and females. Collectively, the results highlight the importance of evaluating sex-specific endpoints when investigating the neuroendocrine system and underscore the need to examine exposure to chemical toxicants within the context of the social environment.

Predicting the sensitivity of populations from individual exposure to chemicals: the role of ecological interactions.

PubMed

Gabsi, Faten; Schäffer, Andreas; Preuss, Thomas G

2014-07-01

Population responses to chemical stress exposure are influenced by nonchemical, environmental processes such as species interactions. A realistic quantification of chemical toxicity to populations calls for the use of methodologies that integrate these multiple stress effects. The authors used an individual-based model for Daphnia magna as a virtual laboratory to determine the influence of ecological interactions on population sensitivity to chemicals with different modes of action on individuals. In the model, hypothetical chemical toxicity targeted different vital individual-level processes: reproduction, survival, feeding rate, or somatic growth rate. As for species interactions, predatory and competition effects on daphnid populations were implemented following a worst-case approach. The population abundance was simulated at different food levels and exposure scenarios, assuming exposure to chemical stress solely or in combination with either competition or predation. The chemical always targeted one vital endpoint. Equal toxicity-inhibition levels differently affected the population abundance with and without species interactions. In addition, population responses to chemicals were highly sensitive to the environmental stressor (predator or competitor) and to the food level. Results show that population resilience cannot be attributed to chemical stress only. Accounting for the relevant ecological interactions would reduce uncertainties when extrapolating effects of chemicals from individuals to the population level. Validated population models should be used for a more realistic risk assessment of chemicals. © 2014 SETAC.

The Public Health Response to Toxic Shock Syndrome: A Historical Review and Lessons Learned

ERIC Educational Resources Information Center

Rasberry, Catherine N.

2005-01-01

The toxic shock syndrome (TSS) crisis is a historical public health success story from which much can be learned and applied to contemporary public health issues. Following the first reports, multiple research teams initiated studies designed to ascertain the risk factors associated with TSS. Those studies evolved over several years--each building…

The development of platinum compounds and their possible combination.

PubMed

Pasetto, Lara Maria; D'Andrea, Mario Rosario; Brandes, Alba Ariela; Rossi, Elena; Monfardini, Silvio

2006-10-01

Cisplatin plays a central role in cancer chemotherapy in spite of its toxicity. To circumvent this toxicity and to enhance its therapeutic index a lot of preclinical and clinical studies have been conducted and several thousand analogues have been synthesized. Much more analysis remains to be done, but nowadays, the absence of any definitive, biologically interpretable molecular predictor of activity is consistent with the idea that platinum compounds have multiple intracellular targets and that cells can have multiple mechanisms of resistance. This review analyses a part of these platinum compounds analyzed to date, their mechanism of action, resistance and the future trends in this sector.

Molecular Mechanisms of Anticancer Effects of Phytoestrogens in Breast Cancer.

PubMed

Hsieh, Chia-Jung; Hsu, Ya-Ling; Huang, Ya-Fang; Tsai, Eing-Mei

2018-01-01

Phytoestrogens derived from plants exert estrogenic as well as antiestrogenic effects and multiple actions within breast cancer cells. Chemopreventive properties of phytoestrogens have emerged from epidemiological observations. In recent clinical research studies, phytoestrogens are safe and may even protect against breast cancer. In this brief review, the molecular mechanisms of phytoestrogens on regulation of cell cycle, apoptosis, estrogen receptors, cell signaling pathways, and epigenetic modulations in relation to breast cancer are discussed. Phytoestrogens have a preferential affinity for estrogen receptor (ER)-β, which appears to be associated with antiproliferative and anticarcinogenic effects. Moreover, while phytoestrogens not only inhibit ER-positive but also ER-negative breast cancer cells, the possibility of epigenetic modulation playing an important role is also discussed. In conclusion, as there are multiple targets and actions of phytoestrogens, extensive research is still necessary. However, due to low toxicity, low cost, and easy availability, their potent chemoprevention effects deserve further study. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Toxicity assessment of sediments from the Grand Calumet River and Indiana Harbor Canal in northwestern Indiana, USA

USGS Publications Warehouse

Ingersoll, C.G.; MacDonald, D.D.; Brumbaugh, W.G.; Johnson, B. Thomas; Kemble, N.E.; Kunz, J.L.; May, T.W.; Wang, N.; Smith, J.R.; Sparks, D.W.; Ireland, D.S.

2002-01-01

The objective of this study was to evaluate the toxicity of sediments from the Grand Calumet River and Indiana Harbor Canal located in northwestern Indiana, USA. Toxicity tests used in this assessment included 10-day sediment exposures with the amphipod Hyalella azteca, 31-day sediment exposures with the oligochaete Lumbriculus variegatus, and the Microtox® Solid-Phase Sediment Toxicity Test. A total of 30 sampling stations were selected in locations that had limited historic matching toxicity and chemistry data. Toxic effects on amphipod survival were observed in 60% of the samples from the assessment area. Results of a toxicity test with oligochaetes indicated that sediments from the assessment area were too toxic to be used in proposed bioaccumulation testing. Measurement of amphipod length after the 10-day exposures did not provide useful information beyond that provided by the survival endpoint. Seven of the 15 samples that were identified as toxic in the amphipod tests were not identified as toxic in the Microtox test, indicating that the 10-day H. azteca test was more sensitive than the Microtox test. Samples that were toxic tended to have the highest concentrations of metals, polycyclic aromatic hydrocarbons (PAHs), and polychlorinated biphenyls (PCBs). The toxic samples often had an excess of simultaneously extracted metals (SEM) relative to acid volatile sulfide (AVS) and had multiple exceedances of probable effect concentrations (PECs). Metals may have contributed to the toxicity of samples that had both an excess molar concentration of SEM relative to AVS and elevated concentrations of metals in pore water. However, of the samples that had an excess of SEM relative to AVS, only 38% of these samples had elevated concentration of metals in pore water. The lack of correspondence between SEM-AVS and pore water metals indicates that there are variables in addition to AVS controlling the concentrations of metals in pore water. A mean PEC quotient of 3.4 (based on concentrations of metals, PAHs, and PCBs) was exceeded in 33% of the sediment samples and a mean quotient of 0.63 was exceeded in 70% of the thirty sediment samples from the assessment area. A 50% incidence of toxicity has been previously reported in a database for sediment tests with H. azteca at a mean quotient of 3.4 in 10-day exposures and at a mean quotient of 0.63 in 28-day exposures. Among the Indiana Harbor samples, most of the samples with a mean PEC quotient above 0.63 (i.e., 15 of 21; 71%) and above 3.4 (i.e., 10 of 10; 100%) were toxic to amphipods. Results of this study and previous studies demonstrate that sediments from this assessment area are among the most contaminated and toxic that have ever been reported.

Evaluation of developmental toxicity studies of glyphosate with attention to cardiovascular development.

PubMed

Kimmel, Gary L; Kimmel, Carole A; Williams, Amy L; DeSesso, John M

2013-02-01

The herbicide glyphosate has undergone multiple safety tests for developmental toxicity in rats and rabbits. The European Commission's 2002 review of available glyphosate data discusses specific heart defects observed in several individual rabbit developmental toxicity studies, but describes the evidence for a potential causal relationship as equivocal. The present assessment was undertaken to analyze the current body of information generated from seven unpublished rabbit studies in order to determine if glyphosate poses a risk for cardiovascular malformations. In addition, the results of six unpublished developmental toxicity studies in rats were considered. Five of the seven rabbit studies (dose range: 10-500 mg/kg/day) were GLP- and testing guideline-compliant for the era in which the studies were performed; a sixth study predated testing and GLP guidelines, but generally adhered to these principles. The seventh study was judged inadequate. In each of the adequate studies, offspring effects occurred only at doses that also caused maternal toxicity. An integrated evaluation of the six adequate studies, using conservative assumptions, demonstrated that neither the overall malformation rate nor the incidence of cardiovascular malformations increased with dose up to the point where severe maternal toxicity was observed (generally ≥150 mg/kg/day). Random occurrences of cardiovascular malformations were observed across all dose groups (including controls) and did not exhibit a dose-response relationship. In the six rat studies (dose range: 30-3500 mg/kg/day), a low incidence of sporadic cardiovascular malformations was reported that was clearly not related to treatment. In summary, assessment of the entire body of the developmental toxicity data reviewed fails to support a potential risk for increased cardiovascular defects as a result of glyphosate exposure during pregnancy.

Influence of sediment chemistry and sediment toxicity on macroinvertebrate communities across 99 wadable streams of the Midwestern USA

USGS Publications Warehouse

Moran, Patrick W.; Nowell, Lisa H.; Kemble, Nile E.; Mahler, Barbara J.; Waite, Ian R.; Van Metre, Peter C.

2017-01-01

Simultaneous assessment of sediment chemistry, sediment toxicity, and macroinvertebrate communities can provide multiple lines of evidence when investigating relations between sediment contaminants and ecological degradation. These three measures were evaluated at 99 wadable stream sites across 11 states in the Midwestern United States during the summer of 2013 to assess sediment pollution across a large agricultural landscape. This evaluation considers an extensive suite of sediment chemistry totaling 274 analytes (polycyclic aromatic hydrocarbons, organochlorine compounds, polychlorinated biphenyls, polybrominated diphenyl ethers, trace elements, and current-use pesticides) and a mixture assessment based on the ratios of detected compounds to available effects-based benchmarks. The sediments were tested for toxicity with the amphipod Hyalella azteca (28-d exposure), the midge Chironomus dilutus (10-d), and, at a few sites, with the freshwater mussel Lampsilis siliquoidea (28-d). Sediment concentrations, normalized to organic carbon content, infrequently exceeded benchmarks for aquatic health, which was generally consistent with low rates of observed toxicity. However, the benchmark-based mixture score and the pyrethroid insecticide bifenthrin were significantly related to observed sediment toxicity. The sediment mixture score and bifenthrin were also significant predictors of the upper limits of several univariate measures of the macroinvertebrate community (EPT percent, MMI (Macroinvertebrate Multimetric Index) Score, Ephemeroptera and Trichoptera richness) using quantile regression. Multivariate pattern matching (Mantel-like tests) of macroinvertebrate species per site to identified contaminant metrics and sediment toxicity also indicate that the sediment mixture score and bifenthrin have weak, albeit significant, influence on the observed invertebrate community composition. Together, these three lines of evidence (toxicity tests, univariate metrics, and multivariate community analysis) suggest that elevated contaminant concentrations in sediments, in particular bifenthrin, is limiting macroinvertebrate communities in several of these Midwest streams.

Evaluation of developmental toxicity studies of glyphosate with attention to cardiovascular development

PubMed Central

Kimmel, Gary L.; Kimmel, Carole A.; Williams, Amy L.

2013-01-01

The herbicide glyphosate has undergone multiple safety tests for developmental toxicity in rats and rabbits. The European Commission’s 2002 review of available glyphosate data discusses specific heart defects observed in several individual rabbit developmental toxicity studies, but describes the evidence for a potential causal relationship as equivocal. The present assessment was undertaken to analyze the current body of information generated from seven unpublished rabbit studies in order to determine if glyphosate poses a risk for cardiovascular malformations. In addition, the results of six unpublished developmental toxicity studies in rats were considered. Five of the seven rabbit studies (dose range: 10–500 mg/kg/day) were GLP- and testing guideline-compliant for the era in which the studies were performed; a sixth study predated testing and GLP guidelines, but generally adhered to these principles. The seventh study was judged inadequate. In each of the adequate studies, offspring effects occurred only at doses that also caused maternal toxicity. An integrated evaluation of the six adequate studies, using conservative assumptions, demonstrated that neither the overall malformation rate nor the incidence of cardiovascular malformations increased with dose up to the point where severe maternal toxicity was observed (generally ≥150 mg/kg/day). Random occurrences of cardiovascular malformations were observed across all dose groups (including controls) and did not exhibit a dose–response relationship. In the six rat studies (dose range: 30–3500 mg/kg/day), a low incidence of sporadic cardiovascular malformations was reported that was clearly not related to treatment. In summary, assessment of the entire body of the developmental toxicity data reviewed fails to support a potential risk for increased cardiovascular defects as a result of glyphosate exposure during pregnancy. PMID:23286529

Optimal choice of pH for toxicity and bioaccumulation studies of ionizing organic chemicals.

PubMed

Rendal, Cecilie; Kusk, Kresten Ole; Trapp, Stefan

2011-11-01

It is recognized that the pH of exposure solutions can influence the toxicity and bioaccumulation of ionizing compounds. The present study investigates whether it can be considered a general rule that an ionizable compound is more toxic and more bioaccumulative when in the neutral state. Three processes were identified to explain the behavior of ionizing compounds with changing pH: the change in lipophilicity when a neutral compound becomes ionized, electrical attraction, and the ion trap. The literature was screened for bioaccumulation and toxicity tests of ionizing organic compounds performed at multiple pH levels. Toxicity and bioconcentration factors (BCFs) were higher for acids at lower pH values, whereas the opposite was true for bases. The effect of pH was most pronounced when pH - pK(a) was in the range of -1 to 3 for acids, and -3 to 1 for bases. The factor by which toxicity and BCF changed with pH was correlated with the lipophilicity of the compound (log K(OW) of the neutral compound). For both acids and bases, the correlation was positive, but it was significant only for acids. Because experimental data in the literature were limited, results were supplemented with model simulations using a dynamic flux model based on the Fick-Nernst-Planck diffusion equation known as the cell model. The cell model predicts that bases with delocalized charges may in some cases show declining bioaccumulation with increasing pH. Little information is available for amphoteric and zwitterionic compounds; however, based on simulations with the cell model, it is expected that the highest toxicity and bioaccumulation of these compounds will be found where the compounds are most neutral, at the isoelectric point. Copyright © 2011 SETAC.

Multiple inorganic toxic substances contaminating the groundwater of Myingyan Township, Myanmar: arsenic, manganese, fluoride, iron, and uranium.

PubMed

Bacquart, Thomas; Frisbie, Seth; Mitchell, Erika; Grigg, Laurie; Cole, Christopher; Small, Colleen; Sarkar, Bibudhendra

2015-06-01

In South Asia, the technological and societal shift from drinking surface water to groundwater has resulted in a great reduction of acute diseases due to water borne pathogens. However, arsenic and other naturally occurring inorganic toxic substances present in groundwater in the region have been linked to a variety of chronic diseases, including cancers, heart disease, and neurological problems. Due to the highly specific symptoms of chronic arsenic poisoning, arsenic was the first inorganic toxic substance to be noticed at unsafe levels in the groundwater of West Bengal, India and Bangladesh. Subsequently, other inorganic toxic substances, including manganese, uranium, and fluoride have been found at unsafe levels in groundwater in South Asia. While numerous drinking water wells throughout Myanmar have been tested for arsenic, relatively little is known about the concentrations of other inorganic toxic substances in Myanmar groundwater. In this study, we analyzed samples from 18 drinking water wells (12 in Myingyan City and 6 in nearby Tha Pyay Thar Village) and 2 locations in the Ayeyarwaddy River for arsenic, boron, barium, beryllium, cadmium, cobalt, chromium, copper, fluoride, iron, mercury, manganese, molybdenum, nickel, lead, antimony, selenium, thallium, uranium, vanadium, and zinc. Concentrations of arsenic, manganese, fluoride, iron, or uranium exceeded health-based reference values in most wells. In addition, any given well usually contained more than one toxic substance at unsafe concentrations. While water testing and well sharing could reduce health risks, none of the wells sampled provide water that is entirely safe with respect to inorganic toxic substances. It is imperative that users of these wells, and users of other wells that have not been tested for multiple inorganic toxic substances throughout the region, be informed of the need for drinking water testing and the health consequences of drinking water contaminated with inorganic toxic substances. Copyright © 2015 Elsevier B.V. All rights reserved.

Stable Gene Targeting in Human Cells Using Single-Strand Oligonucleotides with Modified Bases

PubMed Central

Rios, Xavier; Briggs, Adrian W.; Christodoulou, Danos; Gorham, Josh M.; Seidman, Jonathan G.; Church, George M.

2012-01-01

Recent advances allow multiplexed genome engineering in E. coli, employing easily designed oligonucleotides to edit multiple loci simultaneously. A similar technology in human cells would greatly expedite functional genomics, both by enhancing our ability to test how individual variants such as single nucleotide polymorphisms (SNPs) are related to specific phenotypes, and potentially allowing simultaneous mutation of multiple loci. However, oligo-mediated targeting of human cells is currently limited by low targeting efficiencies and low survival of modified cells. Using a HeLa-based EGFP-rescue reporter system we show that use of modified base analogs can increase targeting efficiency, in part by avoiding the mismatch repair machinery. We investigate the effects of oligonucleotide toxicity and find a strong correlation between the number of phosphorothioate bonds and toxicity. Stably EGFP-corrected cells were generated at a frequency of ~0.05% with an optimized oligonucleotide design combining modified bases and reduced number of phosphorothioate bonds. We provide evidence from comparative RNA-seq analysis suggesting cellular immunity induced by the oligonucleotides might contribute to the low viability of oligo-corrected cells. Further optimization of this method should allow rapid and scalable genome engineering in human cells. PMID:22615794

Predicting herbicide mixture effects on multiple algal species using mixture toxicity models.

PubMed

Nagai, Takashi

2017-10-01

The validity of the application of mixture toxicity models, concentration addition and independent action, to a species sensitivity distribution (SSD) for calculation of a multisubstance potentially affected fraction was examined in laboratory experiments. Toxicity assays of herbicide mixtures using 5 species of periphytic algae were conducted. Two mixture experiments were designed: a mixture of 5 herbicides with similar modes of action and a mixture of 5 herbicides with dissimilar modes of action, corresponding to the assumptions of the concentration addition and independent action models, respectively. Experimentally obtained mixture effects on 5 algal species were converted to the fraction of affected (>50% effect on growth rate) species. The predictive ability of the concentration addition and independent action models with direct application to SSD depended on the mode of action of chemicals. That is, prediction was better for the concentration addition model than the independent action model for the mixture of herbicides with similar modes of action. In contrast, prediction was better for the independent action model than the concentration addition model for the mixture of herbicides with dissimilar modes of action. Thus, the concentration addition and independent action models could be applied to SSD in the same manner as for a single-species effect. The present study to validate the application of the concentration addition and independent action models to SSD supports the usefulness of the multisubstance potentially affected fraction as the index of ecological risk. Environ Toxicol Chem 2017;36:2624-2630. © 2017 SETAC. © 2017 SETAC.

Mitigation in Multiple Effects of Graphene Oxide Toxicity in Zebrafish Embryogenesis Driven by Humic Acid.

PubMed

Chen, Yuming; Ren, Chaoxiu; Ouyang, Shaohu; Hu, Xiangang; Zhou, Qixing

2015-08-18

Graphene oxide (GO) is a widely used carbonaceous nanomaterial. To date, the influence of natural organic matter (NOM) on GO toxicity in aquatic vertebrates has not been reported. During zebrafish embryogenesis, GO induced a significant hatching delay and cardiac edema. The intensive interactions of GO with the chorion induces damage to chorion protuberances, excessive generation of (•)OH, and changes in protein secondary structure. In contrast, humic acid (HA), a ubiquitous form of NOM, significantly relieved the above adverse effects. HA reduced the interactions between GO and the chorion and mitigated chorion damage by regulating the morphology, structures, and surface negative charges of GO. HA also altered the uptake and deposition of GO and decreased the aggregation of GO in embryonic yolk cells and deep layer cells. Furthermore, HA mitigated the mitochondrial damage and oxidative stress induced by GO. This work reveals a feasible antidotal mechanism for GO in the presence of NOM and avoids overestimating the risks of GO in the natural environment.

Repurposing cephalosporin antibiotics as pro-senescent radiosensitizers

PubMed Central

Flor, Amy C.; Sutton, Harold G.; Kron, Stephen J.; Weichselbaum, Ralph R.

2016-01-01

Radiation therapy remains a significant therapeutic modality in the treatment of cancer. An attractive strategy would be to enhance the benefits of ionizing radiation (IR)with radiosensitizers. A high-content drug repurposing screen of approved and investigational agents, natural products and other small molecules has identified multiple candidates that blocked repair of IR damage in vitro. Here, we validated a subset of these hits in vitro and then examined effects on tumor growth after IR in a murine tumor model. Based on robust radiosensitization in vivo and other favorable properties of cephalexin, we conducted additional studies with other beta-lactam antibiotics. When combined with IR, each cephalosporin tested increased DNA damage and slowed tumor growth without affecting normal tissue toxicity. Our data implicate reactive oxygen species in the mechanism by which cephalosporins augment the effects of IR. This work provides a rationale for using commonly prescribed beta-lactam antibiotics as non-toxic radiosensitizers to enhance the therapeutic ratio of radiotherapy. PMID:27129153

Short-term effects of military fog oil on the fountain darter (Etheostoma fonticola).

PubMed

Ryan, T A; Kohl, A N; Soucek, D J; Smith, T S; Brandt, T M; Bonner, T H; Cropek, D M

2013-11-01

Toxicity tests evaluated chronic and sublethal effects of fog oil (FO) on a freshwater endangered fish. FO is released during military training as an obscurant smoke that can drift into aquatic habitats. Fountain darters, Etheostoma fonticola, of four distinct life stages were exposed under laboratory conditions to three forms of FO. FO was vaporized into smoke and allowed to settle onto water, violently agitated with water, and dosed onto water followed by photo-oxidization by ultraviolet irradiation. Single smoke exposures of spawning adult fish did not affect egg production, egg viability, or adult fish survival in 21-day tests. Multiple daily smoke exposures induced mortality after 5 days for larvae fish. Larvae and juvenile fish were more sensitive than eggs in 96-h lethal concentration (LC50) tests with FO–water mixtures and photo-oxidized FO. Water-soluble FO components photo-modified by ultraviolet radiation were the most toxic, thus indicating the value of examining weathering and aging of chemicals for the best determination of environmental impact.

Nonnarcotic analgesics and tricyclic antidepressants for the treatment of chronic nonmalignant pain.

PubMed

Richlin, D M

1991-05-01

Chronic nonmalignant pain is often characterized by multiple treatment failures, a pattern of maladaptive behavior, and depression. Often there is a history of inappropriate and excessive use of medications for pain. Prior and ongoing use of narcotics and sedatives acts to compound and aggravate the chronic pain syndrome. A first step in treatment is controlled withdrawal of these agents. Nonnarcotic analgesics, NSAIDs, and tricyclic antidepressants are commonly employed in patients with chronic pain. Effective use of these agents requires understanding of their pharmacokinetic and pharmacodynamic properties. Use of a fixed-time schedule is necessary to achieve an effective, sustained therapeutic response. Careful patient education and monitoring for side effects and toxicity are necessary, particularly in the elderly and patients with coexisting medical disorders. Incidence of side effects and toxicity may be reduced by choice of drug and modification of dosing regimen. Nonnarcotic analgesics, TCAs, and NSAIDs are seldom effective by themselves in resolving the pain and distress of patients with chronic nonmalignant pain. This is particularly true when maladaptive behavior coexists. A comprehensive multimodal pain management program encompassing additional pain-relieving strategies and behavior-modifying techniques should be considered and utilized in conjunction with medication.

Natural health products that inhibit angiogenesis: a potential source for investigational new agents to treat cancer—Part 1

PubMed Central

Sagar, S.M.; Yance, D.; Wong, R.K.

2006-01-01

An integrative approach for managing a patient with cancer should target the multiple biochemical and physiologic pathways that support tumour development and minimize normal-tissue toxicity. Angiogenesis is a key process in the promotion of cancer. Many natural health products that inhibit angiogenesis also manifest other anticancer activities. The present article focuses on products that have a high degree of anti-angiogenic activity, but it also describes some of the many other actions of these agents that can inhibit tumour progression and reduce the risk of metastasis. Natural health products target molecular pathways other than angiogenesis, including epidermal growth factor receptor, the HER2/neu gene, the cyclooxygenase-2 enzyme, the nuclear factor kappa-B transcription factor, the protein kinases, the Bcl-2 protein, and coagulation pathways. The herbs that are traditionally used for anticancer treatment and that are anti-angiogenic through multiple interdependent processes (including effects on gene expression, signal processing, and enzyme activities) include Artemisia annua (Chinese wormwood), Viscum album (European mistletoe), Curcuma longa (curcumin), Scutellaria baicalensis (Chinese skullcap), resveratrol and proanthocyanidin (grape seed extract), Magnolia officinalis (Chinese magnolia tree), Camellia sinensis (green tea), Ginkgo biloba, quercetin, Poria cocos, Zingiber officinalis (ginger), Panax ginseng, Rabdosia rubescens hora (Rabdosia), and Chinese destagnation herbs. Quality assurance of appropriate extracts is essential prior to embarking upon clinical trials. More data are required on dose–response, appropriate combinations, and potential toxicities. Given the multiple effects of these agents, their future use for cancer therapy probably lies in synergistic combinations. During active cancer therapy, they should generally be evaluated in combination with chemotherapy and radiation. In this role, they act as modifiers of biologic response or as adaptogens, potentially enhancing the efficacy of the conventional therapies. PMID:17576437

A Phase III Study of Conventional Radiation Therapy Plus Thalidomide Versus Conventional Radiation Therapy for Multiple Brain Metastases (RTOG 0118)

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

Knisely, Jonathan P.S.; Berkey, Brian; Chakravarti, Arnab

2008-05-01

Purpose: To compare whole-brain radiation therapy (WBRT) with WBRT combined with thalidomide for patients with brain metastases not amenable to resection or radiosurgery. Patients and Methods: Patients with Zubrod performance status 0-1, MRI-documented multiple (>3), large (>4 cm), or midbrain brain metastases arising from a histopathologically confirmed extracranial primary tumor, and an anticipated survival of >8 weeks were randomized to receive WBRT to a dose of 37.5 Gy in 15 fractions with or without thalidomide during and after WBRT. Prerandomization stratification used Radiation Therapy Oncology Group (RTOG) Recursive Partitioning Analysis (RPA) Class and whether post-WBRT chemotherapy was planned. Endpoints includedmore » overall survival, progression-free survival, time to neurocognitive progression, the cause of death, toxicities, and quality of life. A protocol-planned interim analysis documented that the trial had an extremely low probability of ever showing a significant difference favoring the thalidomide arm given the results at the time of the analysis, and it was therefore closed on the basis of predefined statistical guidelines. Results: Enrolled in the study were 332 patients. Of 183 accrued patients, 93 were randomized to receive WBRT alone and 90 to WBRT and thalidomide. Median survival was 3.9 months for both arms. No novel toxicities were seen, but thalidomide was not well tolerated in this population. Forty-eight percent of patients discontinued thalidomide because of side effects. Conclusion: Thalidomide provided no survival benefit for patients with multiple, large, or midbrain metastases when combined with WBRT; nearly half the patients discontinued thalidomide due to side effects.« less

Protein Nanoscaffolds for Delivering Toxic Inorganic Cargo to Cancer Cells

NASA Astrophysics Data System (ADS)

Cioloboc, Daniela

Targeted delivery of anticancer drugs or prodrugs to tumors can minimize systemic toxicity and side effects. This study develops platforms for targeted delivery of two potentially less systemically toxic prodrugs by exploiting the native and/or bioinorganic properties of two ferritins, both of which function naturally as iron storage proteins. Two delivery approaches were investigated. The first system was designed to serve as either an enhancement or alternative to traditional photodynamic therapy by generating hydroxyl radical in addition to singlet oxygen as the toxic reactive oxygen species. This system used Escherichia coli bacterioferritin (Bfr) loaded with 2,500 irons and multiple zinc-porphyrin (ZnP) photosensitizers. Ferrous iron was released by photoreduction of ferric iron stored within the Bfr protein shell. Hydroxyl radicals were generated via the Fenton reaction between hydrogen peroxide and the released ferrous iron. The outer surface of the Bfr protein shell was coated with peptides that specifically bind to a receptor known to be overexpressed in many tumor cells and tumor vasculature. The iron-loaded peptide-ZnP-Bfr was endocytosed by melanoma cells, where it showed photo-triggered release of iron and light-dependent cytotoxicity. The second system, built around human heavy chain ferritin (HFn), was loaded with arsenate as a less toxic "prodrug" and designed to release arsenic in its toxic, therapeutically effective reduced form, arsenic trioxide (ATO). The Hfn shell was coated with peptides targeting receptors that are hyperexpressed in triple negative breast cancers. The arsenate/iron-loaded-Hfn was endocytosed by a breast cancer cell line and showed cytotoxicity equivalent to that of free ATO on an arsenic basis, whereas the "empty" or iron-only loaded Hfn showed no cytotoxicity. Although HFn has previously been used to deliver organic drugs and imaging agents, these new results demonstrate that both Bfr and HFn can be manipulated to function as 'Trojan horse' nanocarriers for inorganic drugs.

Effects of defined mixtures of persistent organic pollutants (POPs) on multiple cellular responses in the human hepatocarcinoma cell line, HepG2, using high content analysis screening

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

Wilson, Jodie; Berntsen, Hanne Friis; Zimmer, Karin Elisabeth

Persistent organic pollutants (POPs) are toxic substances, highly resistant to environmental degradation, which can bio-accumulate and have long-range atmospheric transport potential. Most studies focus on single compound effects, however as humans are exposed to several POPs simultaneously, investigating exposure effects of real life POP mixtures on human health is necessary. A defined mixture of POPs was used, where the compound concentration reflected its contribution to the levels seen in Scandinavian human serum (total mix). Several sub mixtures representing different classes of POPs were also constructed. The perfluorinated (PFC) mixture contained six perfluorinated compounds, brominated (Br) mixture contained seven brominated compounds,more » chlorinated (Cl) mixture contained polychlorinated biphenyls and also p,p’-dichlorodiphenyldichloroethylene, hexachlorobenzene, three chlordanes, three hexachlorocyclohexanes and dieldrin. Human hepatocarcinoma (HepG2) cells were used for 2 h and 48 h exposures to the seven mixtures and analysis on a CellInsight™ NXT High Content Screening platform. Multiple cytotoxic endpoints were investigated: cell number, nuclear intensity and area, mitochondrial mass and membrane potential (MMP) and reactive oxygen species (ROS). Both the Br and Cl mixtures induced ROS production but did not lead to apoptosis. The PFC mixture induced ROS production and likely induced cell apoptosis accompanied by the dissipation of MMP. Synergistic effects were evident for ROS induction when cells were exposed to the PFC + Br mixture in comparison to the effects of the individual mixtures. No significant effects were detected in the Br + Cl, PFC + Cl or total mixtures, which contain the same concentrations of chlorinated compounds as the Cl mixture plus additional compounds; highlighting the need for further exploration of POP mixtures in risk assessment. - Highlights: • High content analysis (HCA) is a novel approach for determining toxicity of complex mixtures. • Multiple cytotoxic endpoints were investigated for defined mixtures of persistent organic pollutants (POPs). • POP mixtures are based on levels relevant to human exposure. • POP mixtures can increase ROS induction and impact mitochondrial health, which could result in apoptosis. • HCA can detect pre-lethal and reversible signs of cellular stress.« less

Primary sources and toxicity of PAHs in Milwaukee-area streambed sediment

USGS Publications Warehouse

Baldwin, Austin K.; Corsi, Steven R.; Lutz, Michelle A.; Ingersoll, Christopher G.; Dorman, Rebecca A.; Magruder, Christopher; Magruder, Matthew

2017-01-01

High concentrations of polycyclic aromatic hydrocarbons (PAHs) in streams can be a significant stressor to aquatic organisms. To understand the likely sources and toxicity of PAHs in Milwaukee-area streams, streambed sediment samples from 40 sites and parking lot dust samples from 6 sites were analyzed for 38 parent PAHs and 25 alkylated PAHs. Diagnostic ratios, profile correlations, principal components analysis, source-receptor modeling, and mass fractions analysis were used to identify potential PAH sources to streambed sediment samples, and land-use analysis was used to relate streambed sediment PAH concentrations to different urban-related land uses. On the basis of this multiple lines-of-evidence approach, coal-tar pavement sealant was indicated as the primary source of PAHs in a majority of streambed sediment samples, contributing an estimated 77% of total PAHs to samples, on average. Comparison to the Probable Effect Concentrations and (or) the Equilibrium Partitioning Sediment Benchmark indicates that 78% of stream sediment samples are likely to cause adverse effects to benthic organisms. Laboratory toxicity tests on a 16-sample subset of the streambed sites using the amphipod Hyalella azteca (28-day) and the midge Chironomus dilutus (10-day) measured significant reductions in one or more biological endpoints, including survival, in 75% of samples, with H. azteca more responsive than C. dilutus.

Predicting the aquatic risk of realistic pesticide mixtures to species assemblages in Portuguese river basins.

PubMed

Silva, Emília; Daam, Michiel A; Cerejeira, Maria José

2015-05-01

Although pesticide regulatory tools are mainly based on individual substances, aquatic ecosystems are usually exposed to multiple pesticides from their use on the variety of crops within the catchment of a river. This study estimated the impact of measured pesticide mixtures in surface waters from 2002 and 2008 within three important Portuguese river basins ('Mondego', 'Sado' and 'Tejo') on primary producers, arthropods and fish by toxic pressure calculation. Species sensitivity distributions (SSDs), in combination with mixture toxicity models, were applied. Considering the differences in the responses of the taxonomic groups as well as in the pesticide exposures that these organisms experience, variable acute multi-substance potentially affected fractions (msPAFs) were obtained. The median msPAF for primary producers and arthropods in surface waters of all river basins exceeded 5%, the cut-off value used in the prospective SSD approach for deriving individual environmental quality standards. A ranking procedure identified various photosystem II inhibiting herbicides, with oxadiazon having the relatively largest toxic effects on primary producers, while the organophosphorus insecticides, chlorfenvinphos and chlorpyrifos, and the organochloride endosulfan had the largest effects on arthropods and fish, respectively. These results ensure compliance with European legislation with regard to ecological risk assessment and management of pesticides in surface waters. Copyright © 2015. Published by Elsevier B.V.

Respiratory bronchiolitis-associated interstitial lung disease secondary to electronic nicotine delivery system use confirmed with open lung biopsy.

PubMed

Flower, Mark; Nandakumar, Lakshmy; Singh, Mahendra; Wyld, David; Windsor, Morgan; Fielding, David

2017-05-01

As a modern phenomenon, there is currently limited understanding of the possible toxic effects and broader implications of electronic nicotine delivery systems (ENDS). Large volumes of aerosolized particles are inhaled during "vaping" and there are now an increasing number of case reports demonstrating toxic effects of ENDS, as well as human studies demonstrating impaired lung function in users. This article presents a case of respiratory bronchiolitis interstitial lung disease (RB-ILD) precipitated by vaping in a 33-year-old male with 10 pack years of traditional cigarette and prior treatment for mixed germ cell tumour. The patient had started vaping 10-15 times per day while continuing to smoke 10 traditional cigarettes per day. After 3 months of exposure to e-cigarette vapour, chest computed tomography demonstrated multiple new poorly defined pulmonary nodules with fluffy parenchyma opacification centred along the terminal bronchovascular units. Video-assisted thoracoscopy with lung biopsy of the right upper and right middle lobes was undertaken. The microscopic findings were overall consistent with RB-ILD. This case demonstrates toxicity with use of ENDS on open lung biopsy with resolution of radiographic findings on cessation. We believe that this is the first case where open lung biopsy has demonstrated this and our findings are consistent with RB-ILD.

Advancing drug delivery systems for the treatment of multiple sclerosis.

PubMed

Tabansky, Inna; Messina, Mark D; Bangeranye, Catherine; Goldstein, Jeffrey; Blitz-Shabbir, Karen M; Machado, Suly; Jeganathan, Venkatesh; Wright, Paul; Najjar, Souhel; Cao, Yonghao; Sands, Warren; Keskin, Derin B; Stern, Joel N H

2015-12-01

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system. It is characterized by demyelination of neurons and loss of neuronal axons and oligodendrocytes. In MS, auto-reactive T cells and B cells cross the blood-brain barrier (BBB), causing perivenous demyelinating lesions that form multiple discrete inflammatory demyelinated plaques located primarily in the white matter. In chronic MS, cortical demyelination and progressive axonal transections develop. Treatment for MS can be stratified into disease-modifying therapies (DMTs) and symptomatic therapy. DMTs aim to decrease circulating immune cells or to prevent these cells from crossing the BBB and reduce the inflammatory response. There are currently 10 DMTs approved for the relapsing forms of MS; these vary with regard to their efficacy, route and frequency of administration, adverse effects, and toxicity profile. Better drug delivery systems are being developed in order to decrease adverse effects, increase drug efficacy, and increase patient compliance through the direct targeting of pathologic cells. Here, we address the uses and benefits of advanced drug delivery systems, including nanoparticles, microparticles, fusion antibodies, and liposomal formulations. By altering the properties of therapeutic particles and enhancing targeting, breakthrough drug delivery technologies potentially applicable to multiple disease treatments may rapidly emerge.

Pre-clinical efficacy assessment of Malva sylvestris on chronic skin inflammation.

PubMed

Prudente, Arthur S; Sponchiado, Graziela; Mendes, Daniel A G B; Soley, Bruna S; Cabrini, Daniela A; Otuki, Michel F

2017-09-01

In the search for improved quality of life, the treatment of skin diseases like psoriasis (hyperproliferative disease) is valid, since it causes huge social discomfort to the patient. In this context, earlier studies showed that Malva sylvestris L. has anti-inflammatory activity demonstrated by acute animal models of skin inflammation, becoming a promising target for further studies. The present investigation aimed to verify the effect of hydroalcoholic extract of M. sylvestris (HEMS) on the chronic inflammatory and hyperproliferative response caused by multiple applications of 12-O-tetradecanoylphorbol-13-acetate (TPA) on mouse ears. Topical application of HEMS reduced oedema, leukocyte migration (mono- and polymorphonuclear cells) and keratinocyte hyperproliferation, confirmed by histology and proliferating cell nuclear antigen (PCNA) immunostaining. It was found that the anti-inflammatory effects of the extract did not involve the glucocorticoid system, and its incubation with HaCaT keratinocytes caused low toxicity and reduced cell proliferation by apoptosis. Thus, HEMS proved to be effective as an anti-psoriatic therapy, with the ability to prevent keratinocyte hyperproliferation and with low toxicity by topical application. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Heparin use in a rat hemorrhagic shock model induces biologic activity in mesenteric lymph separate from shock

PubMed Central

Qin, Yong; Prescott, Lauriston M.; Deitch, Edwin A.; Kaiser, Vicki L.

2011-01-01

Experimental data has shown that mesenteric lymph from rats subjected to trauma-hemorrhagic shock (THS) but not trauma-sham shock (TSS) induces neutrophil activation, cytotoxicity, decreased red blood cell deformability and bone marrow colony growth suppression. These data have lead to the hypothesis that gut factors produced from THS enter the systemic circulation via the mesenteric lymphatics and contribute to the progression of Multiple Organ Failure (MOF) following THS. Ongoing studies designed to identify bioactive lymph agents implicated factors associated with the heparin use in the THS procedure. We investigated if heparin itself was responsible for reported toxicity to human umbilical vein endothelial cells (HUVECs). HUVEC toxicity was not induced by lymph when alternate anti-coagulants (citrate and EDTA) were used in THS. HUVEC toxicity was induced by lymph after heparin but not saline or citrate injection into TSS and naïve animals and was dose dependent. Activities of both heparin-releasable lipases (lipoprotein (LPL) and hepatic (HL)) were detected in the plasma and lymph from THS and naïve animals receiving heparin but not citrate or saline. Lymph-induced HUVEC toxicity correlated with lymph lipase activities. Finally, incubation of HUVECs with purified LPL added to naïve lymph induced toxicity in vitro. These data show that heparin, not THS, is responsible for the reported lymph-mediated HUVEC toxicity through its release of lipases into the lymph. These findings can provide alternative explanations for several of the THS effects reported in the literature using heparin models thus necessitating a review of previous work in this field. PMID:21063238

Heparin use in a rat hemorrhagic shock model induces biologic activity in mesenteric lymph separate from shock.

PubMed

Qin, Yong; Prescott, Lauriston M; Deitch, Edwin A; Kaiser, Vicki L

2011-04-01

Experimental data have shown that mesenteric lymph from rats subjected to trauma-hemorrhagic shock (THS) but not trauma-sham shock induces neutrophil activation, cytotoxicity, decreased red blood cell (RBC) deformability, and bone marrow colony growth suppression. These data have led to the hypothesis that gut factors produced from THS enter the systemic circulation via the mesenteric lymphatics and contribute to the progression of multiple organ failure after THS. Ongoing studies designed to identify bioactive lymph agents implicated factors associated with the heparin use in the THS procedure. We investigated if heparin itself was responsible for reported toxicity to human umbilical vein endothelial cells (HUVECs). Human umbilical vein endothelial cell toxicity was not induced by lymph when alternate anticoagulants (citrate and EDTA) were used in THS. Human umbilical vein endothelial cell toxicity was induced by lymph after heparin but not saline or citrate injection into trauma-sham shock and naive animals and was dose dependent. Activities of both heparin-releasable lipases (lipoprotein and hepatic) were detected in the plasma and lymph from THS and naive animals receiving heparin but not citrate or saline. Lymph-induced HUVEC toxicity correlated with lymph lipase activities. Finally, incubation of HUVECs with purified lipoprotein lipase added to naive lymph-induced toxicity in vitro. These data show that heparin, not THS, is responsible for the reported lymph-mediated HUVEC toxicity through its release of lipases into the lymph. These findings can provide alternative explanations for several of the THS effects reported in the literature using heparin models, thus necessitating a review of previous work in this field.

Thermochemical Wastewater Valorization via Enhanced Microbial Toxicity Tolerance

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

Beckham, Gregg T; Thelhawadigedara, Lahiru Niroshan Jayakody; Johnson, Christopher W

Thermochemical (TC) biomass conversion processes such as pyrolysis and liquefaction generate considerable amounts of wastewater, which often contains highly toxic compounds that are incredibly challenging to convert via standard wastewater treatment approaches such as anaerobic digestion. These streams represent a cost for TC biorefineries, and a potential valorization opportunity, if effective conversion methods are developed. The primary challenge hindering microbial conversion of TC wastewater is toxicity. In this study, we employ a robust bacterium, Pseudomonas putida, with TC wastewater streams to demonstrate that aldehydes are the most inhibitory compounds in these streams. Proteomics, transcriptomics, and fluorescence-based immunoassays of P. putidamore » grown in a representative wastewater stream indicate that stress results from protein damage, which we hypothesize is a primary toxicity mechanism. Constitutive overexpression of the chaperone genes, groEL, groES, and clpB, in a genome-reduced P. putida strain improves the tolerance towards multiple TC wastewater samples up to 200-fold. Moreover, the concentration ranges of TC wastewater are industrially relevant for further bioprocess development for all wastewater streams examined here, representing different TC process configurations. Furthermore, we demonstrate proof-of-concept polyhydroxyalkanoate production from the usable carbon in an exemplary TC wastewater stream. Overall, this study demonstrates that protein quality control machinery and repair mechanisms can enable substantial gains in microbial tolerance to highly toxic substrates, including heterogeneous waste streams. When coupled to other metabolic engineering advances such as expanded substrate utilization and enhanced product accumulation, this study generally enables new strategies for biological conversion of highly-toxic, organic-rich wastewater via engineered aerobic monocultures or designer consortia.« less

Nrf2 protects human bladder urothelial cells from arsenite and monomethylarsonous acid toxicity

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

Wang Xiaojun; Sun Zheng; Chen Weimin

2007-12-01

Arsenic is widely spread in our living environment and imposes a big challenge on human health worldwide. Arsenic damages biological systems through multiple mechanisms including the generation of reactive oxygen species. The transcription factor Nrf2 regulates the cellular antioxidant response that protects cells from various insults. In this study, the protective role of Nrf2 in arsenic toxicity was investigated in a human bladder urothelial cell line, UROtsa. Using a UROtsa cell line stably infected with Nrf2-siRNA, we clearly demonstrate that compromised Nrf2 expression sensitized the cells to As(III)- and MMA(III)-induced toxicity. On the other hand, the activation of the Nrf2more » pathway by tert-butylhydroquinone (tBHQ) and sulforaphane (SF), the known Nrf2-inducers, rendered UROtsa cells more resistant to As(III) and MMA(III). Furthermore, the wild-type mouse embryo fibroblast (WT-MEF) cells were protected from As(III)- and MMA(III)-induced toxicity following Nrf2 activation by tBHQ or SF, whereas neither tBHQ nor SF conferred protection in the Nrf2{sup -/-}MEF cells, demonstrating that tBHQ- or SF-mediated protection against As(III)- and MMA(III)-induced toxicity depends on Nrf2 activation. These results, obtained by both loss of function and gain of function analyses, clearly demonstrate the protective role of Nrf2 in arsenic-induced toxicity. The current work lays the groundwork for using Nrf2 activators for therapeutic and dietary interventions against adverse effects of arsenic.« less

Advancing environmental toxicology through chemical dosimetry: External exposures versus tissue residues

USGS Publications Warehouse

McCarty, L.S.; Landrum, P.F.; Luoma, S.N.; Meador, J.P.; Merten, A.A.; Shephard, B.K.; van Wezelzz, A.P.

2011-01-01

The tissue residue dose concept has been used, although in a limited manner, in environmental toxicology for more than 100 y. This review outlines the history of this approach and the technical background for organic chemicals and metals. Although the toxicity of both can be explained in tissue residue terms, the relationship between external exposure concentration, body and/or tissues dose surrogates, and the effective internal dose at the sites of toxic action tends to be more complex for metals. Various issues and current limitations related to research and regulatory applications are also examined. It is clear that the tissue residue approach (TRA) should be an integral component in future efforts to enhance the generation, understanding, and utility of toxicity testing data, both in the laboratory and in the field. To accomplish these goals, several key areas need to be addressed: 1) development of a risk-based interpretive framework linking toxicology and ecology at multiple levels of biological organization and incorporating organism-based dose metrics; 2) a broadly applicable, generally accepted classification scheme for modes/mechanisms of toxic action with explicit consideration of residue information to improve both single chemical and mixture toxicity data interpretation and regulatory risk assessment; 3) toxicity testing protocols updated to ensure collection of adequate residue information, along with toxicokinetics and toxicodynamics information, based on explicitly defined toxicological models accompanied by toxicological model validation; 4) continued development of residueeffect databases is needed ensure their ongoing utility; and 5) regulatory guidance incorporating residue-based testing and interpretation approaches, essential in various jurisdictions. ??:2010 SETAC.

In vivo tumor targeting of gold nanoparticles: effect of particle type and dosing strategy.

PubMed

Puvanakrishnan, Priyaveena; Park, Jaesook; Chatterjee, Deyali; Krishnan, Sunil; Tunnell, James W

2012-01-01

Gold nanoparticles (GNPs) have gained significant interest as nanovectors for combined imaging and photothermal therapy of tumors. Delivered systemically, GNPs preferentially accumulate at the tumor site via the enhanced permeability and retention effect, and when irradiated with near infrared light, produce sufficient heat to treat tumor tissue. The efficacy of this process strongly depends on the targeting ability of the GNPs, which is a function of the particle's geometric properties (eg, size) and dosing strategy (eg, number and amount of injections). The purpose of this study was to investigate the effect of GNP type and dosing strategy on in vivo tumor targeting. Specifically, we investigated the in vivo tumor-targeting efficiency of pegylated gold nanoshells (GNSs) and gold nanorods (GNRs) for single and multiple dosing. We used Swiss nu/nu mice with a subcutaneous tumor xenograft model that received intravenous administration for a single and multiple doses of GNS and GNR. We performed neutron activation analysis to quantify the gold present in the tumor and liver. We performed histology to determine if there was acute toxicity as a result of multiple dosing. Neutron activation analysis results showed that the smaller GNRs accumulated in higher concentrations in the tumor compared to the larger GNSs. We observed a significant increase in GNS and GNR accumulation in the liver for higher doses. However, multiple doses increased targeting efficiency with minimal effect beyond three doses of GNPs. These results suggest a significant effect of particle type and multiple doses on increasing particle accumulation and on tumor targeting ability.

The Potential Role of Aerobic Exercise to Modulate Cardiotoxicity of Molecularly Targeted Cancer Therapeutics

PubMed Central

Lakoski, Susan; Mackey, John R.; Douglas, Pamela S.; Haykowsky, Mark J.; Jones, Lee W.

2013-01-01

Molecularly targeted therapeutics (MTT) are the future of cancer systemic therapy. They have already moved from palliative therapy for advanced solid malignancies into the setting of curative-intent treatment for early-stage disease. Cardiotoxicity is a frequent and potentially serious adverse complication of some targeted therapies, leading to a broad range of potentially life-threatening complications, therapy discontinuation, and poor quality of life. Low-cost pleiotropic interventions are therefore urgently required to effectively prevent and/or treat MTT-induced cardiotoxicity. Aerobic exercise therapy has the unique capacity to modulate, without toxicity, multiple gene expression pathways in several organ systems, including a plethora of cardiac-specific molecular and cell-signaling pathways implicated in MTT-induced cardiac toxicity. In this review, we examine the molecular signaling of antiangiogenic and HER2-directed therapies that may underpin cardiac toxicity and the hypothesized molecular mechanisms underlying the cardioprotective properties of aerobic exercise. It is hoped that this knowledge can be used to maximize the benefits of small molecule inhibitors, while minimizing cardiac damage in patients with solid malignancies. PMID:23335619

Facilitation of trace metal uptake in cells by inulin coating of metallic nanoparticles

NASA Astrophysics Data System (ADS)

Santillán-Urquiza, Esmeralda; Arteaga-Cardona, Fernando; Torres-Duarte, Cristina; Cole, Bryan; Wu, Bing; Méndez-Rojas, Miguel A.; Cherr, Gary N.

2017-09-01

Trace elements such as zinc and iron are essential for the proper function of biochemical processes, and their uptake and bioavailability are dependent on their chemical form. Supplementation of trace metals through nanostructured materials is a new field, but its application raises concerns regarding their toxicity. Here, we compared the intracellular zinc uptake of different sources of zinc: zinc sulfate, and ZnO and core-shell α-Fe2O3@ZnO nanoparticles, coated or uncoated with inulin, an edible and biocompatible polysaccharide. Using mussel haemocytes, a well-known model system to assess nanomaterial toxicity, we simultaneously assessed zinc accumulation and multiple cellular response endpoints. We found that intracellular zinc uptake was strongly enhanced by inulin coating, in comparison to the uncoated nanoparticles, while no significant effects on cell death, cell viability, mitochondrial membrane integrity, production of reactive oxygen species or lysosome abundance were observed at concentrations up to 20 ppm. Since no significant increments in toxicity were observed, the coated nanomaterials may be useful to increase in vivo zinc uptake for nutritional applications.

Detoxification of furfural in Corynebacterium glutamicum under aerobic and anaerobic conditions.

PubMed

Tsuge, Yota; Hori, Yoshimi; Kudou, Motonori; Ishii, Jun; Hasunuma, Tomohisa; Kondo, Akihiko

2014-10-01

The toxic fermentation inhibitors in lignocellulosic hydrolysates raise serious problems for the microbial production of fuels and chemicals. Furfural is considered to be one of the most toxic compounds among these inhibitors. Here, we describe the detoxification of furfural in Corynebacterium glutamicum ATCC13032 under both aerobic and anaerobic conditions. Under aerobic culture conditions, furfuryl alcohol and 2-furoic acid were produced as detoxification products of furfural. The ratio of the products varied depending on the initial furfural concentration. Neither furfuryl alcohol nor 2-furoic acid showed any toxic effect on cell growth, and both compounds were determined to be the end products of furfural degradation. Interestingly, unlike under aerobic conditions, most of the furfural was converted to furfuryl alcohol under anaerobic conditions, without affecting the glucose consumption rate. Both the NADH/NAD(+) and NADPH/NADP(+) ratio decreased in the accordance with furfural concentration under both aerobic and anaerobic conditions. These results indicate the presence of a single or multiple endogenous enzymes with broad and high affinity for furfural and co-factors in C. glutamicum ATCC13032.

Detection of the Cyanotoxins L-BMAA Uptake and Accumulation in Primary Neurons and Astrocytes.

PubMed

Tan, Vanessa X; Mazzocco, Claire; Varney, Bianca; Bodet, Dominique; Guillemin, Tristan A; Bessede, Alban; Guillemin, Gilles J

2018-01-01

We show for the first time that a newly developed polyclonal antibody (pAb) can specifically target the cyanotoxin β-methylamino-L-alanine (BMAA) and can be used to enable direct visualization of BMAA entry and accumulation in primary brain cells. We used this pAb to investigate the effect of acute and chronic accumulation, and toxicity of both BMAA and its natural isomer 2,4-diaminobutyric acid (DAB), separately or in combination, on primary cultures of rat neurons. We further present evidence that co-treatment with BMAA and DAB increased neuronal death, as measured by MAP2 fluorescence level, and appeared to reduce BMAA accumulation. DAB is likely to be acting synergistically with BMAA resulting in higher level of cellular toxicity. We also found that glial cells such as microglia and astrocytes are also able to directly uptake BMAA indicating that additional brain cell types are affected by BMAA-induced toxicity. Therefore, BMAA clearly acts at multiple cellular levels to possibly increase the risk of developing neurodegenerative diseases, including neuro- and gliotoxicity and synergetic exacerbation with other cyanotoxins.

Integrative Chemical-Biological Read-Across Approach for Chemical Hazard Classification

PubMed Central

Low, Yen; Sedykh, Alexander; Fourches, Denis; Golbraikh, Alexander; Whelan, Maurice; Rusyn, Ivan; Tropsha, Alexander

2013-01-01

Traditional read-across approaches typically rely on the chemical similarity principle to predict chemical toxicity; however, the accuracy of such predictions is often inadequate due to the underlying complex mechanisms of toxicity. Here we report on the development of a hazard classification and visualization method that draws upon both chemical structural similarity and comparisons of biological responses to chemicals measured in multiple short-term assays (”biological” similarity). The Chemical-Biological Read-Across (CBRA) approach infers each compound's toxicity from those of both chemical and biological analogs whose similarities are determined by the Tanimoto coefficient. Classification accuracy of CBRA was compared to that of classical RA and other methods using chemical descriptors alone, or in combination with biological data. Different types of adverse effects (hepatotoxicity, hepatocarcinogenicity, mutagenicity, and acute lethality) were classified using several biological data types (gene expression profiling and cytotoxicity screening). CBRA-based hazard classification exhibited consistently high external classification accuracy and applicability to diverse chemicals. Transparency of the CBRA approach is aided by the use of radial plots that show the relative contribution of analogous chemical and biological neighbors. Identification of both chemical and biological features that give rise to the high accuracy of CBRA-based toxicity prediction facilitates mechanistic interpretation of the models. PMID:23848138

Simulated Watershed Mercury and Nitrate Flux Responses to Multiple Land Cover Conversion Scenarios

EPA Science Inventory

Water quality and toxic exposure science is transitioning towards analysis of multiple stressors rather than one particular environmental concern (e.g., mercury) or a group of similarly reacting chemicals (e.g., nutrients). However, two of the most important water quality constit...

Survival of the hermit crab, Clibanarius vittatus, exposed to selenium and other environmental factors

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

Not Available

Recent investigations of water quality criteria have frequently examined the effects of a pollutant; however, a more realistic investigation would consider effects of multiple environmental factors and their interactions with the pollutant. Awareness of selenium as a pollutant is increasing. The growing sulfur and petroleum industries are only two of the potential sources of the element on the Texas coast. This study examined the toxicity of selenium to hermit crab Clibanarius vittatus (Bosc) under twelve different combinations of temperature and salinity. Additionally, the impact of the organisms' original environment was considered as an environmental factor.

Zingerone ameliorates cisplatin-induced ovarian and uterine toxicity via suppression of sex hormone imbalances, oxidative stress, inflammation and apoptosis in female wistar rats.

PubMed

Kaygusuzoglu, Erdal; Caglayan, Cuneyt; Kandemir, Fatih Mehmet; Yıldırım, Serkan; Kucukler, Sefa; Kılınc, Mehmet Akif; Saglam, Yavuz Selim

2018-06-01

Cisplatin (CP) is a widely used chemotherapeutic drug, effective against a variety of solid tumours, though its utility is limited due to its multiple organ toxicity. Zingerone (ZO), one of the most important components of dry ginger root, has several pharmacological activities, such as antioxidant, anti-inflammatory and anti-apoptotic properties. This study aimed to investigate the ameliorative effect of ZO on CP-induced ovarian and uterine toxicity in female rats. The rats were subjected to a prophylactic oral treatment of ZO (25 and 50 mg/kg body weight) for seven days to measure the protective effect against ovarian and uterine toxicity induced by a single (i.p.) of CP (7 mg/kg body weight) on the first day whereas the rats were sacrificed on the eighth day. The results showed that ZO decreased the serum FSH hormone level, increased the serum E2 hormone level, and also maintained the ovarian and uterine histological architecture and integrity. In addition, ZO obviously increased the measured activity of antioxidant enzymes (SOD, CAT and GPx) and the GSH content, and significantly reduced MDA levels. ZO was able to reduce the levels of the inflammatory markers NF-κB, TNF-α, IL-1β, IL-6, COX-2 and iNOS in CP-induced ovarian and uterine damage. It also inhibited apoptosis and reduced oxidative DNA damage markers by the downregulation of caspase-3 and 8-OHdG expression coupled with an upregulated Bcl-2 level. The results indicate that ZO may be beneficial in ameliorating CP-induced oxidative stress, sex hormone imbalances, inflammation and apoptosis in ovarian and uterine tissues of female rats. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Ameliorative effect of naringin in acetaminophen-induced hepatic and renal toxicity in laboratory rats: role of FXR and KIM-1.

PubMed

Adil, Mohammad; Kandhare, Amit D; Ghosh, Pinaki; Venkata, Shivakumar; Raygude, Kiran S; Bodhankar, Subhash L

2016-07-01

Acetaminophen (APAP) is an analgesic and antipyretic agent commonly known agent to cause hepatic and renal toxicity at a higher dose. Naringin, a bioflavonoid possesses multiple pharmacological properties such as antioxidant, anti-inflammatory, analgesic and anti-hyperlipidemic activity. To evaluate the effect of naringin against the APAP-induced hepatic and renal toxicity. Male Wistar albino rats (180-220 g) were divided into various groups, and toxicity was induced by APAP (700 mg/kg, p.o., 14 days). Naringin (20, 40 and 80 mg/kg, p.o.) or Silymarin (25 mg/kg) was administered to rats 2 h before APAP oral administration. Various biochemical, molecular and histopathological parameter were accessed in hepatic and renal tissue. Naringin pretreatment significantly decreased (p < 0.05) serum creatinine, blood urea nitrogen, bilirubin, aspartate transaminase, alanine transaminase, lactate dehydrogenase, low-density lipoprotein, very low-density lipoprotein, cholesterol and triglycerides as compared with APAP control rats. Decreased level of serum albumin, uric acid, and high-density lipoprotein were also significantly restored (p < 0.05) by naringin pretreatment. It also significantly restores (p < 0.05) the altered level of superoxide dismutase, reduced glutathione, malondialdehyde and nitric oxide in hepatic and renal tissue. Moreover, altered mRNA expression of hepatic farnesoid X receptor and renal injury molecule-1 (KIM-1) were significantly restored (p < 0.05) by naringin treatment. Naringin treatment also reduced histological alteration induced by APAP in the liver and kidney. Naringin exerts its hepato- and nephroprotective effect via modulation of oxido-nitrosative stress, FXR and KIM-1 mRNA expression.

Avian mercury exposure and toxicological risk across western North America: A synthesis

USGS Publications Warehouse

Ackerman, Joshua T.; Eagles-Smith, Collin A.; Herzog, Mark; Hartman, Christopher; Peterson, Sarah; Evers, David C.; Jackson, Allyson K.; Elliott, John E.; Vander Pol, Stacy S.; Bryan, Colleen E.

2016-01-01

Methylmercury contamination of the environment is an important issue globally, and birds are useful bioindicators for mercury monitoring programs. The available data on mercury contamination of birds in western North America were synthesized. Original data from multiple databases were obtained and a literature review was conducted to obtain additional mercury concentrations. In total, 29219 original bird mercury concentrations from 225 species were compiled, and an additional 1712 mean mercury concentrations, representing 19998 individuals and 176 species, from 200 publications were obtained. To make mercury data comparable across bird tissues, published equations of tissue mercury correlations were used to convert all mercury concentrations into blood-equivalent mercury concentrations. Blood-equivalent mercury concentrations differed among species, foraging guilds, habitat types, locations, and ecoregions. Piscivores and carnivores exhibited the greatest mercury concentrations, whereas herbivores and granivores exhibited the lowest mercury concentrations. Bird mercury concentrations were greatest in ocean and salt marsh habitats and lowest in terrestrial habitats. Bird mercury concentrations were above toxicity benchmarks in many areas throughout western North America, and multiple hotspots were identified. Additionally, published toxicity benchmarks established in multiple tissues were summarized and translated into a common blood-equivalent mercury concentration. Overall, 66% of birds sampled in western North American exceeded a blood-equivalent mercury concentration of 0.2 μg/g wet weight (ww; above background levels), which is the lowest-observed effect level, 28% exceeded 1.0 μg/g ww (moderate risk), 8% exceeded 3.0 μg/g ww (high risk), and 4% exceeded 4.0 μg/g ww (severe risk). Mercury monitoring programs should sample bird tissues, such as adult blood and eggs, that are most-easily translated into tissues with well-developed toxicity benchmarks and that are directly relevant to bird reproduction. Results indicate that mercury contamination of birds is prevalent in many areas throughout western North America, and large-scale ecological attributes are important factors influencing bird mercury concentrations.

Avian mercury exposure and toxicological risk across western North America: A synthesis

PubMed Central

Ackerman, Joshua T.; Eagles-Smith, Collin A.; Herzog, Mark P.; Hartman, C. Alex; Peterson, Sarah H.; Evers, David C.; Jackson, Allyson K.; Elliott, John E.; Vander Pol, Stacy S.; Bryan, Colleen E.

2017-01-01

Methylmercury contamination of the environment is an important issue globally and birds are useful bioindicators for mercury monitoring programs. The available data on mercury contamination of birds in western North America were synthesized. Original data from multiple databases were obtained and a literature review was conducted to obtain additional mercury concentrations. In total, 29219 original bird mercury concentrations from 225 species were compiled, and an additional 1712 mean mercury concentrations, representing 19998 individuals and 176 species, from 200 publications were obtained. To make mercury data comparable across bird tissues, published equations of tissue mercury correlations were used to convert all mercury concentrations into blood-equivalent mercury concentrations. Blood-equivalent mercury concentrations differed among species, foraging guilds, habitat types, locations, and ecoregions. Piscivores and carnivores exhibited the greatest mercury concentrations, whereas herbivores and granivores exhibited the lowest mercury concentrations. Bird mercury concentrations were greatest in ocean and salt marsh habitats and lowest in terrestrial habitats. Bird mercury concentrations were above toxicity benchmarks in many areas throughout western North America, and multiple hotspots were identified. Additionally, published toxicity benchmarks established in multiple tissues were summarized and translated into a common blood-equivalent mercury concentration. Overall, 66% of birds sampled in western North American exceeded a blood-equivalent mercury concentration of 0.2 μg/g wet weight (ww; above background levels), which is the lowest-observed effect level, 28% exceeded 1.0 μg/g ww (moderate risk), 8% exceeded 3.0 μg/g ww (high risk), and 4% exceeded 4.0 μg/g ww (severe risk). Mercury monitoring programs should sample bird tissues, such as adult blood and eggs, that are most-easily translated into tissues with well-developed toxicity benchmarks and that are directly relevant to bird reproduction. Results indicate that mercury contamination of birds is prevalent in many areas throughout western North America, and large-scale ecological attributes are important factors influencing bird mercury concentrations. PMID:27093907

Reversible metronidazole-induced cerebellar toxicity in a multiple transplant recipient.

PubMed

Graves, Tracey D; Condon, Marie; Loucaidou, Marina; Perry, Richard J

2009-10-15

Metronidazole-induced central nervous system (CNS) toxicity causes a spectrum of neurological symptoms including ataxia, encephalopathy and peripheral neuropathy. It is associated with characteristic MRI changes of high signal intensity in the dentate nuclei. Given the increasing use of metronidazole, it is import to recognise this drug as a cause of ataxia, as it is entirely reversible on drug withdrawal.

Pharmacogenomics of antimicrobial agents

PubMed Central

Aung, Ar Kar; Haas, David W; Hulgan, Todd; Phillips, Elizabeth J

2015-01-01

Antimicrobial efficacy and toxicity varies between individuals owing to multiple factors. Genetic variants that affect drug-metabolizing enzymes may influence antimicrobial pharmacokinetics and pharmacodynamics, thereby determining efficacy and/or toxicity. In addition, many severe immune-mediated reactions have been associated with HLA class I and class II genes. In the last two decades, understanding of pharmacogenomic factors that influence antimicrobial efficacy and toxicity has rapidly evolved, leading to translational success such as the routine use of HLA-B*57:01 screening to prevent abacavir hypersensitivity reactions. This article examines recent advances in the field of antimicrobial pharmacogenomics that potentially affect treatment efficacy and toxicity, and challenges that exist between pharmacogenomic discovery and translation into clinical use. PMID:25495412

Subchronic toxicity, immunoregulation and anti-breast tumor effect of Nordamnacantal, an anthraquinone extracted from the stems of Morinda citrifolia L.

PubMed

Abu, Nadiah; Zamberi, Nur Rizi; Yeap, Swee Keong; Nordin, Noraini; Mohamad, Nurul Elyani; Romli, Muhammad Firdaus; Rasol, Nurulfazlina Edayah; Subramani, Tamilselvan; Ismail, Nor Hadiani; Alitheen, Noorjahan Banu

2018-01-27

Morinda citrifolia L. that was reported with immunomodulating and cytotoxic effects has been traditionally used to treat multiple illnesses including cancer. An anthraquinone derived from fruits of Morinda citrifolia L., nordamnacanthal, is a promising agent possessing several in vitro biological activities. However, the in vivo anti-tumor effects and the safety profile of nordamnacanthal are yet to be evaluated. In vitro cytotoxicity of nordamnacanthal was tested using MTT, cell cycle and Annexin V/PI assays on human MCF-7 and MDA-MB231 breast cancer cells. Mice were orally fed with nordamnacanthal daily for 28 days for oral subchronic toxicity study. Then, the in vivo anti-tumor effect was evaluated on 4T1 murine cancer cells-challenged mice. Changes of tumor size and immune parameters were evaluated on the untreated and nordamnacanthal treated mice. Nordamnacanthal was found to possess cytotoxic effects on MDA-MB231, MCF-7 and 4T1 cells in vitro. Moreover, based on the cell cycle and Annexin V results, nordamnacanthal managed to induce cell death in both MDA-MB231 and MCF-7 cells. Additionally, no mortality, signs of toxicity and changes of serum liver profile were observed in nordamnacanthal treated mice in the subchronic toxicity study. Furthermore, 50 mg/kg body weight of nordamncanthal successfully delayed the progression of 4T1 tumors in Balb/C mice after 28 days of treatment. Treatment with nordamnacanthal was also able to increase tumor immunity as evidenced by the immunophenotyping of the spleen and YAC-1 cytotoxicity assays. Nordamnacanthal managed to inhibit the growth and induce cell death in MDA-MB231 and MCF-7 cell lines in vitro and cease the tumor progression of 4T1 cells in vivo. Overall, nordamnacanthal holds interesting anti-cancer properties that can be further explored.

Synergistic stress exacerbation in hippocampal neurons: Evidence favoring the dual hit hypothesis of neurodegeneration

PubMed Central

Heinemann, Scott D.; Posimo, Jessica M.; Mason, Daniel M.; Hutchison, Daniel F.; Leak, Rehana K.

2016-01-01

The dual hit hypothesis of neurodegeneration states that severe stress sensitizes vulnerable cells to subsequent challenges so that the two hits are synergistic in their toxic effects. Although the hippocampus is vulnerable to a number of neurodegenerative disorders, there are no models of synergistic cell death in hippocampal neurons in response to combined proteotoxic and oxidative stressors, the two major characteristics of these diseases. Therefore, we developed a relatively high-throughput dual hit model of stress synergy in primary hippocampal neurons. In order to increase the rigor of our study and strengthen our interpretations, we employed three independent, unbiased viability assays at multiple timepoints. Stress synergy was elicited when hippocampal neurons were treated with the proteasome inhibitor MG132 followed by exposure to the oxidative toxicant paraquat, but only after 48h. MG132 and paraquat only elicited additive effects 24h after the final hit and even loss of heat shock protein 70 activity and glutathione did not promote stress synergy at this early timepoint. Dual hits of MG132 elicited modest glutathione loss and slightly synergistic toxic effects 48h after the second hit, but only at some concentrations and only according to two viability assays (metabolic fitness and cytoskeletal integrity). The thiol N-acetyl cysteine protected hippocampal neurons against dual MG132/MG132 hits but not dual MG132/paraquat hits. Our findings support the view that proteotoxic and oxidative stress propel and propagate each other in hippocampal neurons, leading to synergistically toxic effects, but not as the default response and only after a delay. The neuronal stress synergy observed here lies in contrast to astrocytic responses to dual hits, because astrocytes that survive severe proteotoxic stress resist additional cell loss following second hits. In conclusion, we present a new model of hippocampal vulnerability in which to test therapies, because neuroprotective treatments that are effective against severe, synergistic stress are more likely to succeed in the clinic. PMID:26934478

Effects of the calcium channel blocker verapamil and sulphydryl reducing agent dithiothreitol on atractyloside toxicity in precision-cut rat renal cortical and liver slices.

PubMed

Obatomi, D K; Blackburn, R O; Bach, P H

2001-10-01

The effects of dithiothreitol (DTT), a sulfhydryl-containing agent and verapamil (VRP), a calcium channel blocker as possible cytoprotectants against the atractyloside-induced toxicity were characterized in rat kidney and liver slices in vitro using multiple markers of toxicity. Precision-cut slices (200 microM thick) were either incubated with atractyloside (2 mM) or initially preincubated with either DTT (5 mM) or VRP (100 microM) for 30 min followed by exposure to atractyloside (2 mM) for 3 h at 37 degrees C on a rocker platform rotated at approximately 3 rpm. All of the toxicity parameters were sensitive to exposure to atractyloside, but treatment with DTT or VRP alone did not provide any indication of damage to the tissues. Preincubation of slices containing either DTT or VRP for 30 min provided total protection against atractyloside-induced increase in LDH leakage in both kidney and liver slices. Increased induction of lipid peroxidation by atractyloside in liver slices was completely abolished by DTT and VRP. Both DTT and VRP provided partial protection against atractyloside-induced inhibition of gluconeogenesis in both kidney and liver slices. Atractyloside-induced ATP depletion in both kidney and liver slices was partially abolished by VRP but not DTT. The significant depletion of GSH in the kidney slices by atractyloside was completely reversed by DTT only, while VRP alone reversed the same process in liver slices. Decreased MTT reductive capacity and significant increase in ALT leakage caused by atractyloside in liver slices was partially reversed. Complete protection was achieved with both DTT and VRP against atractyloside-induced inhibition of PAH uptake in kidney slices. These findings suggest that both DTT and VRP exert cytoprotective effects in atractyloside-induced biochemical perturbation, effects that differ in liver and kidney. The effect of these agents on atractyloside has provided us with a further understanding of the molecular mechanism of its action.

Hydrogen gas alleviates oxygen toxicity by reducing hydroxyl radical levels in PC12 cells

PubMed Central

Yu, Junchao; Yu, Qiuhong; Liu, Yaling; Zhang, Ruiyun; Xue, Lianbi

2017-01-01

Hyperbaric oxygen (HBO) therapy through breathing oxygen at the pressure of above 1 atmosphere absolute (ATA) is useful for varieties of clinical conditions, especially hypoxic-ischemic diseases. Because of generation of reactive oxygen species (ROS), breathing oxygen gas at high pressures can cause oxygen toxicity in the central nervous system, leading to multiple neurological dysfunction, which limits the use of HBO therapy. Studies have shown that Hydrogen gas (H2) can diminish oxidative stress and effectively reduce active ROS associated with diseases. However, the effect of H2 on ROS generated from HBO therapy remains unclear. In this study, we investigated the effect of H2 on ROS during HBO therapy using PC12 cells. PC12 cells cultured in medium were exposed to oxygen gas or mixed oxygen gas and H2 at 1 ATA or 5 ATA. Cells viability and oxidation products and ROS were determined. The data showed that H2 promoted the cell viability and inhibited the damage in the cell and mitochondria membrane, reduced the levels of lipid peroxidation and DNA oxidation, and selectively decreased the levels of •OH but not disturbing the levels of O2•-, H2O2, or NO• in PC12 cells during HBO therapy. These results indicated that H2 effectively reduced •OH, protected cells against oxygen toxicity resulting from HBO therapy, and had no effect on other ROS. Our data supported that H2 could be potentially used as an antioxidant during HBO therapy. PMID:28362819

Moving beyond a descriptive aquatic toxicology: the value of biological process and trait information.

PubMed

Segner, Helmut

2011-10-01

In order to improve the ability to link chemical exposure to toxicological and ecological effects, aquatic toxicology will have to move from observing what chemical concentrations induce adverse effects to more explanatory approaches, that are concepts which build on knowledge of biological processes and pathways leading from exposure to adverse effects, as well as on knowledge on stressor vulnerability as given by the genetic, physiological and ecological (e.g., life history) traits of biota. Developing aquatic toxicology in this direction faces a number of challenges, including (i) taking into account species differences in toxicant responses on the basis of the evolutionarily developed diversity of phenotypic vulnerability to environmental stressors, (ii) utilizing diversified biological response profiles to serve as biological read across for prioritizing chemicals, categorizing them according to modes of action, and for guiding targeted toxicity evaluation; (iii) prediction of ecological consequences of toxic exposure from knowledge of how biological processes and phenotypic traits lead to effect propagation across the levels of biological hierarchy; and (iv) the search for concepts to assess the cumulative impact of multiple stressors. An underlying theme in these challenges is that, in addition to the question of what the chemical does to the biological receptor, we should give increasing emphasis to the question how the biological receptor handles the chemicals, i.e., through which pathways the initial chemical-biological interaction extends to the adverse effects, how this extension is modulated by adaptive or compensatory processes as well as by phenotypic traits of the biological receptor. 2011 Elsevier B.V. All rights reserved.

Dexamethasone-induced catatonia in a patient with multiple myeloma.

PubMed

Vanstechelman, Sylvie; Vantilborgh, Anna; Lemmens, Gilbert

2016-12-01

Catatonia is a complex neuropsychiatric syndrome, caused by different underlying metabolic, neurologic, psychiatric and toxic conditions. Although catatonia is often associated with psychiatric disorders such as schizophrenia or depression, in about 20 to 39% of the patients a somatic illness is found. Unfortunately, this diagnosis is often missed although catatonia is characterized by a specific symptom complex. We report a case of acute catatonia with psychotic features in a patient with multiple myeloma (MM), caused by systemic use of dexamethasone. Physicians should be aware of possible psychiatric side effects when prescribing high doses of dexamethasone. Further, MM patients on corticosteroids should be closely monitored for mild psychological and/or psychiatric symptoms since they may be predictive for the onset of catatonia.

The use of lisuride in the treatment of multiple system atrophy with autonomic failure (Shy-Drager syndrome).

PubMed Central

Lees, A J; Bannister, R

1981-01-01

In a controlled trial lisuride, an ergolene derivative with dopamine receptor agonist properties was given maximum tolerated doses (2.4 mg/day) to seven patients with multiple system atrophy with autonomic failure (Shy-Drager syndrome). Improvement in Parkinsonian features occurred in only one patient and another patient who had been deriving marked benefit from levodopa treatment before the study began failed to respond to large doses of lisuride. Psychiatric side effects (including nightmares, isolated visual hallucinations and toxic confusional states) were the dose-limiting factor in six patients. A modest reduction in orthostatic hypotension occurred in two patients, one of whom had experienced an aggravation of this disturbance on levodopa and bromocriptine. Destruction of post-synaptic dopamine receptors and damage to central noradrenergic systems may offer an explanation for the lack of therapeutic effect of lisuride. PMID:7241162

ToxPi Prioritization and Profiling of 1060 ToxCast Chemicals Across Multiple Sectors of Toxicological Concern

EPA Science Inventory

The Toxicological Prioritization Index (ToxPi™) framework was developed as a decision-support tool to aid in the prioritization of chemicals for integrated toxicity testing. ToxPi consolidates information from multiple domains - including ToxCast™ in vitro bioactivity profiles (a...

Detection of Mutant Huntingtin Aggregation Conformers and Modulation of SDS-Soluble Fibrillar Oligomers by Small Molecules

PubMed Central

Sontag, Emily Mitchell; Lotz, Gregor P.; Yang, Guocheng; Sontag, Christopher J.; Cummings, Brian J.; Glabe, Charles G.; Muchowski, Paul J.; Thompson, Leslie Michels

2012-01-01

The Huntington’s disease (HD) mutation leads to a complex process of Huntingtin (Htt) aggregation into multimeric species that eventually form visible inclusions in cytoplasm, nuclei and neuronal processes. One hypothesis is that smaller, soluble forms of amyloid proteins confer toxic effects and contribute to early cell dysfunction. However, analysis of mutant Htt aggregation intermediates to identify conformers that may represent toxic forms of the protein and represent potential drug targets remains difficult. We performed a detailed analysis of aggregation conformers in multiple in vitro, cell and ex vivo models of HD. Conformation-specific antibodies were used to identify and characterize aggregation species, allowing assessment of multiple conformers present during the aggregation process. Using a series of assays together with these antibodies, several forms could be identified. Fibrillar oligomers, defined as having a β-sheet rich conformation, are observed in vitro using recombinant protein and in protein extracts from cells in culture or mouse brain and shown to be globular, soluble and non-sedimentable structures. Compounds previously described to modulate visible inclusion body formation and reduce toxicity in HD models were also tested and consistently found to alter the formation of fibrillar oligomers. Interestingly, these compounds did not alter the rate of visible inclusion formation, indicating that fibrillar oligomers are not necessarily the rate limiting step of inclusion body formation. Taken together, we provide insights into the structure and formation of mutant Htt fibrillar oligomers that are modulated by small molecules with protective potential in HD models. PMID:24086178

Effects of conversion of mangroves into gei wai ponds on sediment heavy metals accumulation in tidal flat estuary, South China

NASA Astrophysics Data System (ADS)

Li, R.; Qiu, G.; Chai, M.; Li, R.

2017-12-01

Gei wai ponds act as important component in mangrove ecosystem, but the conversion of mangroves into gei wai ponds and its ecological function on heavy metal accumulation is still not clear. The study quantified the sediment heavy metal concentration and speciation in gei wai pond, Avicennia marina marsh and mudflat in Futian mangrove wetlands, South China. The results showed that gei wai pond acidified the sediment and reduced its fertility due to reduced pH, electronic conductivity (EC) and total organic carbon (TOC) compared to A. marina marsh and mudflat. The concentrations of Cd, Cu, Zn and Pb at all depth in gei wai pond sediment were also lower than other sites, indicating reduced storage function on heavy metals. Multiple analysis implied that heavy metals in all sites could be attributed to anthropogenic sources, with Cr as natural and anthropogenic sources in gei wai pond. Gei wai pond sediment had lower heavy metal pollution based on multiple evaluation methods, including potential ecological risk coefficient (Eir), potential ecological risk index (RI), geo-accumulation index (Igeo), mean PEL quotients (m-PEL-q), pollution load index (PLI), mean ERM quotients (m-ERM-q) and total toxic unit (∑TU). Heavy metal speciation analysis indicated that gei wai pond improved the conversion from the immobilized Cd and Cr to the mobilized fraction. SEM-AVS analysis indicated no adverse toxicity occurred in all sites, and the role of TOC in relieving sediment heavy metal toxicity of gei wai pond is limited.

Lectin-based food poisoning: a new mechanism of protein toxicity.

PubMed

Miyake, Katsuya; Tanaka, Toru; McNeil, Paul L

2007-08-01

Ingestion of the lectins present in certain improperly cooked vegetables can result in acute GI tract distress, but the mechanism of toxicity is unknown. In vivo, gut epithelial cells are constantly exposed to mechanical and other stresses and consequently individual cells frequently experience plasma membrane disruptions. Repair of these cell surface disruptions allows the wounded cell to survive: failure results in necrotic cell death. Plasma membrane repair is mediated, in part, by an exocytotic event that adds a patch of internal membrane to the defect site. Lectins are known to inhibit exocytosis. We therefore tested the novel hypothesis that lectin toxicity is due to an inhibitory effect on plasma membrane repair. Repair of plasma membrane disruptions and exocytosis of mucus was assessed after treatment of cultured cell models and excised segments of the GI tract with lectins. Plasma membrane disruptions were produced by focal irradiation of individual cells, using a microscope-based laser, or by mechanical abrasion of multiple cells, using a syringe needle. Repair was then assessed by monitoring the cytosolic penetration of dyes incapable of crossing the intact plasma membrane. We found that cell surface-bound lectins potently inhibited plasma membrane repair, and the exocytosis of mucus that normally accompanies the repair response. Lectins potently inhibit plasma membrane repair, and hence are toxic to wounded cells. This represents a novel form of protein-based toxicity, one that, we propose, is the basis of plant lectin food poisoning.

A Yeast Model of FUS/TLS-Dependent Cytotoxicity

PubMed Central

Ju, Shulin; Tardiff, Daniel F.; Han, Haesun; Divya, Kanneganti; Zhong, Quan; Maquat, Lynne E.; Bosco, Daryl A.; Hayward, Lawrence J.; Brown, Robert H.; Lindquist, Susan; Ringe, Dagmar; Petsko, Gregory A.

2011-01-01

FUS/TLS is a nucleic acid binding protein that, when mutated, can cause a subset of familial amyotrophic lateral sclerosis (fALS). Although FUS/TLS is normally located predominantly in the nucleus, the pathogenic mutant forms of FUS/TLS traffic to, and form inclusions in, the cytoplasm of affected spinal motor neurons or glia. Here we report a yeast model of human FUS/TLS expression that recapitulates multiple salient features of the pathology of the disease-causing mutant proteins, including nuclear to cytoplasmic translocation, inclusion formation, and cytotoxicity. Protein domain analysis indicates that the carboxyl-terminus of FUS/TLS, where most of the ALS-associated mutations are clustered, is required but not sufficient for the toxicity of the protein. A genome-wide genetic screen using a yeast over-expression library identified five yeast DNA/RNA binding proteins, encoded by the yeast genes ECM32, NAM8, SBP1, SKO1, and VHR1, that rescue the toxicity of human FUS/TLS without changing its expression level, cytoplasmic translocation, or inclusion formation. Furthermore, hUPF1, a human homologue of ECM32, also rescues the toxicity of FUS/TLS in this model, validating the yeast model and implicating a possible insufficiency in RNA processing or the RNA quality control machinery in the mechanism of FUS/TLS mediated toxicity. Examination of the effect of FUS/TLS expression on the decay of selected mRNAs in yeast indicates that the nonsense-mediated decay pathway is probably not the major determinant of either toxicity or suppression. PMID:21541368

Efficacy and toxicity of the combination chemotherapy of thalidomide, alkylating agent, and steroid for relapsed/refractory myeloma patients: a report from the Korean Multiple Myeloma Working Party (KMMWP) retrospective study.

PubMed

Kwon, Jihyun; Min, Chang-Ki; Kim, Kihyun; Han, Jae-Joon; Moon, Joon Ho; Kang, Hye Jin; Eom, Hyeon-Seok; Kim, Min Kyoung; Kim, Hyo Jung; Yoon, Dok Hyun; Lee, Jeong-Ok; Lee, Won Sik; Lee, Jae Hoon; Lee, Je-Jung; Choi, Yoon-Seok; Kim, Sung Hyun; Yoon, Sung-Soo

2017-01-01

We analyzed the treatment responses, toxicities, and survival outcomes of patients with relapsed or refractory multiple myeloma who received daily thalidomide, cyclophosphamide, and dexamethasone (CTD) or daily thalidomide, melphalan, and prednisolone (MTP) at 17 medical centers in Korea. Three-hundred and seventy-six patients were enrolled. The combined chemotherapy of thalidomide, corticosteroid, and an alkylating agent (TAS) was second-line chemotherapy in 142 (37.8%) patients, and third-line chemotherapy in 135 (35.9%) patients. The response rate overall was 69.4%. Patients who were not treated with bortezomib and lenalidomide before TAS showed a higher response rate compared to those who were exposed to these agents. The estimated median progression-free survival and overall survival times were 10.4 months and 28.0 months, respectively. The adverse events during TAS were generally tolerable, but 39 (10.4%) patients experienced severe infectious complications. There were no differences in terms of efficacy between CTD and MTP, but infectious complications were more common in CTD group. TAS is an effective treatment regimen which induces a high response rate in relapsed or refractory multiple myeloma patients. Due to the high incidence of grade 3 or 4 infection, proper management of infection is necessary during the TAS treatment, especially the CTD. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Prioritization of reproductive toxicants in unconventional oil and gas operations using a multi-country regulatory data-driven hazard assessment.

PubMed

Inayat-Hussain, Salmaan H; Fukumura, Masao; Muiz Aziz, A; Jin, Chai Meng; Jin, Low Wei; Garcia-Milian, Rolando; Vasiliou, Vasilis; Deziel, Nicole C

2018-08-01

Recent trends have witnessed the global growth of unconventional oil and gas (UOG) production. Epidemiologic studies have suggested associations between proximity to UOG operations with increased adverse birth outcomes and cancer, though specific potential etiologic agents have not yet been identified. To perform effective risk assessment of chemicals used in UOG production, the first step of hazard identification followed by prioritization specifically for reproductive toxicity, carcinogenicity and mutagenicity is crucial in an evidence-based risk assessment approach. To date, there is no single hazard classification list based on the United Nations Globally Harmonized System (GHS), with countries applying the GHS standards to generate their own chemical hazard classification lists. A current challenge for chemical prioritization, particularly for a multi-national industry, is inconsistent hazard classification which may result in misjudgment of the potential public health risks. We present a novel approach for hazard identification followed by prioritization of reproductive toxicants found in UOG operations using publicly available regulatory databases. GHS classification for reproductive toxicity of 157 UOG-related chemicals identified as potential reproductive or developmental toxicants in a previous publication was assessed using eleven governmental regulatory agency databases. If there was discordance in classifications across agencies, the most stringent classification was assigned. Chemicals in the category of known or presumed human reproductive toxicants were further evaluated for carcinogenicity and germ cell mutagenicity based on government classifications. A scoring system was utilized to assign numerical values for reproductive health, cancer and germ cell mutation hazard endpoints. Using a Cytoscape analysis, both qualitative and quantitative results were presented visually to readily identify high priority UOG chemicals with evidence of multiple adverse effects. We observed substantial inconsistencies in classification among the 11 databases. By adopting the most stringent classification within and across countries, 43 chemicals were classified as known or presumed human reproductive toxicants (GHS Category 1), while 31 chemicals were classified as suspected human reproductive toxicants (GHS Category 2). The 43 reproductive toxicants were further subjected to analysis for carcinogenic and mutagenic properties. Calculated hazard scores and Cytoscape visualization yielded several high priority chemicals including potassium dichromate, cadmium, benzene and ethylene oxide. Our findings reveal diverging GHS classification outcomes for UOG chemicals across regulatory agencies. Adoption of the most stringent classification with application of hazard scores provides a useful approach to prioritize reproductive toxicants in UOG and other industries for exposure assessments and selection of safer alternatives. Copyright © 2018 Elsevier Ltd. All rights reserved.

Pharmacological Effects of Biotin in Animals.

PubMed

Riveron-Negrete, Leticia; Fernandez-Mejia, Cristina

2017-01-01

In recent decades, it was found that vitamins affect biological functions in ways other than their long-known functions; niacin is the best example of a water-soluble vitamin known to possess multiple actions. Biotin, also known as vitamin B7 or vitamin H, is a water-soluble B-complex vitamin that serves as a covalently-bound coenzyme of carboxylases. It is now well documented that biotin has actions other than participating in classical enzyme catalysis reactions. Several lines of evidence have demonstrated that pharmacological concentrations of biotin affect glucose and lipid metabolism, hypertension, reproduction, development, and immunity. The effect of biotin on these functions is related to its actions at the transcriptional, translational, and post-translational levels. The bestsupported mechanism involved in the genetic effects of biotin is the soluble guanylate cyclase/protein kinase G (PKG) signaling cascade. Although there are commercially-available products containing pharmacological concentrations of biotin, the toxic effects of biotin have been poorly studied. This review summarizes the known actions and molecular mechanisms of pharmacological doses of biotin in animals and current information regarding biotin toxicity. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Late effect of multiple daily fraction palliation schedule for advanced pelvic malignancies (RTOG 8502)

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

Spanos, W.J. Jr.; Clery, M.; Perez, C.A.

1994-07-30

The purpose was to determine late complication incidence for pelvic palliation using accelerated multiple daily fraction radiation [Radiation Therapy Oncology Group (RTOG) 8502]. None of the patients with < 30 Gy (less than three courses) developed late toxicity. A total of 11/193 (6%) developed Grade 3+ late toxicity (nine Grade 3, on Grade 4, one Grade 5). Actuarial analysis of complication rate by survival time for Grades 3, 4, and 5 shows a cumulative incidence for complications after 6 months that plateaus at 6.9% by 18 months. The cumulative incidence for Grades 4 and 5 is 2.0% by 12 months.more » The difference in late effect for the 2-week rest vs. 4-week rest was not statistically different (p = .47). Patient factors evaluated for increased risk of late complications included prior surgeries, age, sex, KPS and primary. None were found to have significant statistical correlations with late effects. The crude late complications rate is 6%. Actuarial analysis using cumulative incidence shows 6.9% by 18 months. This represents a significant decrease in late complications from 49% seen with higher dose per fraction (10 Gy {times} 3) piloted by Radiation Therapy Oncology Group (7905) for a similar group of patients. Long-term analysis of late complication indicates this schedule can be used in the pelvis with relatively low incidence of complication. This schedule has significant logistic benefits and has been shown to produce good tumor regression and excellent palliation of symptoms. 14 refs., 4 figs., 4 tabs.« less

Cytochrome P{sub 450}-dependent toxic effects of primaquine on human erythrocytes

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

Ganesan, Shobana; Department of Pharmacology, School of Pharmacy, University of Mississippi, University MS 38677; Tekwani, Babu L., E-mail: btekwani@olemiss.ed

Primaquine, an 8-aminoquinoline, is the drug of choice for radical cure of relapsing malaria. Use of primaquine is limited due to its hemotoxicity, particularly in populations with glucose-6-phosphate dehydrogenase deficiency [G6PD(-)]. Biotransformation appears to be central to the anti-infective and hematological toxicities of primaquine, but the mechanisms are still not well understood. Metabolic studies with primaquine have been hampered due to the reactive nature of potential hemotoxic metabolites. An in vitro metabolism-linked hemotoxicity assay has been developed. Co-incubation of the drug with normal or G6PD(-) erythrocytes, microsomes or recombinant cytochrome P{sub 450} (CYP) isoforms has allowed in situ generation ofmore » potential hemotoxic metabolite(s), which interact with the erythrocytes to generate hemotoxicity. Methemoglobin formation, real-time generation of reactive oxygen intermediates (ROIs) and depletion of reactive thiols were monitored as multiple biochemical end points for hemotoxicity. Primaquine alone did not produce any hemotoxicity, while a robust increase was observed in methemoglobin formation and generation of ROIs by primaquine in the presence of human or mouse liver microsomes. Multiple CYP isoforms (CYP2E1, CYP2B6, CYP1A2, CYP2D6 and CYP3A4) variably contributed to the hemotoxicity of primaquine. This was further confirmed by significant inhibition of primaquine hemotoxicity by the selective CYP inhibitors, namely thiotepa (CYP2B6), fluoxetine (CYP2D6) and troleandomycin (CYP3A4). Primaquine caused similar methemoglobin formation in G6PD(-) and normal human erythrocytes. However, G6PD(-) erythrocytes suffered higher oxidative stress and depletion of thiols than normal erythrocytes due to primaquine toxicity. The results provide significant insights regarding CYP isoforms contributing to hemotoxicity and may be useful in controlling toxicity of primaquine to increase its therapeutic utility.« less

Thalidomide, clarithromycin, lenalidomide and dexamethasone therapy in newly diagnosed, symptomatic multiple myeloma.

PubMed

Mark, Tomer M; Bowman, Isaac A; Rossi, Adriana C; Shah, Manan; Rodriguez, Melissa; Quinn, Ryann; Pearse, Roger N; Zafar, Faiza; Pekle, Karen; Jayabalan, David; Ely, Scott; Coleman, Morton; Chen-Kiang, Selina; Niesvizky, Ruben

2014-12-01

We studied T-BiRD (thalidomide [Thalomid(®)], clarithromycin [Biaxin(®)], lenalidomide [Revlimid(®)] and dexamethasone) in symptomatic, newly diagnosed multiple myeloma. In 28-day cycles, patients received dexamethasone 40 mg/day on days 1, 8, 15, 22, clarithromycin 500 mg twice daily on days 1-28; lenalidomide 25 mg/day on days 1-21; and thalidomide 100 mg/day (50 mg/day on days 1-7 of cycle 1 only) on days 1-28. Twenty-six patients received a median of 6 cycles (range 0-41). Overall response rate (ORR) was 80% for the group and 100% in 11 patients who underwent autologous stem cell transplantation as part of first-line therapy. The 4-year overall survival rate was 74.9%, and the median progression-free survival was 35.6 months. Eight patients discontinued due to regimen toxicity. Grade 3 non hematologic toxicity affected 12 patients (46.2%). T-BiRD is a highly active regimen with potential toxicity limitations. ClinicalTrials.gov identifier: NCT00538733.

Gastrointestinal Toxicities With Combined Antiangiogenic and Stereotactic Body Radiation Therapy

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

Pollom, Erqi L.; Deng, Lei; Pai, Reetesh K.

2015-07-01

Combining the latest targeted biologic agents with the most advanced radiation technologies has been an exciting development in the treatment of cancer patients. Stereotactic body radiation therapy (SBRT) is an ablative radiation approach that has become established for the treatment of a variety of malignancies, and it has been increasingly used in combination with biologic agents, including those targeting angiogenesis-specific pathways. Multiple reports have emerged describing unanticipated toxicities arising from the combination of SBRT and angiogenesis-targeting agents, particularly of late luminal gastrointestinal toxicities. In this review, we summarize the literature describing these toxicities, explore the biological mechanism of action ofmore » toxicity with the combined use of antiangiogenic therapies, and discuss areas of future research, so that this combination of treatment modalities can continue to be used in broader clinical contexts.« less

Detecting and removing multiplicative spatial bias in high-throughput screening technologies.

PubMed

Caraus, Iurie; Mazoure, Bogdan; Nadon, Robert; Makarenkov, Vladimir

2017-10-15

Considerable attention has been paid recently to improve data quality in high-throughput screening (HTS) and high-content screening (HCS) technologies widely used in drug development and chemical toxicity research. However, several environmentally- and procedurally-induced spatial biases in experimental HTS and HCS screens decrease measurement accuracy, leading to increased numbers of false positives and false negatives in hit selection. Although effective bias correction methods and software have been developed over the past decades, almost all of these tools have been designed to reduce the effect of additive bias only. Here, we address the case of multiplicative spatial bias. We introduce three new statistical methods meant to reduce multiplicative spatial bias in screening technologies. We assess the performance of the methods with synthetic and real data affected by multiplicative spatial bias, including comparisons with current bias correction methods. We also describe a wider data correction protocol that integrates methods for removing both assay and plate-specific spatial biases, which can be either additive or multiplicative. The methods for removing multiplicative spatial bias and the data correction protocol are effective in detecting and cleaning experimental data generated by screening technologies. As our protocol is of a general nature, it can be used by researchers analyzing current or next-generation high-throughput screens. The AssayCorrector program, implemented in R, is available on CRAN. makarenkov.vladimir@uqam.ca. Supplementary data are available at Bioinformatics online. © The Author (2017). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

The Evolution of Fangs, Venom, and Mimicry Systems in Blenny Fishes.

PubMed

Casewell, Nicholas R; Visser, Jeroen C; Baumann, Kate; Dobson, James; Han, Han; Kuruppu, Sanjaya; Morgan, Michael; Romilio, Anthony; Weisbecker, Vera; Mardon, Karine; Ali, Syed A; Debono, Jordan; Koludarov, Ivan; Que, Ivo; Bird, Gregory C; Cooke, Gavan M; Nouwens, Amanda; Hodgson, Wayne C; Wagstaff, Simon C; Cheney, Karen L; Vetter, Irina; van der Weerd, Louise; Richardson, Michael K; Fry, Bryan G

2017-04-24

Venom systems have evolved on multiple occasions across the animal kingdom, and they can act as key adaptations to protect animals from predators [1]. Consequently, venomous animals serve as models for a rich source of mimicry types, as non-venomous species benefit from reductions in predation risk by mimicking the coloration, body shape, and/or movement of toxic counterparts [2-5]. The frequent evolution of such deceitful imitations provides notable examples of phenotypic convergence and are often invoked as classic exemplars of evolution by natural selection. Here, we investigate the evolution of fangs, venom, and mimetic relationships in reef fishes from the tribe Nemophini (fangblennies). Comparative morphological analyses reveal that enlarged canine teeth (fangs) originated at the base of the Nemophini radiation and have enabled a micropredatory feeding strategy in non-venomous Plagiotremus spp. Subsequently, the evolution of deep anterior grooves and their coupling to venom secretory tissue provide Meiacanthus spp. with toxic venom that they effectively employ for defense. We find that fangblenny venom contains a number of toxic components that have been independently recruited into other animal venoms, some of which cause toxicity via interactions with opioid receptors, and result in a multifunctional biochemical phenotype that exerts potent hypotensive effects. The evolution of fangblenny venom has seemingly led to phenotypic convergence via the formation of a diverse array of mimetic relationships that provide protective (Batesian mimicry) and predatory (aggressive mimicry) benefits to other fishes [2, 6]. Our results further our understanding of how novel morphological and biochemical adaptations stimulate ecological interactions in the natural world. Copyright © 2017 Elsevier Ltd. All rights reserved.

Building a developmental toxicity ontology.

PubMed

Baker, Nancy; Boobis, Alan; Burgoon, Lyle; Carney, Edward; Currie, Richard; Fritsche, Ellen; Knudsen, Thomas; Laffont, Madeleine; Piersma, Aldert H; Poole, Alan; Schneider, Steffen; Daston, George

2018-04-03

As more information is generated about modes of action for developmental toxicity and more data are generated using high-throughput and high-content technologies, it is becoming necessary to organize that information. This report discussed the need for a systematic representation of knowledge about developmental toxicity (i.e., an ontology) and proposes a method to build one based on knowledge of developmental biology and mode of action/ adverse outcome pathways in developmental toxicity. This report is the result of a consensus working group developing a plan to create an ontology for developmental toxicity that spans multiple levels of biological organization. This report provide a description of some of the challenges in building a developmental toxicity ontology and outlines a proposed methodology to meet those challenges. As the ontology is built on currently available web-based resources, a review of these resources is provided. Case studies on one of the most well-understood morphogens and developmental toxicants, retinoic acid, are presented as examples of how such an ontology might be developed. This report outlines an approach to construct a developmental toxicity ontology. Such an ontology will facilitate computer-based prediction of substances likely to induce human developmental toxicity. © 2018 Wiley Periodicals, Inc.

Low pH, aluminum and phosphorus coordinately regulate malate exudation through GmALMT1 to improve soybean adaptation to acid soils

USDA-ARS?s Scientific Manuscript database

Low pH, aluminum (Al) toxicity and low phosphorus (P) often coexist in acid soils where crops need to cope with these multiple limiting factors. In this study we found that P addition to acid soils alleviates Al toxicity and enhanced soybean adaptation to acid soils, especially for the P-efficient g...

Toxicity potentials from waste cellular phones, and a waste management policy integrating consumer, corporate, and government responsibilities

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

Lim, Seong-Rin; Schoenung, Julie M., E-mail: jmschoenung@ucdavis.ed

Cellular phones have high environmental impact potentials because of their heavy metal content and current consumer attitudes toward purchasing new phones with higher functionality and neglecting to return waste phones into proper take-back systems. This study evaluates human health and ecological toxicity potentials from waste cellular phones; highlights consumer, corporate, and government responsibilities for effective waste management; and identifies key elements needed for an effective waste management strategy. The toxicity potentials are evaluated by using heavy metal content, respective characterization factors, and a pathway and impact model for heavy metals that considers end-of-life disposal in landfills or by incineration. Cancermore » potentials derive primarily from Pb and As; non-cancer potentials primarily from Cu and Pb; and ecotoxicity potentials primarily from Cu and Hg. These results are not completely in agreement with previous work in which leachability thresholds were the metric used to establish priority, thereby indicating the need for multiple or revised metrics. The triple bottom line of consumer, corporate, and government responsibilities is emphasized in terms of consumer attitudes, design for environment (DfE), and establishment and implementation of waste management systems including recycling streams, respectively. The key strategic elements for effective waste management include environmental taxation and a deposit-refund system to motivate consumer responsibility, which is linked and integrated with corporate and government responsibilities. The results of this study can contribute to DfE and waste management policy for cellular phones.« less

Biocompatible Colloidal Suspensions Based on Magnetic Iron Oxide Nanoparticles: Synthesis, Characterization and Toxicological Profile

PubMed Central

Coricovac, Dorina-Elena; Moacă, Elena-Alina; Pinzaru, Iulia; Cîtu, Cosmin; Soica, Codruta; Mihali, Ciprian-Valentin; Păcurariu, Cornelia; Tutelyan, Victor A.; Tsatsakis, Aristidis; Dehelean, Cristina-Adriana

2017-01-01

The use of magnetic iron oxide nanoparticles in biomedicine has evolved intensely in the recent years due to the multiple applications of these nanomaterials, mainly in domains like cancer. The aim of the present study was: (i) to develop biocompatible colloidal suspensions based on magnetic iron oxide nanoparticles as future theranostic tools for skin pathology and (ii) to test their effects in vitro on human keratinocytes (HaCat cells) and in vivo by employing an animal model of acute dermal toxicity. Biocompatible colloidal suspensions were obtained by coating the magnetic iron oxide nanoparticles resulted during the solution combustion synthesis with a double layer of oleic acid, as innovative procedure in increasing bioavailability. The colloidal suspensions were characterized in terms of dynamic light scattering (DLS) and transmission electron microscopy (TEM). The in vitro effects of these suspensions were tested by means of Alamar blue assay and the noxious effects at skin level were measured using non-invasive methods. The in vitro results indicated a lack of toxicity on normal human cells induced by the iron oxide nanoparticles colloidal suspensions after an exposure of 24 h to different concentrations (5, 10, and 25 μg·mL−1). The dermal acute toxicity test showed that the topical applications of the colloidal suspensions on female and male SKH-1 hairless mice were not associated with significant changes in the quality of barrier skin function. PMID:28400730

Toxicity potentials from waste cellular phones, and a waste management policy integrating consumer, corporate, and government responsibilities.

PubMed

Lim, Seong-Rin; Schoenung, Julie M

2010-01-01

Cellular phones have high environmental impact potentials because of their heavy metal content and current consumer attitudes toward purchasing new phones with higher functionality and neglecting to return waste phones into proper take-back systems. This study evaluates human health and ecological toxicity potentials from waste cellular phones; highlights consumer, corporate, and government responsibilities for effective waste management; and identifies key elements needed for an effective waste management strategy. The toxicity potentials are evaluated by using heavy metal content, respective characterization factors, and a pathway and impact model for heavy metals that considers end-of-life disposal in landfills or by incineration. Cancer potentials derive primarily from Pb and As; non-cancer potentials primarily from Cu and Pb; and ecotoxicity potentials primarily from Cu and Hg. These results are not completely in agreement with previous work in which leachability thresholds were the metric used to establish priority, thereby indicating the need for multiple or revised metrics. The triple bottom line of consumer, corporate, and government responsibilities is emphasized in terms of consumer attitudes, design for environment (DfE), and establishment and implementation of waste management systems including recycling streams, respectively. The key strategic elements for effective waste management include environmental taxation and a deposit-refund system to motivate consumer responsibility, which is linked and integrated with corporate and government responsibilities. The results of this study can contribute to DfE and waste management policy for cellular phones. 2010 Elsevier Ltd. All rights reserved.

Chemical mixtures in untreated water from public-supply wells in the U.S. — Occurrence, composition, and potential toxicity

USGS Publications Warehouse

Toccalino, Patricia L.; Norman, Julia E.; Scott, Jonathon C.

2012-01-01

Chemical mixtures are prevalent in groundwater used for public water supply, but little is known about their potential health effects. As part of a large-scale ambient groundwater study, we evaluated chemical mixtures across multiple chemical classes, and included more chemical contaminants than in previous studies of mixtures in public-supply wells. We (1) assessed the occurrence of chemical mixtures in untreated source-water samples from public-supply wells, (2) determined the composition of the most frequently occurring mixtures, and (3) characterized the potential toxicity of mixtures using a new screening approach. The U.S. Geological Survey collected one untreated water sample from each of 383 public wells distributed across 35 states, and analyzed the samples for as many as 91 chemical contaminants. Concentrations of mixture components were compared to individual human-health benchmarks; the potential toxicity of mixtures was characterized by addition of benchmark-normalized component concentrations. Most samples (84%) contained mixtures of two or more contaminants, each at concentrations greater than one-tenth of individual benchmarks. The chemical mixtures that most frequently occurred and had the greatest potential toxicity primarily were composed of trace elements (including arsenic, strontium, or uranium), radon, or nitrate. Herbicides, disinfection by-products, and solvents were the most common organic contaminants in mixtures. The sum of benchmark-normalized concentrations was greater than 1 for 58% of samples, suggesting that there could be potential for mixtures toxicity in more than half of the public-well samples. Our findings can be used to help set priorities for groundwater monitoring and suggest future research directions for drinking-water treatment studies and for toxicity assessments of chemical mixtures in water resources.

Determining stressor presence in streams receiving urban and agricultural runoff: development of a benthic in situ toxicity identification evaluation method.

PubMed

Custer, Kevin W; Burton, G Allen; Coelho, Ricardo S; Smith, Preston R

2006-09-01

Determining toxicity in streams during storm-water runoff can be highly problematic because of the fluctuating exposures of a multitude of stressors and the difficulty of linking these dynamic exposures with biological effects. An underlying problem with assessing storm-water quality is determining if toxicity exists and then which contaminant is causing the toxicity. The goal of this research is to provide an alternative to standard toxicity testing methods by incorporating an in situ toxicity identification evaluation (TIE) approach. A benthic in situ TIE bioassay (BiTIE) was developed for separating key chemical classes of stressors in streams during both low- and high-flow events to help discern between point and nonpoint sources of pollution. This BiTIE method allows for chemical class fractionation through the use of resins, and these resins are relatively specific for removing nonpolar organics (Dowex Optipore), ammonia (zeolite), and polywool (control). Three indigenous aquatic insects, a mayfly (Isonychia spp.), a caddisfly (Hydropsyche spp.), and a water beetle (Psephenus herricki), were placed in BiTIE chambers that were filled with natural substrates. Acute 96-h exposures were conducted at Honey Creek, New Carlisle, Ohio, USA (reference site), and Little Beavercreek, Beavercreek, Ohio, USA (impaired site). At both sites, significant (p < 0.025) stressor responses were observed using multiple species with polywool or no resin (control) treatments exhibiting < 80% survival and resin treatments with >80% survival. The BiTIE method showed stressor-response relationships in both runoff and base flow events during 96-h exposures. The method appears useful for discerning stressors with indigenous species in situ.

Multidrug Resistance Protein 1 Deficiency Promotes Doxorubicin-Induced Ovarian Toxicity in Female Mice.

PubMed

Wang, Yingzheng; Liu, Mingjun; Zhang, Jiyang; Liu, Yuwen; Kopp, Megan; Zheng, Weiwei; Xiao, Shuo

2018-05-01

Multidrug resistance protein 1 (MDR1), a phase III drug transporter that exports substrates out of cells, has been discovered in both cancerous and normal tissues. The over expression of MDR1 in cancer cells contributes to multiple drug resistance, whereas the MDR1 in normal tissues protects them from chemical-induced toxicity. Currently, the role of MDR1 in the ovary has not been entirely understood. Our objective is to determine the function of MDR1 in protecting against chemotherapy-induced ovarian toxicity. Using both the in vivo transgenic mouse model and in vitro follicle culture model, we investigated the expression of MDR1 in the ovary, the effect of MDR1 deficiency on doxorubicin (DOX)-induced ovarian toxicity, and the ovarian steroid hormonal regulation of MDR1. Results showed that the MDR1 was expressed in the ovarian epithelial cells, stroma cells, theca cell layers, endothelial cells, and luteal cells. The lack of MDR1 did not affect female ovarian function and fertility; however, its deficiency significantly exacerbated the DOX-induced ovarian toxicity in both in vivo and in vitro models. The MDR1 showed significantly higher expression levels in the ovaries at estrus and metestrus stages than those at proestrus and diestrus stages. However, this dynamic expression pattern was not regulated by the ovarian steroid hormones of estrogen (E2) and progesterone (P4) but correlated to the number and status of corpus luteum. In conclusion, our study demonstrates that the lack of MDR1 promotes DOX-induced ovarian toxicity, suggesting the critical role of MDR1 in protecting female ovarian functions during chemotherapy.

Cannabinoid receptor antagonist-induced striated muscle toxicity and ethylmalonic-adipic aciduria in beagle dogs.

PubMed

Tomlinson, Lindsay; Tirmenstein, Mark A; Janovitz, Evan B; Aranibar, Nelly; Ott, Karl-Heinz; Kozlosky, John C; Patrone, Laura M; Achanzar, William E; Augustine, Karen A; Brannen, Kimberly C; Carlson, Kenneth E; Charlap, Jeffrey H; Dubrow, Katherine M; Kang, Liya; Rosini, Laura T; Panzica-Kelly, Julieta M; Flint, Oliver P; Moulin, Frederic J; Megill, John R; Zhang, Haiying; Bennett, Michael J; Horvath, Joseph J

2012-10-01

Ibipinabant (IBI), a potent cannabinoid-1 receptor (CB1R) antagonist, previously in development for the treatment of obesity, causes skeletal and cardiac myopathy in beagle dogs. This toxicity was characterized by increases in muscle-derived enzyme activity in serum and microscopic striated muscle degeneration and accumulation of lipid droplets in myofibers. Additional changes in serum chemistry included decreases in glucose and increases in non-esterified fatty acids and cholesterol, and metabolic acidosis, consistent with disturbances in lipid and carbohydrate metabolism. No evidence of CB1R expression was detected in dog striated muscle as assessed by polymerase chain reaction, immunohistochemistry, Western blot analysis, and competitive radioligand binding. Investigative studies utilized metabonomic technology and demonstrated changes in several intermediates and metabolites of fatty acid metabolism including plasma acylcarnitines and urinary ethylmalonate, methylsuccinate, adipate, suberate, hexanoylglycine, sarcosine, dimethylglycine, isovalerylglycine, and 2-hydroxyglutarate. These results indicated that the toxic effect of IBI on striated muscle in beagle dogs is consistent with an inhibition of the mitochondrial flavin-containing enzymes including dimethyl glycine, sarcosine, isovaleryl-CoA, 2-hydroxyglutarate, and multiple acyl-CoA (short, medium, long, and very long chain) dehydrogenases. All of these enzymes converge at the level of electron transfer flavoprotein (ETF) and ETF oxidoreductase. Urinary ethylmalonate was shown to be a biomarker of IBI-induced striated muscle toxicity in dogs and could provide the ability to monitor potential IBI-induced toxic myopathy in humans. We propose that IBI-induced toxic myopathy in beagle dogs is not caused by direct antagonism of CB1R and could represent a model of ethylmalonic-adipic aciduria in humans.

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

Effects of HMX-lead mixtures on reproduction of the earthworm Eisenia andrei.

PubMed

Savard, Kathleen; Berthelot, Yann; Auroy, Aurelie; Spear, Philip A; Trottier, Bertin; Robidoux, Pierre Yves

2007-10-01

High metal (e.g., Pb) concentrations are typically found in explosive-contaminated soil, and their presence may increase, decrease, or not influence toxicity predicted on the basis of one explosive alone (e.g., HMX). Nevertheless, few data are available in the scientific literature for this type of multiple exposure. Soil organisms, such as earthworms, are one of the first receptors affected by the contamination of soil. Therefore, a reproductive study was conducted using Eisenia andrei in a forest-type soil. Both HMX and Pb decreased reproduction parameters (number of total cocoons, hatched cocoons, and surviving juveniles) individually. Based on the total number of cocoons, HMX was more toxic in a forest soil than Pb, with EC(50) of 31 mg kg(-1), and 1068 mg kg(-1), respectively. The slope of the concentration-response curve was significantly greater in the case of Pb, which is consistent with the possibility that the two compounds do not act on the same target site. The response-addition model was used to predict the response of earthworms and to test for interaction between the two contaminants. The predicted toxicity was not significantly different than the observed toxicity, implying that Pb and HMX were considered noninteractive compounds. The combined action of Pb-HMX may be described, therefore, as dissimilar-noninteractive joint action in a forest soil. The results illustrate the relevance of considering the presence of metals in the risk assessment of explosive-contaminated sites because metals can add their toxicity to explosives. Extension of this study to other types of soil and other metals would improve the understanding of toxicity at these sites.

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

PubMed

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

2016-09-01

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

Stress, Behavior, and Children and Youth Who Are Deafblind

ERIC Educational Resources Information Center

Nelson, Catherine; Greenfield, Robin G.; Hyte, Holly A.; Shaffer, Jason P.

2013-01-01

Children and youth who are deafblind with multiple disabilities have several identified risk factors for experiencing toxic levels of stress, and such stress is known to impair physical, mental, and emotional health. This single-case multiple baseline study examined the frequency and duration of behaviors thought to indicate stress, the duration…

METHAMPHETAMINE TOXICITY AND MESSENGERS OF DEATH

PubMed Central

Krasnova, Irina N.; Cadet, Jean Lud

2009-01-01

Methamphetamine (METH) is an illicit psychostimulant that is widely abused in the world. Several lines of evidence suggest that chronic METH abuse leads to neurodegenerative changes in the human brain. These include damage to dopamine and serotonin axons, loss of gray matter accompanied by hypertrophy of the white matter and microgliosis in different brain areas. In the present review, we summarize data on the animal models of METH neurotoxicity which include degeneration of monoaminergic terminals and neuronal apoptosis. In addition, we discuss molecular and cellular bases of METH-induced neuropathologies. The accumulated evidence indicates that multiple events, including oxidative stress, excitotoxicity, hyperthermia, neuroinflammatory responses, mitochondrial dysfunction, endoplasmic reticulum stress converge to mediate METH-induced terminal degeneration and neuronal apoptosis. When taken together, these findings suggest that pharmacological strategies geared towards the prevention and treatment of the deleterious effects of this drug will need to attack the various pathways that form the substrates of METH toxicity. PMID:19328213

Translational Applications of Nanodiamonds: From Biocompatibility to Theranostics

NASA Astrophysics Data System (ADS)

Moore, Laura Kent

Nanotechnology marks the next phase of development for drug delivery, contrast agents and gene therapy. For these novel systems to achieve success in clinical translation we must see that they are both effective and safe. Diamond nanoparticles, also known as nanodiamonds (NDs), have been gaining popularity as molecular delivery vehicles over the last decade. The uniquely faceted, carbon nanoparticles possess a number of beneficial properties that are being harnessed for applications ranging from small-molecule drug delivery to biomedical imaging and gene therapy. In addition to improving the effectiveness of a variety of therapeutics and contrast agents, initial studies indicate that NDs are biocompatible. In this work we evaluate the translational potential of NDs by demonstrating efficacy in molecular delivery and scrutinizing particle tolerance. Previous work has demonstrated that NDs are effective vehicles for the delivery of anthracycline chemotherapeutics and gadolinium(III) based contrast agents. We have sought to enhance the gains made in both areas through the addition of active targeting. We find that ND-mediated targeted delivery of epirubicin to triple negative breast cancers induces tumor regression and virtually eliminates drug toxicities. Additionally, ND-mediated delivery of the MRI contrast agent ProGlo boosts the per gadolinium relaxivity four fold, eliminates water solubility issues and effectively labels progesterone receptor expressing breast cancer cells. Both strategies open the door to the development of targeted, theranostic constructs based on NDs, capable of treating and labeling breast cancers at the same time. Although we have seen that NDs are effective vehicles for molecular delivery, for any nanoparticle to achieve clinical utility it must be biocompatible. Preliminary research has shown that NDs are non-toxic, however only a fraction of the ND-subtypes have been evaluated. Here we present an in depth analysis of the cellular response to multiple subtypes of NDs, including pristine, amine functionalized, fluorescent and daunorubicin-loaded NDs. Furthermore, we present the most comprehensive analysis of in vivo tolerance of nanodiamonds to date. We find that NDs, regardless of subtype, are non-toxic to multiple cell types. Furthermore, we find that NDs are well tolerated by mice and rats at both acute and sub-acute time frames. These results indicate that NDs are biocompatible and will serve as the foundation for future clinical translation of diamond-based imaging, therapeutic or theranostic agents.

Alleviation of heavy metal toxicity and phytostimulation of Brassica campestris L. by endophytic Mucor sp. MHR-7.

PubMed

Zahoor, Mahwish; Irshad, Muhammad; Rahman, Hazir; Qasim, Muhammad; Afridi, Sahib Gul; Qadir, Muhammad; Hussain, Anwar

2017-08-01

Heavy metal (HM) pollution is of great concern in countries like Pakistan where a huge proportion of human population is exposed to it. These toxic metals are making their way from water bodies to soil where it not only interferes with plant growth and development but also initiates serious health issues in human consuming the produce of such soils. Bioremediation is one of the most viable and efficient solution for the problem. Purpose of the current study was to isolate endophytic fungi from plants grown on HM contaminated soil and screen them for their ability to tolerate multiple HM including chromium (Cr 6+ ), manganese (Mn 2+ ), cobalt (Co 2+ ), copper (Cu 2+ ) and zinc (Zn 2+ ). Out of 27 isolated endophytes, only one strain (MHR-7) was selected for multiple heavy metals tolerance. The strain was identified as Mucor sp. by 18S and 28S ribosomal RNA internal transcribed spacer (ITS) 1 and 4 sequence homology. The strain effectively tolerated up to 900µgmL -1 of these heavy metals showing no remarkable effect on its growth. The adverse effect of the heavy metals, measured as reduction of the fungal growth increased with increasing concentration of the metals. The strain was able to remove 60-87% of heavy metals from broth culture when supplied with 300µgmL -1 of these metals. A trend of decline in bioremediation potential of the strain was observed with increasing amount of metals. The strain removed metals by biotransformation and/or accumulation of heavy metal in its hyphae. Application of Mucor sp. MHR-7 locked down HM in tis mycelium thereby making them less available to plant root reducing HM uptake and toxicity in mustard. Besides its bioremediation potential, the strain was also able to produce IAA, ACC deaminase and solubilize phosphate making it excellent phytostimulant fungus. It is concluded that MHR-7 is an excellent candidate for use as biofertilizer in fields affected with heavy metals. Copyright © 2017 Elsevier Inc. All rights reserved.

An expert system for prediction of chemical toxicity

USGS Publications Warehouse

Hickey, James P.; Aldridge, Andrew J.; Passino-Reader, Dora R.; Frank, Anthony M.

1992-01-01

The National Fisheries Research Center- Great Lakes has developed an interactive computer program that uses the structure of an organic molecule to predict its acute toxicity to four aquatic species. The expert system software, written in the muLISP language, identifies the skeletal structures and substituent groups of an organic molecule from a user-supplied standard chemical notation known as a SMILES string, and then generates values for four solvatochromic parameters. Multiple regression equations relate these parameters to the toxicities (expressed as log10LC50s and log10EC50s, along with 95% confidence intervals) for four species. The system is demonstrated by prediction of toxicity for anilide-type pesticides to the fathead minnow (Pimephales promelas). This software is designed for use on an IBM-compatible personal computer by personnel with minimal toxicology background for rapid estimation of chemical toxicity. The system has numerous applications, with much potential for use in the pharmaceutical industry

Copper bioavailability and toxicity to Mytilus galloprovincialis in Shelter Island Yacht Basin, San Diego, CA.

PubMed

Bosse, Casey; Rosen, Gunther; Colvin, Marienne; Earley, Patrick; Santore, Robert; Rivera-Duarte, Ignacio

2014-08-15

The bioavailability and toxicity of copper (Cu) in Shelter Island Yacht Basin (SIYB), San Diego, CA, USA, was assessed with simultaneous toxicological, chemical, and modeling approaches. Toxicological measurements included laboratory toxicity testing with Mytilus galloprovincialis (Mediterranean mussel) embryos added to both site water (ambient) and site water spiked with multiple Cu concentrations. Chemical assessment of ambient samples included total and dissolved Cu concentrations, and Cu complexation capacity measurements. Modeling was based on chemical speciation and predictions of bioavailability and toxicity using a marine Biotic Ligand Model (BLM). Cumulatively, these methods assessed the natural buffering capacity of Cu in SIYB during singular wet and dry season sampling events. Overall, the three approaches suggested negligible bioavailability, and isolated observed or predicted toxicity, despite an observed gradient of increasing Cu concentration, both horizontally and vertically within the water body, exceeding current water quality criteria for saltwater. Published by Elsevier Ltd.

Toxic hepatitis caused by the excretions of the Phyllomedusa bicolor frog - a case report.

PubMed

Pogorzelska, Joanna; Łapiński, Tadeusz W

2017-03-01

The Kambô ritual consists of various types of skin scarification and subsequent application of Phyllomedusa bicolor secretion to the fresh wounds. In Europe, the ritual of Kambô is becoming more popular, but its use can lead to serious multiple organ damage, sometimes life-threatening. Our manuscript shows a patient with toxic liver damage probably associated with the Kambô ritual.

Toxic hepatitis caused by the excretions of the Phyllomedusa bicolor frog – a case report

PubMed Central

Pogorzelska, Joanna

2017-01-01

The Kambô ritual consists of various types of skin scarification and subsequent application of Phyllomedusa bicolor secretion to the fresh wounds. In Europe, the ritual of Kambô is becoming more popular, but its use can lead to serious multiple organ damage, sometimes life-threatening. Our manuscript shows a patient with toxic liver damage probably associated with the Kambô ritual. PMID:28856288

Internal versus External Dose for Describing Ternary Metal Mixture (Ni, Cu, Cd) Chronic Toxicity to Lemna minor.

PubMed

Gopalapillai, Yamini; Hale, Beverley A

2017-05-02

Simultaneous determinations of internal dose ([M] tiss ) and external doses ([M] tot , {M 2+ } in solution) were conducted to study ternary mixture (Ni, Cu, Cd) chronic toxicity to Lemna minor in alkaline solution (pH 8.3). Also, concentration addition (CA) based on internal dose was evaluated as a tool for risk assessment of metal mixture. Multiple regression analysis of dose versus root growth inhibition, as well as saturation binding kinetics, provided insight into interactions. Multiple regressions were simpler for [M] tiss than [M] tot and {M 2+ }, and along with saturation kinetics to the internal biotic ligand(s) in the cytoplasm, they indicated that Ni-Cu-Cd competed for uptake into plant, but once inside, only Cu-Cd shared a binding site. Copper inorganic complexes (hydroxides, carbonates) played a role in metal bioavailability in single metal exposure but not in mixtures. Regardless of interactions, the current regulatory approach of using CA based on [M] tot can sufficiently predict mixture toxicity (∑TU close to 1), but CA based on [M] tiss was closest to unity across a range of doses. Internal dose integrates all metal-metal interactions in solution and during uptake into the organism, thereby providing a more direct metric describing toxicity.

Screening the yeast genome for energetic metabolism pathways involved in a phenotypic response to the anti-cancer agent 3-bromopyruvate.

PubMed

Lis, Paweł; Jurkiewicz, Paweł; Cal-Bąkowska, Magdalena; Ko, Young H; Pedersen, Peter L; Goffeau, Andre; Ułaszewski, Stanisław

2016-03-01

In this study the detailed characteristic of the anti-cancer agent 3-bromopyruvate (3-BP) activity in the yeast Saccharomyces cerevisiae model is described, with the emphasis on its influence on energetic metabolism of the cell. It shows that 3-BP toxicity in yeast is strain-dependent and influenced by the glucose-repression system. Its toxic effect is mainly due to the rapid depletion of intracellular ATP. Moreover, lack of the Whi2p phosphatase results in strongly increased sensitivity of yeast cells to 3-BP, possibly due to the non-functional system of mitophagy of damaged mitochondria through the Ras-cAMP-PKA pathway. Single deletions of genes encoding glycolytic enzymes, the TCA cycle enzymes and mitochondrial carriers result in multiple effects after 3-BP treatment. However, it can be concluded that activity of the pentose phosphate pathway is necessary to prevent the toxicity of 3-BP, probably due to the fact that large amounts of NADPH are produced by this pathway, ensuring the reducing force needed for glutathione reduction, crucial to cope with the oxidative stress. Moreover, single deletions of genes encoding the TCA cycle enzymes and mitochondrial carriers generally cause sensitivity to 3-BP, while totally inactive mitochondrial respiration in the rho0 mutant resulted in increased resistance to 3-BP.

The effects of salinity, pH, and dissolved organic matter on acute copper toxicity to the rotifer, Brachionus plicatilis ("L" strain).

PubMed

Arnold, W R; Diamond, R L; Smith, D S

2010-08-01

This paper presents data from original research for use in the development of a marine biotic ligand model and, ultimately, copper criteria for the protection of estuarine and marine organisms and their uses. Ten 48-h static acute (unfed) copper toxicity tests using the euryhaline rotifer Brachionus plicatilis ("L" strain) were performed to assess the effects of salinity, pH, and dissolved organic matter (measured as dissolved organic carbon; DOC) on median lethal dissolved copper concentrations (LC50). Reconstituted and natural saltwater samples were tested at seven salinities (6, 11, 13, 15, 20, 24, and 29 g/L), over a pH range of 6.8-8.6 and a range of dissolved organic carbon of <0.5-4.1 mg C/L. Water chemistry analyses (alkalinity, calcium, chloride, DOC, hardness, magnesium, potassium, sodium, salinity, and temperature) are presented for input parameters to the biotic ligand model. In stepwise multiple regression analysis of experimental results where salinity, pH, and DOC concentrations varied, copper toxicity was significantly related only to the dissolved organic matter content (pH and salinity not statistically retained; alpha=0.05). The relationship of the 48-h dissolved copper LC50 values and dissolved organic carbon concentrations was LC50 (microg Cu/L)=27.1xDOC (mg C/L)1.25; r2=0.94.

Screening the yeast genome for energetic metabolism pathways involved in a phenotypic response to the anti-cancer agent 3-bromopyruvate

PubMed Central

Lis, Paweł; Jurkiewicz, Paweł; Cal-Bąkowska, Magdalena; Ko, Young H.; Pedersen, Peter L.; Goffeau, Andre; Ułaszewski, Stanisław

2016-01-01

In this study the detailed characteristic of the anti-cancer agent 3-bromopyruvate (3-BP) activity in the yeast Saccharomyces cerevisiae model is described, with the emphasis on its influence on energetic metabolism of the cell. It shows that 3-BP toxicity in yeast is strain-dependent and influenced by the glucose-repression system. Its toxic effect is mainly due to the rapid depletion of intracellular ATP. Moreover, lack of the Whi2p phosphatase results in strongly increased sensitivity of yeast cells to 3-BP, possibly due to the non-functional system of mitophagy of damaged mitochondria through the Ras-cAMP-PKA pathway. Single deletions of genes encoding glycolytic enzymes, the TCA cycle enzymes and mitochondrial carriers result in multiple effects after 3-BP treatment. However, it can be concluded that activity of the pentose phosphate pathway is necessary to prevent the toxicity of 3-BP, probably due to the fact that large amounts of NADPH are produced by this pathway, ensuring the reducing force needed for glutathione reduction, crucial to cope with the oxidative stress. Moreover, single deletions of genes encoding the TCA cycle enzymes and mitochondrial carriers generally cause sensitivity to 3-BP, while totally inactive mitochondrial respiration in the rho0 mutant resulted in increased resistance to 3-BP. PMID:26862728

Multiple bio-analytical methods to reveal possible molecular mechanisms of developmental toxicity in zebrafish embryos/larvae exposed to tris(2-butoxyethyl) phosphate.

PubMed

Han, Zhihua; Wang, Qiangwei; Fu, Jie; Chen, Hongshan; Zhao, Ye; Zhou, Bingsheng; Gong, Zhiyuan; Wei, Si; Li, Jun; Liu, Hongling; Zhang, Xiaowei; Liu, Chunsheng; Yu, Hongxia

2014-05-01

The flame retardant tris(2-butoxyethyl) phosphate (TBEP) is a frequently detected contaminant in the environment, wildlife and human milk. The potentially toxic effects of TBEP and their underlying molecular mechanisms have not been elucidated. Here, zebrafish embryos were exposed to different concentrations of TBEP from 4 hours of post-fertilization (hpf) to 120 hpf, and effects on embryonic development and global protein expression patterns examined. Our results demonstrate that treatment with TBEP (0.8-100mg/L) causes a concentration- and time-dependent decrease in embryonic survival and the hatching percentage. The median lethal concentration was 10.7 mg/L at 120 hpf. Furthermore, exposure to 150 or 800 μg/L TBEP inhibited the degradation and utilization of vitellogenins and down-regulated the expression of proteins related to cation binding, and lipid transport, uptake and metabolism, accompanied by a decrease in heart rate and body length. Exposure to TBEP (150 or 800 μg/L) also decreased the expression of proteins involved in cell proliferation and DNA repair, and led to an increased number of apoptotic cells in the tail region. Collectively, our results suggest that exposure to TBEP causes toxicity in the developing zebrafish by inhibiting the degradation and utilization of nutrients from the mother and inducing apoptosis. Copyright © 2014 Elsevier B.V. All rights reserved.

Bortezomib, a newly approved proteasome inhibitor for the treatment of multiple myeloma: nursing implications.

PubMed

Colson, Kathleen; Doss, Deborah S; Swift, Regina; Tariman, Joseph; Thomas, Teri E

2004-10-01

Multiple myeloma (MM), a malignancy of the plasma cells, accounts for an estimated 14% of all newly diagnosed hematologic malignancies. Advances in chemotherapy and stem cell transplantation have improved survival rates, but MM remains incurable. Bortezomib (Velcade, Millennium Pharmaceuticals, Inc., Cambridge, MA), a first-in-class proteasome inhibitor, has been approved for patients with MM who have received at least two prior treatments and have demonstrated disease progression on the most recent one. During clinical trials, most side effects were manageable with standard interventions. The most common toxicities were asthenic conditions (fatigue, malaise, and weakness), gastrointestinal disturbances (nausea, vomiting, diarrhea, and constipation), thrombocytopenia, peripheral neuropathy, pyrexia, and anemia. Supportive therapies and strategies for side-effect management can prevent worsening of these symptoms, thereby avoiding dose reductions and treatment delays. Oncology nurses play a key role in ensuring the proper and safe administration of bortezomib and often are the first to identify the signs of side effects. Patient education about anticipated side effects and close monitoring of patients can lead to symptom management interventions that are essential to patient comfort and safety.

Tumor-targeted nanomedicines for cancer theranostics

PubMed Central

Lammers, Twan; Shi, Yang

2017-01-01

Chemotherapeutic drugs have multiple drawbacks, including severe side effects and suboptimal therapeutic efficacy. Nanomedicines assist in improving the biodistribution and the target accumulation of chemotherapeutic drugs, and are therefore able to enhance the balance between efficacy and toxicity. Multiple different types of nanomedicines have been evaluated over the years, including liposomes, polymer-drug conjugates and polymeric micelles, which rely on strategies such as passive targeting, active targeting and triggered release for improved tumor-directed drug delivery. Based on the notion that tumors and metastases are highly heterogeneous, it is important to integrate imaging properties in nanomedicine formulations in order to enable non-invasive and quantitative assessment of targeting efficiency. By allowing for patient pre-selection, such next generation nanotheranostics are useful for facilitating clinical translation and personalizing nanomedicine treatments. PMID:27865762

New perspectives of curcumin in cancer prevention

PubMed Central

Park, Wungki; Amin, A.R.M Ruhul; Chen, Zhuo Georgia; Shin, Dong M.

2013-01-01

Numerous natural compounds have been extensively investigated for their potential for cancer prevention over decades. Curcumin, from Curcuma longa, is a highly promising natural compound that can be potentially used for chemoprevention of multiple cancers. Curcumin modulates multiple molecular pathways involved in the lengthy carcinogenesis process to exert its chemopreventive effects through several mechanisms: promoting apoptosis, inhibiting survival signals, scavenging reactive oxidative species (ROS), and reducing the inflammatory cancer microenvironment. Curcumin fulfills the characteristics for an ideal chemopreventive agent with its low toxicity, affordability, and easy accessibility. Nevertheless, the clinical application of curcumin is currently compromised by its poor bioavailability. Here we review the potential of curcumin in cancer prevention, its molecular targets, and action mechanisms. Finally, we suggest specific recommendations to improve its efficacy and bioavailability for clinical applications. PMID:23466484

Effect of Shodhana Treatment on Chronic Toxicity and Recovery of Aconite

PubMed Central

Sarkar, P.K.; Prajapati, P.K.; Shukla, V.J.; Ravishankar, B.

2012-01-01

Aconite is one of the poisonous plants used therapeutically in practice of Ayurveda after proper treatment called as ‘Shodhana’. To determine the effect of Shodhana treatment on chronic toxicity and to assess the effect of recovery period after chronic toxicity of aconite. Raw aconite (RV), urine treated aconite (SM), and milk treated aconite (SD) were administered in 6.25 mg/kg dose in Charles Foster strain albino rats for 90 days for chronic toxicity. Six rats from each were kept for another 30 days without test drugs treatment to observe recovery from chronic toxicity. RV was found to be highly toxic in chronic exposure, SM had no apparent toxicity, but SD had mild toxicity in kidney. The toxicities of RV and SD were reversible, but sudden withdrawal of SM caused adverse effects, suggestive of tapering withdrawal. Shodhana treatments remove toxic effects from raw aconite. Chronic toxicity of aconite is reversible. Confirmed the arrangement of abstract PMID:22736901

A Multi-Route Model of Nicotine-Cotinine Pharmacokinetics, Pharmacodynamics and Brain Nicotinic Acetylcholine Receptor Binding in Humans

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

Teeguarden, Justin G.; Housand, Conrad; Smith, Jordan N.

The pharmacokinetics of nicotine, the pharmacologically active alkaloid in tobacco responsible for addiction, are well characterized in humans. We developed a physiologically based pharmacokinetic/pharmacodynamic model of nicotine pharmacokinetics, brain dosimetry and brain nicotinic acetylcholine receptor (nAChRs) occupancy. A Bayesian framework was applied to optimize model parameters against multiple human data sets. The resulting model was consistent with both calibration and test data sets, but in general underestimated variability. A pharmacodynamic model relating nicotine levels to increases in heart rate as a proxy for the pharmacological effects of nicotine accurately described the nicotine related changes in heart rate and the developmentmore » and decay of tolerance to nicotine. The PBPK model was utilized to quantitatively capture the combined impact of variation in physiological and metabolic parameters, nicotine availability and smoking compensation on the change in number of cigarettes smoked and toxicant exposure in a population of 10,000 people presented with a reduced toxicant (50%), reduced nicotine (50%) cigarette Across the population, toxicant exposure is reduced in some but not all smokers. Reductions are not in proportion to reductions in toxicant yields, largely due to partial compensation in response to reduced nicotine yields. This framework can be used as a key element of a dosimetry-driven risk assessment strategy for cigarette smoke constituents.« less

Accelerating cancer therapy development: the importance of combination strategies and collaboration. Summary of an Institute of Medicine workshop.

PubMed

LoRusso, Patricia M; Canetta, Renzo; Wagner, John A; Balogh, Erin P; Nass, Sharyl J; Boerner, Scott A; Hohneker, John

2012-11-15

Cancer cells contain multiple genetic changes in cell signaling pathways that drive abnormal cell survival, proliferation, invasion, and metastasis. Unfortunately, patients treated with single agents inhibiting only one of these pathways--even if showing an initial response--often develop resistance with subsequent relapse or progression of their cancer, typically via the activation of an alternative uninhibited pathway. Combination therapies offer the potential for inhibiting multiple targets and pathways simultaneously to more effectively kill cancer cells and prevent or delay the emergence of drug resistance. However, there are many unique challenges to developing combination therapies, including devising and applying appropriate preclinical tests and clinical trial designs, prioritizing which combination therapies to test, avoiding overlapping toxicity of multiple agents, and overcoming legal, cultural, and regulatory barriers that impede collaboration among multiple companies, organizations, and/or institutions. More effective strategies to efficiently develop combination cancer therapies are urgently needed. Thus, the Institute of Medicine's National Cancer Policy Forum recently convened a workshop with the goal of identifying barriers that may be impeding the development of combination investigational cancer therapies, as well as potential solutions to overcome those barriers, improve collaboration, and ultimately accelerate the development of promising combinations of investigational cancer therapies. ©2012 AACR.

Distinct role of nitric oxide and peroxynitrite in mediating oligodendrocyte toxicity in culture and in experimental autoimmune encephalomyelitis.

PubMed

Li, S; Vana, A C; Ribeiro, R; Zhang, Y

2011-06-16

Nitric oxide has been implicated in the pathogenesis of multiple sclerosis. However, it is still unclear whether nitric oxide plays a protective role or is deleterious. We have previously shown that peroxynitrite, a reaction product of nitric oxide and superoxide, is toxic to mature oligodendrocytes (OLs). The toxicity is mediated by intracellular zinc release, phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), activation of 12-lipoxygenase (12-LOX) and the formation of reactive oxygen species (ROS). In this study, we found that the donors of nitric oxide, dipropylenetriamine NONOate (DPT NONOate) and diethylenetriamine NONOate (DETA NONOate), protected OLs from peroxynitrite or zinc-induced toxicity. The protective mechanisms appear to be attributable to their inhibition of peroxynitrite- or zinc-induced ERK1/2 phosphorylation and 12-LOX activation. In cultures of mature OLs exposed to lipopolysaccharide (LPS), induction of inducible nitric oxide synthase (iNOS) generated nitric oxide and rendered OLs resistant to peroxynitrite-induced toxicity. The protection was eliminated when 1400W, a specific inhibitor of iNOS, was co-applied with LPS. Using MOG35-55-induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, we found that nitrotyrosine immunoreactivity, an indicator of peroxynitrite formation, was increased in the spinal cord white matter, which correlated with the loss of mature OLs. Targeted gene deletion of the NADPH oxidase component gp91phox reduced clinical scores, the formation of nitrotyrosine and the loss of mature OLs. These results suggest that blocking the formation specifically of peroxynitrite, rather than nitric oxide, may be a protective strategy against oxidative stress induced toxicity to OLs. Published by Elsevier Ltd.

Identifying the causes of sediment-associated toxicity in urban waterways in South China: incorporating bioavailabillity-based measurements into whole-sediment toxicity identification evaluation.

PubMed

Yi, Xiaoyi; Li, Huizhen; Ma, Ping; You, Jing

2015-08-01

Sediments in urban waterways of Guangzhou, China, were contaminated by a variety of chemicals and showed prevalent toxicity to benthic organisms. A combination of whole-sediment toxicity identification evaluation (TIE) and bioavailability-based extraction was used to identify the causes of sediment toxicity. Of the 6 sediment samples collected, 4 caused 100% mortality to Chironomus dilutus in 10-d bioassays, and the potential toxicants were assessed using TIE in these sediments after dilution. The results of phase I characterization showed that organic contaminants were the principal contributors to the mortality of the midges in 2 sediments and that metals and organics jointly caused the mortality in the other 2 sediments. Ammonia played no role in the mortality for any samples. Conventional toxic unit analysis in phase II testing identified Cr, Cu, Ni, Pb, and Zn as the toxic metals, with cypermethrin, lambda-cyhalothrin, deltamethrin, and fipronils being the toxic organics. To improve the accuracy of identifying the toxicants, 4-step sequential extraction and Tenax extraction were conducted to analyze the bioavailability of the metals and organics, respectively. Bioavailable toxic unit analysis narrowed the list of toxic contributors, and the putative toxicants included 3 metals (Zn, Ni, and Pb) and 3 pesticides (cypermethrin, lambda-cyhalothrin, and fipronils). Metals contributed to the mortality in all sediments, but sediment dilution reduced the toxicity and confounded the characterization of toxicity contribution from metals in 2 sediments in phase I. Incorporating bioavailability-based measurements into whole-sediment TIE improved the accuracy of identifying the causative toxicants in urban waterways where multiple stressors occurred and contributed to sediment toxicity jointly. © 2015 SETAC.

Magnitude and extent of sediment toxicity in four bays of the Florida Panhandle: Pensacola, Choctawhatchee, St. Andrew and Apalachicola. National status and trends program for marine environmental quality: Technical memo

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

Long, E.R.; Sloane, G.M.; Carr, R.S.

1997-10-01

The toxicity of sediments in Pensacola, Choctawhatcheee, St. Andrew and Apalachicola Bays was determined as part of bioeffects assessments performed by NOAA`s National Status and Trends Program. The objectives of the survey were to determine: (1) the spatial patterns in toxicity throughout each bay, (2) the spatial extent of toxicity throughout and among the bays, (3) the severity of degree of toxicity, and (4) the relationships between chemical contamination and toxicity. The survey was conducted over two years: Pensacola Bay and St. Andrew Bay were sampled in 1993; and Choctawhatchee Bay, Apalachicola Bay and Bayou Chico (a sub-basin of Pensacolamore » Bay) were sampled during 1994. Surficial sediment samples were collected from 123 randomly-chosen locations throughout the five areas. Multiple toxicity tests were conducted on all samples, and chemical analyses were performed on 102 of the 123 samples. Toxicological tests were conducted to determine survival, reproductive success, morphological development, metabolic activity, and genotoxicity; all bays showed toxicity in at least some of the samples.« less

The protective and toxic effects of rhubarb tannins and anthraquinones in treating hexavalent chromium-injured rats: the Yin/Yang actions of rhubarb.

PubMed

Zeng, Ling-na; Ma, Zhi-jie; Zhao, Yan-ling; Zhang, Lin-dong; Li, Rui-sheng; Wang, Jia-bo; Zhang, Ping; Yan, Dan; Li, Qi; Jiang, Bing-qian; Pu, Shi-biao; Lü, Yang; Xiao, Xiao-he

2013-02-15

Chromium nephrotoxicity (CrNT) is thought to occur through the oxidant lesion mechanism. There is still a lack of specific remedies against CrNT. We primarily screened Chinese herbal medicines with a potential protective effect against CrNT, e.g., rhubarb (Rheum palmatum L.). However, the active constituents in rhubarb and its mechanisms remain unclear. In this study, the total rhubarb extract (TR) was successively separated into three parts: total anthraquinone extract (TA), total tannin extract (TT) and remaining component extract (RC). The effects of each extract on the potassium dichromate (K(2)Cr(2)O(7))-induced nephrotoxicity in rats were comparatively assessed. The results showed that only the administration of TT protected the kidney function in K(2)Cr(2)O(7)-injured rats. Besides, TT showed significant activity to scavenge hydroxyl radicals, which is considered to be the dominant lesion product generated by hexavalent chromium. TT also showed a reduced ability to transform toxic high valence chromium ions into non-toxic low valence ions. And TT was able to further precipitate chromium ions. These results suggested that rhubarb tannins treat CrNT as a free radical scavenger, reductant, and metal precipitant. The multiple protective routes of the plant tannins reveal a superior option for development into a promising natural remedy against CrNT. In addition, the opposite effects of rhubarb anthraquinones in treating CrNT were observed compared to rhubarb tannins, which suggested the duo-directional effects (Yin and Yang) of herbal medicines should be addressed. Copyright © 2012 Elsevier B.V. All rights reserved.

Silibinin Attenuates Sulfur Mustard Analog-Induced Skin Injury by Targeting Multiple Pathways Connecting Oxidative Stress and Inflammation

PubMed Central

Tewari-Singh, Neera; Jain, Anil K.; Inturi, Swetha; Agarwal, Chapla; White, Carl W.; Agarwal, Rajesh

2012-01-01

Chemical warfare agent sulfur mustard (HD) inflicts delayed blistering and incapacitating skin injuries. To identify effective countermeasures against HD-induced skin injuries, efficacy studies were carried out employing HD analog 2-chloroethyl ethyl sulfide (CEES)-induced injury biomarkers in skin cells and SKH-1 hairless mouse skin. The data demonstrate strong therapeutic efficacy of silibinin, a natural flavanone, in attenuating CEES-induced skin injury and oxidative stress. In skin cells, silibinin (10 µM) treatment 30 min after 0.35/0.5 mM CEES exposure caused a significant (p<0.05) reversal in CEES-induced decrease in cell viability, apoptotic and necrotic cell death, DNA damage, and an increase in oxidative stress. Silibinin (1 mg) applied topically to mouse skin 30 min post-CEES exposure (2 mg), was effective in reversing CEES-induced increases in skin bi-fold (62%) and epidermal thickness (85%), apoptotic cell death (70%), myeloperoxidase activity (complete reversal), induction of iNOS, COX-2, and MMP-9 protein levels (>90%), and activation of transcription factors NF-κB and AP-1 (complete reversal). Similarly, silibinin treatment was also effective in attenuating CEES-induced oxidative stress measured by 4-hydroxynonenal and 5,5-dimethyl-2-(8-octanoic acid)-1-pyrolline N-oxide protein adduct formation, and 8-oxo-2-deoxyguanosine levels. Since our previous studies implicated oxidative stress, in part, in CEES-induced toxic responses, the reversal of CEES-induced oxidative stress and other toxic effects by silibinin in this study indicate its pleiotropic therapeutic efficacy. Together, these findings support further optimization of silibinin in HD skin toxicity model to develop a novel effective therapy for skin injuries by vesicants. PMID:23029417

Comparative effects of dimethylsulfoxide on metabolism and toxicity of carbon tetrachloride and dichloromethane.

PubMed

Kim, Sun J; Jung, Young S; Yoon, Mi Y; Kim, Young C

2007-01-01

The effects of dimethylsulfoxide (DMSO) on the metabolism and toxicity of chlorinated methanes were examined. Male mice were treated with DMSO (1, 2.5 or 5 ml kg(-1), i.p.) prior to challenge with dichloromethane (CH(2)Cl(2)) or carbon tetrachloride (CCl(4)). Blood carboxyhemoglobin elevation resulting from metabolic conversion of CH(2)Cl(2) to carbon monoxide was inhibited dose-dependently by DMSO pretreatment. The elevation of serum aspartate aminotransferase, alanine aminotransferase and sorbitol dehydrogenase activities induced by CCl(4) (0.1 mmol kg(-1)) was not changed in mice pretreated with DMSO at 1 ml kg(-1), but depressed significantly at a greater dose of DMSO. However, DMSO failed to alter the hepatotoxicity of CCl(4) injected at a dose of 0.2 mmol kg(-1). DMSO induced the microsomal p-nitrophenol hydroxylase and p-nitroanisole O-demethylase activities as early as 2 h following the treatment. Microsomal disposition of CH(2)Cl(2) and CCl(4) was measured using a vial equilibration technique. The disappearance of CH(2)Cl(2) was inhibited competitively by addition of DMSO. But DMSO did not affect the metabolic degradation of CCl(4). The results indicate that DMSO has multiple effects on metabolism and toxicity of xenobiotics. DMSO induces the hepatic metabolizing activity mediated by CYP2E1, but the presence of this solvent in the enzyme site may inhibit directly the enzymatic interaction with a substrate. The toxicological significance of DMSO-induced effects on such an interaction may be variable depending on the properties of each substrate. The invulnerability of CCl(4) metabolism to the effects of DMSO appears to be related to its high affinity for the lipophilic CYP enzyme site. Copyright 2006 John Wiley & Sons, Ltd.

Silibinin attenuates sulfur mustard analog-induced skin injury by targeting multiple pathways connecting oxidative stress and inflammation.

PubMed

Tewari-Singh, Neera; Jain, Anil K; Inturi, Swetha; Agarwal, Chapla; White, Carl W; Agarwal, Rajesh

2012-01-01

Chemical warfare agent sulfur mustard (HD) inflicts delayed blistering and incapacitating skin injuries. To identify effective countermeasures against HD-induced skin injuries, efficacy studies were carried out employing HD analog 2-chloroethyl ethyl sulfide (CEES)-induced injury biomarkers in skin cells and SKH-1 hairless mouse skin. The data demonstrate strong therapeutic efficacy of silibinin, a natural flavanone, in attenuating CEES-induced skin injury and oxidative stress. In skin cells, silibinin (10 µM) treatment 30 min after 0.35/0.5 mM CEES exposure caused a significant (p<0.05) reversal in CEES-induced decrease in cell viability, apoptotic and necrotic cell death, DNA damage, and an increase in oxidative stress. Silibinin (1 mg) applied topically to mouse skin 30 min post-CEES exposure (2 mg), was effective in reversing CEES-induced increases in skin bi-fold (62%) and epidermal thickness (85%), apoptotic cell death (70%), myeloperoxidase activity (complete reversal), induction of iNOS, COX-2, and MMP-9 protein levels (>90%), and activation of transcription factors NF-κB and AP-1 (complete reversal). Similarly, silibinin treatment was also effective in attenuating CEES-induced oxidative stress measured by 4-hydroxynonenal and 5,5-dimethyl-2-(8-octanoic acid)-1-pyrolline N-oxide protein adduct formation, and 8-oxo-2-deoxyguanosine levels. Since our previous studies implicated oxidative stress, in part, in CEES-induced toxic responses, the reversal of CEES-induced oxidative stress and other toxic effects by silibinin in this study indicate its pleiotropic therapeutic efficacy. Together, these findings support further optimization of silibinin in HD skin toxicity model to develop a novel effective therapy for skin injuries by vesicants.

Rapid dissolution of ZnO nanocrystals in acidic cancer microenvironment leading to preferential apoptosis

NASA Astrophysics Data System (ADS)

Sasidharan, Abhilash; Chandran, Parwathy; Menon, Deepthy; Raman, Sreerekha; Nair, Shantikumar; Koyakutty, Manzoor

2011-09-01

The microenvironment of cancer plays a very critical role in the survival, proliferation and drug resistance of solid tumors. Here, we report an interesting, acidic cancer microenvironment-mediated dissolution-induced preferential toxicity of ZnO nanocrystals (NCs) against cancer cells while leaving primary cells unaffected. Irrespective of the size-scale (5 and 200 nm) and surface chemistry differences (silica, starch or polyethylene glycol coating), ZnO NCs exhibited multiple stress mechanisms against cancer cell lines (IC50 ~150 μM) while normal human primary cells (human dermal fibroblast, lymphocytes, human umbilical vein endothelial cells) remain less affected. Flow cytometry and confocal microscopy studies revealed that ZnO NCs undergo rapid preferential dissolution in acidic (pH ~5-6) cancer microenvironment causing elevated ROS stress, mitochondrial superoxide formation, depolarization of mitochondrial membrane, and cell cycle arrest at S/G2 phase leading to apoptosis. In effect, by elucidating the unique toxicity mechanism of ZnO NCs, we show that ZnO NCs can destabilize cancer cells by utilizing its own hostile acidic microenvironment, which is otherwise critical for its survival.The microenvironment of cancer plays a very critical role in the survival, proliferation and drug resistance of solid tumors. Here, we report an interesting, acidic cancer microenvironment-mediated dissolution-induced preferential toxicity of ZnO nanocrystals (NCs) against cancer cells while leaving primary cells unaffected. Irrespective of the size-scale (5 and 200 nm) and surface chemistry differences (silica, starch or polyethylene glycol coating), ZnO NCs exhibited multiple stress mechanisms against cancer cell lines (IC50 ~150 μM) while normal human primary cells (human dermal fibroblast, lymphocytes, human umbilical vein endothelial cells) remain less affected. Flow cytometry and confocal microscopy studies revealed that ZnO NCs undergo rapid preferential dissolution in acidic (pH ~5-6) cancer microenvironment causing elevated ROS stress, mitochondrial superoxide formation, depolarization of mitochondrial membrane, and cell cycle arrest at S/G2 phase leading to apoptosis. In effect, by elucidating the unique toxicity mechanism of ZnO NCs, we show that ZnO NCs can destabilize cancer cells by utilizing its own hostile acidic microenvironment, which is otherwise critical for its survival. Electronic supplementary information (ESI) available: FTIR data, MTT assay and zinc ion release. See DOI: 10.1039/c1nr10272a

First-in-human study of the toxicity, pharmacokinetics, and pharmacodynamics of CG200745, a pan-HDAC inhibitor, in patients with refractory solid malignancies.

PubMed

Kim, Kyu-pyo; Park, Seong Joon; Kim, Jeong-Eun; Hong, Yong Sang; Lee, Jae-Lyun; Bae, Kyun-Seop; Cha, Hyunju; Kwon, Sool-Ki; Ro, Seonggu; Cho, JoongMyung; Kim, Tae Won

2015-10-01

The aim of the present study was to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and efficacy of single and multiple doses of intravenous CG200745, a novel histone deacetylase (HDAC) inhibitor, in patients with advanced solid malignancies. Two to six patients received intravenous CG200745 according to the 2 + 4 dose-escalating method. This first-in-human trial was comprised of two parts: Part 1 was a single ascending dose, and Part 2 was multiple ascending doses weekly for 3 weeks, and then 1 week off. For the first cycle, pharmacokinetic sampling for CG200745 and pharmacodynamic sampling for acetylated histone H4 in peripheral blood mononuclear cells (PBMCs) were performed on day 1 for Part 1 and on days 1 and 15 for Part 2. Examination of acetylated histone H4 in pre- and post-biopsy samples was performed in accessible patients. In all, 28 patients were treated at 13 dose levels (1.8-250 mg/m(2)) and received a total of 71 cycles of CG200745. Hematologic toxicities included grade 3/4 neutropenia (22.2 %) that did not last a week and non-hematologic toxicities included fatigue (22.2 %) and anorexia (16.7 %) that did not exceed grade 2. No dose-limiting toxic effects were noted. Dose proportionality was observed for both the maximum concentration and area under the curve. The elimination half-life was 5.67 ± 2.69 h (mean ± standard deviation). An increase in PBMC acetylated histone H4 was observed at dose levels up to 51 mg/m(2), which plateaued at higher dose levels. At 24 h, 75 % of patients (6/8) showed higher relative acetylation in tumor tissue compared to PBMCs. Although there was no partial or complete response, 57.1 % of patients (16/28) had stable disease that lasted at least 6 weeks. CG200745 can be safely administered at effective dose levels that inhibit HDAC in PBMCs and tumor tissue. Although MTD was not reached, further escalation was not performed because acetylated histone H4 plateaued at dose levels higher than 51 mg/m(2). Additional phase II trials are recommended at 250 mg/m(2).

Rodentia and lagomorpha

USGS Publications Warehouse

Sheffield, S.R.; Sawicka-Kapusta, K.; Cohen, J.B.; Rattner, B.A.; Shore, Richard F.; Rattner, Barnett A.

2001-01-01

This comprehensive review examines the extensive literature on wild rodents and lagomorphs as biomonitors of environmental contamination. This chapter covers studies dealing with exposure and effects of environmental contaminants on rodent and lagomorph species, including pesticides (organochlorines, organophosphorus and carbamate compounds, herbicides, plant growth regulators, fungicides, and rodenticides), other organic chemicals, metals, radionuclides, and other miscellaneous contaminants. Many research needs become evident when reviewing ecotoxicological data for rodents and lagomorphs, the most striking being the paucity of information on rodent families other than Muridae (mice and rats). While our ability to qualitatively extrapolate effects observed in laboratory studies to field situations is good for a variety of contaminants, quantitative predictions of dose-response relationships are poor because inter-specific variation and differences in exposure patterns between laboratory and wild species to toxicants are for the most part unknown. More sophisticated comparative toxicity studies need to be undertaken that build on previous work in order to develop a database of information, to account for and model differences in exposure pathways, to document interactions among multiple stressors, to generate data establishing thresholds, critical concentrations, and diagnostic guidelines, and even to develop physiologically-based toxicokinetic models. Such efforts may enhance our ability to predict effects on wild populations, including threatened and endangered species.

A COL11A1-correlated pan-cancer gene signature of activated fibroblasts for the prioritization of therapeutic targets

PubMed Central

Jia, Dongyu; Liu, Zhenqiu; Deng, Nan; Tan, Tuan Zea; Huang, Ruby Yun-Ju; Taylor-Harding, Barbie; Cheon, Dong-Joo; Lawrenson, Kate; Wiedemeyer, Wolf R.; Walts, Ann E.; Karlan, Beth Y.; Orsulic, Sandra

2016-01-01

Although cancer-associated fibroblasts (CAFs) are viewed as a promising therapeutic target, the design of rational therapy has been hampered by two key obstacles. First, attempts to ablate CAFs have resulted in significant toxicity because currently used biomarkers cannot effectively distinguish activated CAFs from non-cancer associated fibroblasts and mesenchymal progenitor cells. Second, it is unclear whether CAFs in different organs have different molecular and functional properties that necessitate organ-specific therapeutic designs. Our analyses uncovered COL11A1 as a highly specific biomarker of activated CAFs. Using COL11A1 as a ‘seed’, we identified co-expressed genes in 13 types of primary carcinoma in The Cancer Genome Atlas. We demonstrated that a molecular signature of activated CAFs is conserved in epithelial cancers regardless of organ site and transforming events within cancer cells, suggesting that targeting fibroblast activation should be effective in multiple cancers. We prioritized several potential pan-cancer therapeutic targets that are likely to have high specificity for activated CAFs and minimal toxicity in normal tissues. PMID:27609069

Final report on the United States phase I clinical trial of the hypoxic cell radiosensitizer, misonidazole (Ro-07-0582; NSC No. 261037

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

Phillips, T.L.; Wasserman, T.H.; Johnson, R.J.

1981-10-15

The hypoxic cell sensitizer misonidazole began phase I evaluation in the United States in July 1977. One hundred two patients received 104 individual courses of drug. Drug was administered from once to five times per week over time spans from one to six weeks. The individual doses ranged 1 to 5 g/m. The major toxicity noted was neurologic; 49% of evaluable courses showed peripheral neuropathy, and 9% of evaluable courses showed central nervous system effects and/or ototoxicity. In addition, 48 of 102 patients exhibited some degree of nausea and vomiting. The concomitant administration of dexamethasone and phenytoin sodium appeared tomore » lower the incidence of neuropathy. Observations of efficacy were made comparatively in five patients who had multiple lesions treated with and without misonidazole. All five showed increased response in the lesions treated with misonidazole. It is concluded that misonidazole is a reasonably safe and potentially effective hypoxic cell sensitizer whose dose-limiting toxicity is neurologic.« less

Anti-cancer effects of curcumin on head and neck cancers.

PubMed

Gao, Wei; Chan, Jimmy Yu-Wai; Wei, William Ignance; Wong, Thian-Sze

2012-11-01

Head and neck cancer is the sixth large type of cancer in the world. The treatment regimens for head and neck cancer encompass surgery, radiotherapy and chemotherapy. However, all current treatment regimens for head and neck cancer have adverse effects. Therefore, continuing investigations have been undertaken to seek less toxic therapies to reduce treatment morbidity for head and neck cancer. Substantial evidence has demonstrated that curcumin inhibited proliferation, migration, invasion and metastasis and induced apoptosis via modulating multiple signaling pathways in head and neck cancer. Curcumin also suppressed the growth of xenograft derived from head and neck cancer in vivo in animal models. This review summarizes the evidence demonstrating potential use of curcumin as a single chemotherapeutic agent or in combination with other chemotherapeutic agents and radiation to minimize their toxicity in head and neck cancer. Although curcumin has been shown to be safe at doses of 8 g/d in both phase I and phase II clinical trials, its bioavailability is poor. Overcoming the poor bioavailability of curcumin in the near future would facilitate its clinical use.

Targeting the ubiquitin-proteasome system for cancer treatment: discovering novel inhibitors from nature and drug repurposing.

PubMed

Soave, Claire L; Guerin, Tracey; Liu, Jinbao; Dou, Q Ping

2017-12-01

In the past 15 years, the proteasome has been validated as an anti-cancer drug target and 20S proteasome inhibitors (such as bortezomib and carfilzomib) have been approved by the FDA for the treatment of multiple myeloma and some other liquid tumors. However, there are shortcomings of clinical proteasome inhibitors, including severe toxicity, drug resistance, and no effect in solid tumors. At the same time, extensive research has been conducted in the areas of natural compounds and old drug repositioning towards the goal of discovering effective, economical, low toxicity proteasome-inhibitory anti-cancer drugs. A variety of dietary polyphenols, medicinal molecules, metallic complexes, and metal-binding compounds have been found to be able to selectively inhibit tumor cellular proteasomes and induce apoptotic cell death in vitro and in vivo, supporting the clinical success of specific 20S proteasome inhibitors bortezomib and carfilzomib. Therefore, the discovery of natural proteasome inhibitors and researching old drugs with proteasome-inhibitory properties may provide an alternative strategy for improving the current status of cancer treatment and even prevention.

ZnO and TiO2 nanoparticles as novel antimicrobial agents for oral hygiene: a review

NASA Astrophysics Data System (ADS)

Khan, Shams Tabrez; Al-Khedhairy, Abdulaziz A.; Musarrat, Javed

2015-06-01

Oral cavity is inhabited by more than 25,000 different bacterial phylotypes; some of them cause systemic infections in addition to dental and periodontal diseases. Emergence of multiple antibiotic resistance among these bacteria necessitates the development of alternative antimicrobial agents that are safe, stable, and relatively economic. This review focuses on the significance of metal oxide nanoparticles, especially zinc oxide and titanium dioxide nanoparticles as supplementary antimicrobials for controlling oral infections and biofilm formation. Indeed, the ZnO NPs and TiO2 NPs have exhibited significant antimicrobial activity against oral bacteria at concentrations which is not toxic in in vivo toxicity assays. These nanoparticles are being produced at an industrial scale for use in a variety of commercial products including food products. Thus, the application of ZnO and TiO2 NPs as nanoantibiotics for the development of mouthwashes, dental pastes, and other oral hygiene materials is envisaged. It is also suggested that these NPs could serve as healthier, innocuous, and effective alternative for controlling both the dental biofilms and oral planktonic bacteria with lesser side effects and antibiotic resistance.

Atomic charges of individual reactive chemicals in binary mixtures determine their joint effects: an example of cyanogenic toxicants and aldehydes.

PubMed

Tian, Dayong; Lin, Zhifen; Yin, Daqiang; Zhang, Yalei; Kong, Deyang

2012-02-01

Environmental contaminants are usually encountered as mixtures, and many of these mixtures yield synergistic or antagonistic effects attributable to an intracellular chemical reaction that pose a potential threat on ecological systems. However, how atomic charges of individual chemicals determine their intracellular chemical reactions, and then determine the joint effects for mixtures containing reactive toxicants, is not well understood. To address this issue, the joint effects between cyanogenic toxicants and aldehydes on Photobacterium phosphoreum were observed in the present study. Their toxicological joint effects differed from one another. This difference is inherently related to the two atomic charges of the individual chemicals: the oxygen charge of -CHO (O(aldehyde toxicant)) in aldehyde toxicants and the carbon-atom charge of a carbon chain in the cyanogenic toxicant (C(cyanogenic toxicant)). Based on these two atomic charges, the following QSAR (quantitative structure-activity relationship) model was proposed: When (O(aldehyde toxicant) -C(cyanogenic toxicant) )> -0.125, the joint effect of equitoxic binary mixtures at median inhibition (TU, the sum of toxic units) can be calculated as TU = 1.00 ± 0.20; when (O(aldehyde toxicant) -C(cyanogenic toxicant) ) ≤ -0.125, the joint effect can be calculated using TU = - 27.6 x O (aldehyde toxicant) - 5.22 x C (cyanogenic toxicant) - 6.97 (n = 40, r = 0.887, SE = 0.195, F = 140, p < 0.001, q(2) (Loo) = 0.748; SE is the standard error of the regression, F is the F test statistic). The result provides insight into the relationship between the atomic charges and the joint effects for mixtures containing cyanogenic toxicants and aldehydes. This demonstrates that the essence of the joint effects resulting from intracellular chemical reactions depends on the atomic charges of individual chemicals. The present study provides a possible approach for the development of a QSAR model for mixtures containing reactive toxicants based on the atomic charges. Copyright © 2011 SETAC.

Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes.

PubMed

Wolters, Jarno E J; van Breda, Simone G J; Grossmann, Jonas; Fortes, Claudia; Caiment, Florian; Kleinjans, Jos C S

2018-06-01

We performed a multiple 'omics study by integrating data on epigenomic, transcriptomic, and proteomic perturbations associated with mitochondrial dysfunction in primary human hepatocytes caused by the liver toxicant valproic acid (VPA), to deeper understand downstream events following epigenetic alterations in the mitochondrial genome. Furthermore, we investigated persistence of cross-omics changes after terminating drug treatment. Upon transient methylation changes of mitochondrial genes during VPA-treatment, increasing complexities of gene-interaction networks across time were demonstrated, which normalized during washout. Furthermore, co-expression between genes and their corresponding proteins increased across time. Additionally, in relation to persistently decreased ATP production, we observed decreased expression of mitochondrial complex I and III-V genes. Persistent transcripts and proteins were related to citric acid cycle and β-oxidation. In particular, we identified a potential novel mitochondrial-nuclear signaling axis, MT-CO2-FN1-MYC-CPT1. In summary, this cross-omics study revealed dynamic responses of the mitochondrial epigenome to an impulse toxicant challenge resulting in persistent mitochondrial dysfunctioning. Moreover, this approach allowed for discriminating between the toxic effect of VPA and adaptation. Copyright © 2018 Elsevier B.V. All rights reserved.

Potential Protein Toxicity of Synthetic Pigments: Binding of Poncean S to Human Serum Albumin☆

PubMed Central

Gao, Hong-Wen; Xu, Qing; Chen, Ling; Wang, Shi-Long; Wang, Yuan; Wu, Ling-Ling; Yuan, Yuan

2008-01-01

Using various methods, e.g., spectrophotometry, circular dichroism, and isothermal titration calorimetry, the interaction of poncean S (PS) with human serum albumin (HSA) was characterized at pH 1.81, 3.56, and 7.40 using the spectral correction technique, and Langmuir and Temkin isothermal models. The consistency among results concerning, e.g., binding number, binding energy, and type of binding, showed that ion pair electrostatic attraction fixed the position of PS in HSA and subsequently induced a combination of multiple noncovalent bonds such as H-bonds, hydrophobic interactions, and van der Waals forces. Ion pair attraction and H-bonds produced a stable PS-HSA complex and led to a marked change in the secondary structure of HSA in acidic media. The PS-HSA binding pattern and the process of change in HSA conformation were also investigated. The potentially toxic effect of PS on the transport function of HSA in a normal physiological environment was analyzed. This work provides a useful experimental strategy for studying the interaction of organic substances with biomacromolecules, helping us to understand the activity or mechanism of toxicity of an organic compound. PMID:17905844

Characterization of synergistic embryotoxicity of nickel and buprofezin in zebrafish.

PubMed

Ku, Tingting; Yan, Wei; Jia, Wuyao; Yun, Yang; Zhu, Na; Li, Guangke; Sang, Nan

2015-04-07

Multiple pollutants, usually at low levels, coexist and may interact in the environment. It is therefore important to analyze the toxicity of mixtures of coexisting chemicals to evaluate the potential ecological risk. Concern regarding the co-occurrence and combined bioeffects of heavy metals and organic insecticides in aquatic settings has existed for many years, but a clear understanding of the interactions between and potential combined toxicity of these chemicals remains elusive. In the present study, the combined effects of the heavy metal nickel (NiSO4) and insect growth regulator buprofezin on the induction of embryo toxicity in zebrafish were assessed. By applying nonlinear regression to the concentration-response data with each of the chemicals using the Hill and Langmuir functions and computing the predictions using the model of concentration addition (CA), we confirmed that NiSO4 and buprofezin acted together to produce synergistic embryotoxicity in zebrafish. Subsequently, we further found that the combination of NiSO4 and buprofezin formed a complex that facilitated the uptake of nickel (Ni) and buprofezin by the embryos. Following this, we clarified that an oxidative mechanism of the complex might underlie the synergistic embryotoxicity of NiSO4 and buprofezin.

The evolving role of targeted drugs in the treatment of Hodgkin lymphoma.

PubMed

Eichenauer, Dennis A; Engert, Andreas

2017-09-01

Hodgkin lymphoma (HL) is a B-cell-derived malignancy mostly affecting young adults. More than 80% of patients are cured after stage-adapted first-line treatment with chemotherapy and/or radiotherapy. About 50% of patients with disease recurrence achieve long-term remission with second-line treatment consisting of high-dose chemotherapy and autologous stem cell transplantation. However, HL treatment is often associated with acute toxicity and in part life-threatening late effects. Implementing targeted drugs may reduce toxicity and potentially further optimize efficacy. In recent years, the CD30-directed antibody-drug conjugate brentuximab vedotin (BV) and anti-PD-1 antibodies, nivolumab and pembrolizumab, underwent extensive evaluation in HL. They have exhibited encouraging single agent activity and a favorable toxicity profile in patients with multiple relapses. Therefore, they are currently under investigation in different additional indications. Areas covered: This article gives an overview over clinical trials evaluating targeted drugs either as single agent or as part of combination therapies in HL patients. Expert commentary: A multitude of targeted drugs are investigated in HL. Promising data have particularly emerged from studies with BV and anti-PD-1 antibodies. However, mature data needed for final conclusions are still pending.

Neurotoxicity in the Post-HAART Era: Caution for the Antiretroviral Therapeutics

PubMed Central

Shah, Ankit; Gangwani, Mohitkumar R.; Chaudhari, Nitish S.; Glazyrin, Alexy; Bhat, Hari K.; Kumar, Anil

2016-01-01

Despite the advent of highly active antiretroviral therapy (HAART), HIV-associated neurological disorders (HAND) remain a major challenge in human immunodeficiency virus (HIV) treatment. The early implementation of HAART in the infected individuals helps suppress the viral replication in the plasma and other compartments. Several studies also report the beneficial effect of drugs that successfully penetrate central nervous system (CNS). However, recent data in both clinical setup and in in vitro studies indicate CNS toxicity of the antiretrovirals (ARVs). Although the evidence is limited, correlation between prolonged use of ARVs and neurotoxicity strongly suggests that it is essential to study the underlying mechanisms responsible for such toxicity. Furthermore, closer attention toward clinical outcomes is required to screen various ARV regimens for their association with HAND and other comorbidities. A growing body of literature also indicates a possible role of accelerated aging in the antiretroviral therapy-associated neurotoxicity. Lastly, owing to high pill burden, multiple drugs in the HIV treatment also invite a possible role of drug–drug interaction via various cytochrome P450 enzymes. The particular emphasis of this review is to highlight the need to identify alternative approaches in reducing the CNS toxicity of the ARV drugs in HIV-infected individuals. PMID:27364698

Safety considerations of anesthetic drugs in children.

PubMed

Brown, Raeford E

2017-04-01

Great strides have been made in the last twenty years in providing safe anesthesia care for infants and children. Despite a historical record of safety, recent findings have called to question the toxicities of many anesthetic agents. Observations concerning the inherent safety of these agents, their appropriate management in infants, and new findings which suggest overlooked toxicities will be discussed. Areas covered: A literature search using Pub Med identified journal articles relating to the safety of anesthetic agents in infants and children. From this group, representative classical articles, as well as more recent offerings, were chosen that were germane to the topic of anesthetic drug safety in children. Expert opinion: Anesthetic agents used in children in the US are generally safe in the short term and are administered to thousands of children daily without demonstrable harm. The question of a deleterious effect of anesthetics on the developing central nervous system when used for long periods and on multiple occasions continues to be open to debate. Conservative elective management of these agents in infants and young children is reasonable until such time as more is known about the toxicities on the central nervous system.

Numeric Estimates of Teratogenic Severity from Embryo-Fetal Developmental Toxicity Studies.

PubMed

Wise, L David

2016-02-01

A developing organism exposed to a toxicant will have a response that ranges from none to severe (i.e., death or malformation). The response at a given dosage may be termed teratogenic (or developmental toxic) severity and is dependent on exposure conditions. Prenatal/embryo-fetal developmental (EFD) toxicity studies in rodents and rabbits are the most consistent and definitive assessments of teratogenic severity, and teratogenesis screening assays are best validated against their results. A formula is presented that estimates teratogenic severity for each group, including control, within an EFD study. The developmental components include embryonic/fetal death, malformations, variations, and mean fetal weight. The contribution of maternal toxicity is included with multiplication factors to adjust for the extent of mortality, maternal body weight change, and other parameters deemed important. The derivation of the formula to calculate teratogenic severity is described. Various EFD data sets from the literature are presented to highlight considerations to the calculation of the various components of the formula. Each score is compared to the concurrent control group to obtain a relative teratogenic severity. The limited studies presented suggest relative scores of two- to

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

Dose Escalation to the Dominant Intraprostatic Lesion Defined by Sextant Biopsy in a Permanent Prostate I-125 Implant: A Prospective Comparative Toxicity Analysis

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

Gaudet, Marc; Vigneault, Eric; Aubin, Sylviane

2010-05-01

Purpose: Using real-time intraoperative inverse-planned permanent seed prostate implant (RTIOP/PSI), multiple core biopsy maps, and three-dimensional ultrasound guidance, we planned a boost volume (BV) within the prostate to which hyperdosage was delivered selectively. The aim of this study was to investigate the potential negative effects of such a procedure. Methods and Materials: Patients treated with RTIOP/PSI for localized prostate cancer with topographic biopsy results received an intraprostatic boost (boost group [BG]). They were compared with patients treated with a standard plan (reference group [RG]). Plans were generated using a simulated annealing inverse planning algorithm. Prospectively recorded urinary, rectal, and sexualmore » toxicities and dosimetric parameters were compared between groups. Results: The study included 120 patients treated with boost technique who were compared with 70 patients treated with a standard plan. Boost technique did not significantly change the number of seeds (55.1/RG vs. 53.6/BG). The intraoperative prostate V150 was slightly higher in BG (75.2/RG vs. 77.2/BG, p = 0.039). Urethra V100, urethra D90, and rectal D50 were significantly lower in the BG. No significant differences were seen in acute or late urinary, rectal, or sexual toxicities. Conclusions: Because there were no differences between the groups in acute and late toxicities, we believe that BV can be planned and delivered to the dominant intraprostatic lesion without increasing toxicity. It is too soon to say whether a boost technique will ultimately increase local control.« less

In vitro screening of environmental chemicals for targeted testing prioritization: the ToxCast project.

PubMed

Judson, Richard S; Houck, Keith A; Kavlock, Robert J; Knudsen, Thomas B; Martin, Matthew T; Mortensen, Holly M; Reif, David M; Rotroff, Daniel M; Shah, Imran; Richard, Ann M; Dix, David J

2010-04-01

Chemical toxicity testing is being transformed by advances in biology and computer modeling, concerns over animal use, and the thousands of environmental chemicals lacking toxicity data. The U.S. Environmental Protection Agency's ToxCast program aims to address these concerns by screening and prioritizing chemicals for potential human toxicity using in vitro assays and in silico approaches. This project aims to evaluate the use of in vitro assays for understanding the types of molecular and pathway perturbations caused by environmental chemicals and to build initial prioritization models of in vivo toxicity. We tested 309 mostly pesticide active chemicals in 467 assays across nine technologies, including high-throughput cell-free assays and cell-based assays, in multiple human primary cells and cell lines plus rat primary hepatocytes. Both individual and composite scores for effects on genes and pathways were analyzed. Chemicals displayed a broad spectrum of activity at the molecular and pathway levels. We saw many expected interactions, including endocrine and xenobiotic metabolism enzyme activity. Chemicals ranged in promiscuity across pathways, from no activity to affecting dozens of pathways. We found a statistically significant inverse association between the number of pathways perturbed by a chemical at low in vitro concentrations and the lowest in vivo dose at which a chemical causes toxicity. We also found associations between a small set of in vitro assays and rodent liver lesion formation. This approach promises to provide meaningful data on the thousands of untested environmental chemicals and to guide targeted testing of environmental contaminants.

Toxicity effects of an environmental realistic herbicide mixture on the seagrass Zostera noltei.

PubMed

Diepens, Noël J; Buffan-Dubau, Evelyne; Budzinski, Hélène; Kallerhoff, Jean; Merlina, Georges; Silvestre, Jérome; Auby, Isabelle; Nathalie Tapie; Elger, Arnaud

2017-03-01

Worldwide seagrass declines have been observed due to multiple stressors. One of them is the mixture of pesticides used in intensive agriculture and boat antifouling paints in coastal areas. Effects of mixture toxicity are complex and poorly understood. However, consideration of mixture toxicity is more realistic and ecologically relevant for environmental risk assessment (ERA). The first aim of this study was to determine short-term effects of realistic herbicide mixture exposure on physiological endpoints of Zostera noltei. The second aim was to assess the environmental risks of this mixture, by comparing the results to previously published data. Z. noltei was exposed to a mixture of four herbicides: atrazine, diuron, irgarol and S-metolachlor, simulating the composition of typical cocktail of contaminants in the Arcachon bay (Atlantic coast, France). Three stress biomarkers were measured: enzymatic activity of glutathione reductase, effective quantum yield (EQY) and photosynthetic pigment composition after 6, 24 and 96 h. Short term exposure to realistic herbicide mixtures affected EQY, with almost 100% inhibition for the two highest concentrations, and photosynthetic pigments. Effect on pigment composition was detected after 6 h with a no observed effect concentration (NOEC) of 1 μg/L total mixture concentration. The lowest EQY effect concentration at 10% (EC 10 ) (2 μg/L) and pigment composition NOEC with an assessment factor of 10 were above the maximal field concentrations along the French Atlantic coast, suggesting that there are no potential short term adverse effects of this particular mixture on Z. noltei. However, chronic effects on photosynthesis may lead to reduced energy reserves, which could thus lead to effects at whole plant and population level. Understanding the consequences of chemical mixtures could help to improve ERA and enhance management strategies to prevent further declines of seagrass meadows worldwide. Copyright © 2016. Published by Elsevier Ltd.

High-Dose-Rate Brachytherapy as Monotherapy Delivered in Two Fractions Within One Day for Favorable/Intermediate-Risk Prostate Cancer: Preliminary Toxicity Data

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

Ghilezan, Michel, E-mail: mghilezan@beaumont.edu; Martinez, Alvaro; Gustason, Gary

2012-07-01

Purpose: To report the toxicity profile of high-dose-rate (HDR)-brachytherapy (BT) as monotherapy in a Human Investigation Committee-approved study consisting of a single implant and two fractions (12 Gy Multiplication-Sign 2) for a total dose of 24 Gy, delivered within 1 day. The dose was subsequently increased to 27 Gy (13.5 Gy Multiplication-Sign 2) delivered in 1 day. We report the acute and early chronic genitourinary and gastrointestinal toxicity. Methods and Materials: A total of 173 patients were treated between December 2005 and July 2010. However, only the first 100 were part of the IRB-approved study and out of these, onlymore » 94 had a minimal follow-up of 6 months, representing the study population for this preliminary report. All patients had clinical Stage T2b or less (American Joint Committee on Cancer, 5th edition), Gleason score 6-7 (3+4), and prostate-specific antigen level of {<=}12 ng/mL. Ultrasound-guided HDR-BT with real-time dosimetry was used. The prescription dose was 24 Gy for the first 50 patients and 27 Gy thereafter. The dosimetric goals and constraints were the same for the two dose groups. Toxicity was scored using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. The highest toxicity scores encountered at any point during follow-up are reported. Results: The median follow-up was 17 months (range, 6-40.5). Most patients had Grade 0-1 acute toxicity. The Grade 2 acute genitourinary toxicity was mainly frequency/urgency (13%), dysuria (5%), hematuria, and dribbling/hesitancy (2%). None of the patients required a Foley catheter at any time; however, 8% of the patients experienced transient Grade 1 diarrhea. No other acute gastrointestinal toxicities were found. The most common chronic toxicity was Grade 2 urinary frequency/urgency in 16% of patients followed by dysuria in 4% of patients; 2 patients had Grade 2 rectal bleeding and 1 had Grade 4, requiring laser treatment. Conclusions: Favorable-risk prostate cancer patients treated with a single implant HDR-BT to 24-27 Gy in two fractions within 1 day have excellent tolerance with minimal acute and chronic toxicity. Longer follow-up is needed to confirm these encouraging early results.« less

Functional Genomic Screening Approaches in Mechanistic Toxicology and Potential Future Applications of CRISPR-Cas9

PubMed Central

Shen, Hua; McHale, Cliona M.; Smith, Martyn T; Zhang, Luoping

2015-01-01

Characterizing variability in the extent and nature of responses to environmental exposures is a critical aspect of human health risk assessment. Chemical toxicants act by many different mechanisms, however, and the genes involved in adverse outcome pathways (AOPs) and AOP networks are not yet characterized. Functional genomic approaches can reveal both toxicity pathways and susceptibility genes, through knockdown or knockout of all non-essential genes in a cell of interest, and identification of genes associated with a toxicity phenotype following toxicant exposure. Screening approaches in yeast and human near-haploid leukemic KBM7 cells, have identified roles for genes and pathways involved in response to many toxicants but are limited by partial homology among yeast and human genes and limited relevance to normal diploid cells. RNA interference (RNAi) suppresses mRNA expression level but is limited by off-target effects (OTEs) and incomplete knockdown. The recently developed gene editing approach called clustered regularly interspaced short palindrome repeats-associated nuclease (CRISPR)-Cas9, can precisely knock-out most regions of the genome at the DNA level with fewer OTEs than RNAi, in multiple human cell types, thus overcoming the limitations of the other approaches. It has been used to identify genes involved in the response to chemical and microbial toxicants in several human cell types and could readily be extended to the systematic screening of large numbers of environmental chemicals. CRISPR-Cas9 can also repress and activate gene expression, including that of non-coding RNA, with near-saturation, thus offering the potential to more fully characterize AOPs and AOP networks. Finally, CRISPR-Cas9 can generate complex animal models in which to conduct preclinical toxicity testing at the level of individual genotypes or haplotypes. Therefore, CRISPR-Cas9 is a powerful and flexible functional genomic screening approach that can be harnessed to provide unprecedented mechanistic insight in the field of modern toxicology. PMID:26041264

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

Toxic stress history and hypothalamic-pituitary-adrenal axis function in a social stress task: Genetic and epigenetic factors.

PubMed

Lapp, Hannah E; Ahmed, Sarah; Moore, Celia L; Hunter, Richard G

2018-02-21

Histories of early life stress (ELS) or social discrimination can reach levels of severity characterized as toxic to mental and physical health. Such toxic social stress during development has been linked to altered acute hypothalamic-pituitary-adrenal (HPA) response to social stress in adulthood. However, there are important individual differences in the size and direction of these effects. We explored developmental, genetic, epigenetic, and contextual sources of individual differences in the relationship between ELS, discrimination, and adult responses to acute social stress in a standard laboratory test. Additional measures included perceived status, social support, background activity of HPA axis, and genetic variants in aspects of the stress response system. Participants (n = 90) answered questions about historical and ongoing stress, provided a DNA sample to examine genetic polymorphisms and epigenetic marks, and underwent the Trier Social Stress Test (TSST) during which three saliva samples were collected to assess HPA function. Individuals who reported high levels of childhood adversity had a blunted salivary cortisol response to the TSST. Childhood adversity, discrimination experiences, and FKBP5 genotype were found to predict pretest cortisol levels. Following up on recent observations that the glucocorticoid receptor directly interacts with the mitochondrial genome, particularly the NADH dehydrogenase 6 (MT-ND6) gene, individuals who reported high childhood adversity were also found to have higher percent methylation across six CpG sites upstream of MT-ND6. These findings suggest multiple contributions across psychological, genetic, epigenetic, and social domains to vulnerability and resilience in hypothalamic-pituitary-adrenal axis regulation. Further study to examine how these multiple contributors affect developmental endpoints through integrated or independent pathways will be of use. Copyright © 2018 Elsevier Inc. All rights reserved.

Multi-metal resistance and plant growth promotion potential of a wastewater bacterium Pseudomonas aeruginosa and its synergistic benefits.

PubMed

Biswas, Jayanta Kumar; Mondal, Monojit; Rinklebe, Jörg; Sarkar, Santosh Kumar; Chaudhuri, Punarbasu; Rai, Mahendra; Shaheen, Sabry M; Song, Hocheol; Rizwan, Muhammad

2017-12-01

Water and soil pollution by toxic heavy metals (HMs) is increasing globally because of increase in population, industrialization and urbanization. It is a burning problem for the public, scientists, academicians and politicians how to tackle the toxic contaminants which jeopardize the environment. One possible solution for pollution abatement is a bioremediation-effective and innovative technology that uses biological systems for treatment of contaminants. Many bacteria synthesize indole-3-acetic acid (IAA) which is a product of L-tryptophan metabolism and belongs to the auxin class of plant growth-promoting hormone. The present study aimed at assessing the resistance pattern of wastewater bacteria against multiple HMs and plant growth promotion activity associated with IAA. A Gram-negative bacterial strain Pseudomonas aeruginosa KUJM was isolated from Kalyani Sewage Treatment Plant. This strain showed the potential to tolerate multiple contaminations such as As(III) (50 mM), As(V) (800 mM), Cd (8 mM), Co (18 mM), Cu (7 mM), Cr (2.5 mM), Ni (3 mM) and Zn (14 mM). The capability of IAA production at different tryptophan concentration (1, 2, 5 and 10 mg mL -1 ) was determined, and seed germination-enhancing potential was also estimated on lentil (Lens culinaris). Such type of HM-resistant, IAA-producing and seed germination-enhancing P. aeruginosa KUJM offer great promise as inoculants to promote plant growth in the presence of toxic HMs, as well as plant inoculant systems useful for phytoremediation of polluted soils. Hence, P. aeruginosa KUJM finds significant applications in HM-contaminated poor agricultural field as well as in bioremediation of HM-contaminated wastewater system.

Urine Multi-drug Screening with GC-MS or LC-MS-MS Using SALLE-hybrid PPT/SPE.

PubMed

Lee, Junhui; Park, Jiwon; Go, Ahra; Moon, Heesung; Kim, Sujin; Jung, Sohee; Jeong, Wonjoon; Chung, Heesun

2018-05-14

To intoxicated patients in the emergency room, toxicological analysis can be considerably helpful for identifying the involved toxicants. In order to develop a urine multi-drug screening (UmDS) method, gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS-MS) were used to determine targeted and unknown toxicants in urine. A GC-MS method in scan mode was validated for selectivity, limit of detection (LOD) and recovery. An LC-MS-MS multiple reaction monitoring (MRM) method was validated for lower LOD, recovery and matrix effect. The results of the screening analysis were compared with patient medical records to check the reliability of the screen. Urine samples collected from an emergency room were extracted through a combination of salting-out assisted liquid-liquid extraction (SALLE) and hybrid protein precipitation/solid phase extraction (hybrid PPT/SPE) plates and examined by GC-MS and LC-MS-MS. GC-MS analysis was performed as unknown drug screen and LC-MS-MS analysis was conducted as targeted drug screen. After analysis by GC-MS, a library search was conducted using an in-house library established with the automated mass spectral deconvolution and identification system (AMDISTM). LC-MS-MS used Cliquid®2.0 software for data processing and acquisition in MRM mode. An UmDS method by GC-MS and LC-MS-MS was developed by using a SALLE-hybrid PPT/SPE and in-house library. The results of UmDS by GC-MS and LC-MS-MS showed that toxicants could be identified from 185 emergency room patient samples containing unknown toxicants. Zolpidem, acetaminophen and citalopram were the most frequently encountered drugs in emergency room patients. The UmDS analysis developed in this study can be used effectively to detect toxic substances in a short time. Hence, it could be utilized in clinical and forensic toxicology practices.

Chemical mixtures in potable water in the U.S.

USGS Publications Warehouse

Ryker, Sarah J.

2014-01-01

In recent years, regulators have devoted increasing attention to health risks from exposure to multiple chemicals. In 1996, the US Congress directed the US Environmental Protection Agency (EPA) to study mixtures of chemicals in drinking water, with a particular focus on potential interactions affecting chemicals' joint toxicity. The task is complicated by the number of possible mixtures in drinking water and lack of toxicological data for combinations of chemicals. As one step toward risk assessment and regulation of mixtures, the EPA and the Agency for Toxic Substances and Disease Registry (ATSDR) have proposed to estimate mixtures' toxicity based on the interactions of individual component chemicals. This approach permits the use of existing toxicological data on individual chemicals, but still requires additional information on interactions between chemicals and environmental data on the public's exposure to combinations of chemicals. Large compilations of water-quality data have recently become available from federal and state agencies. This chapter demonstrates the use of these environmental data, in combination with the available toxicological data, to explore scenarios for mixture toxicity and develop priorities for future research and regulation. Occurrence data on binary and ternary mixtures of arsenic, cadmium, and manganese are used to parameterize the EPA and ATSDR models for each drinking water source in the dataset. The models' outputs are then mapped at county scale to illustrate the implications of the proposed models for risk assessment and rulemaking. For example, according to the EPA's interaction model, the levels of arsenic and cadmium found in US groundwater are unlikely to have synergistic cardiovascular effects in most areas of the country, but the same mixture's potential for synergistic neurological effects merits further study. Similar analysis could, in future, be used to explore the implications of alternative risk models for the toxicity and interaction of complex mixtures, and to identify the communities with the highest and lowest expected value for regulation of chemical mixtures.

STP Position Paper: Recommended ("Best") Practices for Sampling, Processing, and Analysis of the Peripheral Nervous System (Nerves and Somatic and Autonomic Ganglia) during Nonclinical Toxicity Studies.

PubMed

Bolon, Brad; Krinke, Georg; Butt, Mark T; Rao, Deepa B; Pardo, Ingrid D; Jortner, Bernard S; Garman, Robert H; Jensen, Karl; Andrews-Jones, Lydia; Morrison, James P; Sharma, Alok K; Thibodeau, Michael S

2018-01-01

Peripheral nervous system (PNS) toxicity is surveyed inconsistently in nonclinical general toxicity studies. These Society of Toxicologic Pathology "best practice" recommendations are designed to ensure consistent, efficient, and effective sampling, processing, and evaluation of PNS tissues for four different situations encountered during nonclinical general toxicity (screening) and dedicated neurotoxicity studies. For toxicity studies where neurotoxicity is unknown or not anticipated (situation 1), PNS evaluation may be limited to one sensorimotor spinal nerve. If somatic PNS neurotoxicity is suspected (situation 2), analysis minimally should include three spinal nerves, multiple dorsal root ganglia, and a trigeminal ganglion. If autonomic PNS neuropathy is suspected (situation 3), parasympathetic and sympathetic ganglia should be assessed. For dedicated neurotoxicity studies where a neurotoxic effect is expected (situation 4), PNS sampling follows the strategy for situations 2 and/or 3, as dictated by functional or other compound/target-specific data. For all situations, bilateral sampling with unilateral processing is acceptable. For situations 1-3, PNS is processed conventionally (immersion in buffered formalin, paraffin embedding, and hematoxylin and eosin staining). For situation 4 (and situations 2 and 3 if resources and timing permit), perfusion fixation with methanol-free fixative is recommended. Where PNS neurotoxicity is suspected or likely, at least one (situations 2 and 3) or two (situation 4) nerve cross sections should be postfixed with glutaraldehyde and osmium before hard plastic resin embedding; soft plastic embedding is not a suitable substitute for hard plastic. Special methods may be used if warranted to further characterize PNS findings. Initial PNS analysis should be informed, not masked ("blinded"). Institutions may adapt these recommendations to fit their specific programmatic requirements but may need to explain in project documentation the rationale for their chosen PNS sampling, processing, and evaluation strategy.

Ignoring Adjuvant Toxicity Falsifies the Safety Profile of Commercial Pesticides

PubMed Central

Mesnage, Robin; Antoniou, Michael N.

2018-01-01

Commercial formulations of pesticides are invariably not single ingredients. Instead they are cocktails of chemicals, composed of a designated pesticidal “active principle” and “other ingredients,” with the latter collectively also known as “adjuvants.” These include surfactants, antifoaming agents, dyes, etc. Some adjuvants are added to influence the absorption and stability of the active principle and thus promote its pesticidal action. Currently, the health risk assessment of pesticides in the European Union and in the United States focuses almost exclusively on the stated active principle. Nonetheless, adjuvants can also be toxic in their own right with numerous negative health effects having been reported in humans and on the environment. Despite the known toxicity of adjuvants, they are regulated differently from active principles, with their toxic effects being generally ignored. Adjuvants are not subject to an acceptable daily intake, and they are not included in the health risk assessment of dietary exposures to pesticide residues. Here, we illustrate this gap in risk assessment by reference to glyphosate, the most used pesticide active ingredient. We also investigate the case of neonicotinoid insecticides, which are strongly suspected to be involved in bee and bumblebee colony collapse disorder. Authors of studies sometimes use the name of the active principle (for example glyphosate) when they are testing a commercial formulation containing multiple (active principle plus adjuvant) ingredients. This results in confusion in the scientific literature and within regulatory circles and leads to a misrepresentation of the safety profile of commercial pesticides. Urgent action is needed to lift the veil on the presence of adjuvants in food and human bodily fluids, as well as in the environment (such as in air, water, and soil) and to characterize their toxicological properties. This must be accompanied by regulatory precautionary measures to protect the environment and general human population from some toxic adjuvants that are currently missing from risk assessments. PMID:29404314

Coating of Quantum Dots strongly defines their effect on lysosomal health and autophagy.

PubMed

Peynshaert, Karen; Soenen, Stefaan J; Manshian, Bella B; Doak, Shareen H; Braeckmans, Kevin; De Smedt, Stefaan C; Remaut, Katrien

2017-01-15

In the last decade the interest in autophagy got an incredible boost and the phenomenon quickly turned into an extensive research field. Interestingly, dysfunction of this cytoplasmic clearance system has been proposed to lie at the root of multiple diseases including cancer. We therefore consider it crucial from a toxicological point of view to investigate if nanomaterials that are developed for biomedical applications interfere with this cellular process. Here, we study the highly promising 'gradient alloyed' Quantum Dots (QDs) that differ from conventional ones by their gradient core composition which allows for better fluorescent properties. We carefully examined the toxicity of two identical gradient alloyed QDs, differing only in their surface coatings, namely 3-mercaptopropionic (MPA) acid and polyethylene glycol (PEG). Next to more conventional toxicological endpoints like cytotoxicity and oxidative stress, we examined the influence of these QDs on the autophagy pathway. Our study shows that the cellular effects induced by QDs on HeLa cells were strongly dictated by the surface coat of the otherwise identical particles. MPA-coated QDs proved to be highly biocompatible as a result of lysosomal activation and ROS reduction, two cellular responses that help the cell to cope with nanomaterial-induced stress. In contrast, PEGylated QDs were significantly more toxic due to increased ROS production and lysosomal impairment. This impairment next results in autophagy dysfunction which likely adds to their toxic effects. Taken together, our study shows that coating QDs with MPA is a better strategy than PEGylation for long term cell tracking with minimal cytotoxicity. Gradient alloyed Quantum Dots (GA-QDs) are highly promising nanomaterials for biomedical imaging seeing they exhibit supremely fluorescent properties over conventional QDs. The translation of these novel QDs to the clinic requires a detailed toxicological examination, though the data on this is very limited. We therefore applied a systematic approach to examine the toxicity of GA-QDs coated with two commonly applied surface ligands, this while focusing on the autophagy pathway. The impact of QDs on this pathway is of importance since it has been connected with various diseases, including cancer. Our data accentuates that the coating defines the impact on autophagy and therefore the toxicity induced by QDs on cells: while MPA coated QDs were highly biocompatible, PEGylated QDs were toxic. Copyright © 2016 Acta Materialia Inc. All rights reserved.

Treatment of chronically digoxin-poisoned patients with a newer digoxin immune fab--a retrospective study.

PubMed

Schaeffer, Tammi H; Mlynarchek, Sara L; Stanford, Christopher F; Delgado, João; Holstege, Christopher P; Olsen, Dean; Bogdan, Gregory M

2010-10-01

Digoxin is used in the treatment of patients with cardiac dysfunction, though toxicity sometimes results from the use of this medication. In 1986, the US Food and Drug Administration (FDA) approved a digoxin immune Fab for the treatment of such patients. In 2001, the FDA approved a newer digoxin immune Fab, a digoxin-specific antibody (DSAb) known as DigiFab (Protherics Inc, Brentwood, Tennessee), though minimal literature exists on the clinical effects of this DSAb. To characterize a cohort of patients presenting with chronic digoxin toxicity and to describe the clinical course of these patients with the use of DSAb. A retrospective study included patients with life-threatening cardiotoxicity and serum digoxin level greater than 2 ng/mL who were treated at two US hospitals from 2003 to 2006. Trained investigators abstracted data from patients' medical records and assessed changes in clinical and laboratory parameters at regular intervals (0-4, >4-12, >12-24, and >24-72 hours) after treatment with DSAb. An expert panel reviewed electrocardiogram results to identify life-threatening manifestations of digoxin toxicity before and after DSAb treatment. Efficacy of treatment was assessed as rates of improvement in clinical parameters and cardiotoxic effects. Rates of adverse drug reactions were used to characterize safety. All data were analyzed with descriptive statistics. Fourteen patients (mean [SD] age, 71.3 [10.4] years) were treated for chronic digoxin toxicity. At presentation, 12 patients had a heart rate of less than 45 beats per minute, 1 had third-degree heart block, and 1 had asystole. Mean serum digoxin level was 3.6 ng/mL. Eleven patients had abnormal renal function. After administration of DSAb, clinical parameters improved in all patients. Within 24 hours, cardiotoxicity resolved in 7 of 9 evaluable patients. Two adverse drug reactions possibly related to DigiFab occurred, both of which resolved with conventional measures. Two patients died from conditions unrelated to treatment. The newer DSAb appears to be a safe and effective treatment for resolving digoxin toxicity in adults, as indicated by electrocardiogram and clinical assessments. Because patients with multiple comorbidities may be at greater risk for digoxin toxicity, they should be closely monitored during treatment with digoxin.

The Transient Receptor Potential Melastatin 2 (TRPM2) Channel Contributes to β-Amyloid Oligomer-Related Neurotoxicity and Memory Impairment.

PubMed

Ostapchenko, Valeriy G; Chen, Megan; Guzman, Monica S; Xie, Yu-Feng; Lavine, Natalie; Fan, Jue; Beraldo, Flavio H; Martyn, Amanda C; Belrose, Jillian C; Mori, Yasuo; MacDonald, John F; Prado, Vania F; Prado, Marco A M; Jackson, Michael F

2015-11-11

In Alzheimer's disease, accumulation of soluble oligomers of β-amyloid peptide is known to be highly toxic, causing disturbances in synaptic activity and neuronal death. Multiple studies relate these effects to increased oxidative stress and aberrant activity of calcium-permeable cation channels leading to calcium imbalance. The transient receptor potential melastatin 2 (TRPM2) channel, a Ca(2+)-permeable nonselective cation channel activated by oxidative stress, has been implicated in neurodegenerative diseases, and more recently in amyloid-induced toxicity. Here we show that the function of TRPM2 is augmented by treatment of cultured neurons with β-amyloid oligomers. Aged APP/PS1 Alzheimer's mouse model showed increased levels of endoplasmic reticulum stress markers, protein disulfide isomerase and phosphorylated eukaryotic initiation factor 2α, as well as decreased levels of the presynaptic marker synaptophysin. Elimination of TRPM2 in APP/PS1 mice corrected these abnormal responses without affecting plaque burden. These effects of TRPM2 seem to be selective for β-amyloid toxicity, as ER stress responses to thapsigargin or tunicamycin in TRPM2(-/-) neurons was identical to that of wild-type neurons. Moreover, reduced microglial activation was observed in TRPM2(-/-)/APP/PS1 hippocampus compared with APP/PS1 mice. In addition, age-dependent spatial memory deficits in APP/PS1 mice were reversed in TRPM2(-/-)/APP/PS1 mice. These results reveal the importance of TRPM2 for β-amyloid neuronal toxicity, suggesting that TRPM2 activity could be potentially targeted to improve outcomes in Alzheimer's disease. Transient receptor potential melastatin 2 (TRPM2) is an oxidative stress sensing calcium-permeable channel that is thought to contribute to calcium dysregulation associated with neurodegenerative diseases, including Alzheimer's disease. Here we show that oligomeric β-amyloid, the toxic peptide in Alzheimer's disease, facilitates TRPM2 channel activation. In mice designed to model Alzheimer's disease, genetic elimination of TRPM2 normalized deficits in synaptic markers in aged mice. Moreover, the absence of TRPM2 improved age-dependent spatial memory deficits observed in Alzheimer's mice. Our results reveal the importance of TRPM2 for neuronal toxicity and memory impairments in an Alzheimer's mouse model and suggest that TRPM2 could be targeted for the development of therapeutic agents effective in the treatment of dementia. Copyright © 2015 the authors 0270-6474/15/3515158-13$15.00/0.

Chronic toxicity of copper and ammonia to juvenile freshwater mussels (Unionidae)

USGS Publications Warehouse

Wang, N.; Ingersoll, C.G.; Greer, I.E.; Hardesty, D.K.; Ivey, C.D.; Kunz, J.L.; Brumbaugh, W.G.; Dwyer, F.J.; Roberts, A.D.; Augspurger, T.; Kane, C.M.; Neves, R.J.; Barnhart, M.C.

2007-01-01

The objectives of the present study were to develop methods for conducting chronic toxicity tests with juvenile mussels under flow-through conditions and to determine the chronic toxicity of copper and ammonia to juvenile mussels using these methods. In two feeding tests, two-month-old fatmucket (Lampsilis siliquoidea) and rainbow mussel (Villosa iris) were fed various live algae or nonviable algal mixture for 28 d. The algal mixture was the best food resulting in high survival (???90%) and growth. Multiple copper and ammonia toxicity tests were conducted for 28 d starting with two-month-old mussels. Six toxicity tests using the algal mixture were successfully completed with a control survival of 88 to 100%. Among copper tests with rainbow mussel, fatmucket, and oyster mussel (Epioblasma capsaeformis), chronic value ([ChV], geometric mean of the no-observed-effect concentration and the lowest-observed-effect concentration) ranged from 8.5 to 9.8 ??g Cu/L for survival and from 4.6 to 8.5 ??g Cu/L for growth. Among ammonia tests with rainbow mussel, fatmucket, and wavy-rayed lampmussel (L. fasciola), the ChV ranged from 0.37 to 1.2 mg total ammonia N/L for survival and from 0.37 to 0.67 mg N/L for growth. These ChVs were below the U.S. Environmental Protection Agency 1996 chronic water quality criterion (WQC) for copper (15 ??g/L; hardness 170 mg/L) and 1999 WQC for total ammonia (1.26 mg N/L; pH 8.2 and 20??C). Results indicate that toxicity tests with two-month-old mussels can be conducted for 28 d with >80% control survival; growth was frequently a more sensitive endpoint compared to survival; and the 1996 chronic WQC for copper and the 1999 chronic WQC for total ammonia might not be adequately protective of the mussel species tested. However, a recently revised 2007 chronic WQC for copper based on the biotic ligand model may be more protective in the water tested. ?? 2007 SETAC.

Hsp60-induced tolerance in the rotifer Brachionus plicatilis exposed to multiple environmental contaminants.

PubMed

Wheelock, C E; Wolfe, M F; Olsen, H; Tjeerdema, R S; Sowby, M L

1999-04-01

Hsp60 induction was selected as a sublethal endpoint of toxicity for Brachionus plicatilis exposed to a water accommodated fraction (WAF) of Prudhoe Bay crude oil (PBCO), a PBCO/dispersant (Corexit 9527(R)) fraction and Corexit 9527(R) alone. To examine the effect of multiple stressors, exposures modeled San Francisco Bay, where copper levels are approximately 5 microgram/L, salinity is 22 per thousand, significant oil transport and refining occurs, and petroleum releases have occurred historically. Rotifers were exposed to copper at 5 microgram/L for 24 h, followed by one of the oil/dispersant preparations for 24 h. Batch-cultured rotifers were used in this study to model wild populations instead of cysts. SDS-PAGE with Western Blotting using hsp60-specific antibodies and chemiluminescent detection were used to isolate, identify, and measure induced hsp60 as a percentage of control values. Both PBCO/dispersant and dispersant alone preparations induced significant levels of hsp60. However, hsp60 expression was reduced to that of controls at high WAF concentrations, suggesting interference with protein synthesis. Rotifers that had been preexposed to copper maintained elevated levels of hsp60 upon treatment with WAF at all concentrations. Results suggest that induction of hsp60 by chronic low-level exposure may serve as a protective mechanism against subsequent or multiple stressors and that hsp60 levels are not additive for the toxicants tested in this study, giving no dose-response relationship. The methods employed in this study could be useful for quantifying hsp60 levels in wild rotifer populations.

Assessing interactions of binary mixtures of Penicillium mycotoxins (PMs) by using a bovine macrophage cell line (BoMacs)

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

Oh, Se-Young, E-mail: ohs@uoguelph.ca

Penicillium mycotoxins (PMs) are toxic contaminants commonly found as mixtures in animal feed. Therefore, it is important to investigate potential joint toxicity of PM mixtures. In the present study, we assessed the joint effect of binary combinations of the following PMs: citrinin (CIT), ochratoxin A (OTA), patulin (PAT), mycophenolic acid (MPA) and penicillic acid (PA) using independent action (IA) and concentration addition (CA) concepts. Previously published toxicity data (i.e. IC25; PM concentration that inhibited bovine macrophage (BoMacs) proliferation by 25%) were initially analyzed, and both concepts agreed that OTA + PA demonstrated synergism (p < 0.05), while PAT + PAmore » showed antagonism (p < 0.05). When a follow-up dilution study was carried out using binary combinations of PMs at three different dilution levels (i.e. IC25, 0.5 ∗ IC25, 0.25 ∗ IC25), only the mixture of CIT + OTA at 0.5 ∗ IC25 was determined to have synergism by both IA and CA concepts with Model Deviation Ratios (MDRs; the ratio of predicted versus observed effect concentrations) of 1.4 and 1.7, respectively. The joint effect of OTA + MPA, OTA + PA and CIT + PAT complied with the IA concept, while CIT + PA, PAT + MPA and PAT + PA were better predicted with the CA over the IA concept. The present study suggests to test both IA and CA concepts using multiple doses when assessing risk of mycotoxin mixtures if the mode of action is unknown. In addition, the study showed that the tested PMs could be predicted by IA or CA within an approximate two-fold certainty, raising the possibility for a joint risk assessment of mycotoxins in food and feed. - Highlights: • We investigated the potential joint toxicity of Penicillium mycotoxin (PM) mixtures. • Independent action (IA) and concentration addition (CA) concepts were used. • 7 out of 10 mixtures followed joint toxicity described by IA or CA concepts. • Both concepts agreed that CIT + OTA mixture had synergistic interaction.« less

Gene Expression Profiling of Lung Tissue of Rats Exposed to Lunar Dust Particles

NASA Technical Reports Server (NTRS)

Zhang, Ye; Feiveson, Alan H.; Lam, Chiu-Wing; Kidane, Yared H.; Ploutz-Snyder Robert; Yeshitla, Samrawit; Zalesak, Selina M.; Scully, Robert R.; Wu, Honglu; James, John T.

2014-01-01

The purpose of the study is to analyze the dynamics of global gene expression changes in the lung tissue of rats exposed to lunar dust particles. Multiple pathways and transcription factors were identified using the Ingenuity Pathway Analysis tool, showing the potential networks of these signaling regulations involved in lunar dust-induced prolonged proflammatory response and toxicity. The data presented in this study, for the first time, explores the molecular mechanisms of lunar dust induced toxicity. This work contributes not only to the risk assessment for future space exploration, but also to the understanding of the dust-induced toxicity to humans on earth.

Toxic effects of selenium and copper on the planarian, Dugesia dorotocephala

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

Rauscher, J.D.

1988-01-01

Aquatic toxicologists have become increasingly concerned with the effects of sublethal concentrations of toxicants on aquatic organisms. Sublethal effects of toxicants on freshwater invertebrates were reviewed. Selenium (Se) and copper (Cu) are both essential trace elements and toxicants. Se has been reported to alter the toxicity of heavy metals. Planarians, Dugesia dorotocephala, were used as test animals. The objectives of this study were to determine: (1) acute toxicity of Se on planarians and the effect of the number of planarians per test chamber, (2) interaction of the acute toxicity of Se and Cu on planarians, and (3) sublethal effects ofmore » Se and Cu on planarians.« less

Therapeutic effects of gold nanoparticles synthesized using Musa paradisiaca peel extract against multiple antibiotic resistant Enterococcus faecalis biofilms and human lung cancer cells (A549).

PubMed

Vijayakumar, S; Vaseeharan, B; Malaikozhundan, B; Gopi, N; Ekambaram, P; Pachaiappan, R; Velusamy, P; Murugan, K; Benelli, G; Suresh Kumar, R; Suriyanarayanamoorthy, M

2017-01-01

Botanical-mediated synthesis of nanomaterials is currently emerging as a cheap and eco-friendly nanotechnology, since it does not involve the use of toxic chemicals. In the present study, we focused on the synthesis of gold nanoparticles using the aqueous peel extract of Musa paradisiaca (MPPE-AuNPs) following a facile and cheap fabrication process. The green synthesized MPPE-AuNPs were bio-physically characterized by UV-Vis spectroscopy, FTIR, XRD, TEM, Zeta potential analysis and EDX. MPPE-AuNPs were crystalline in nature, spherical to triangular in shape, with particle size ranging within 50 nm. The biofilm inhibition activity of MPPE-AuNPs was higher against multiple antibiotic resistant (MARS) Gram-positive Enterococcus faecalis. Light and confocal laser scanning microscopic observations evidenced that the MPPE-AuNPs effectively inhibited the biofilm of E. faecalis when tested at 100 μg mL -1 . Cytotoxicity studies demonstrated that MPPE-AuNPs were effective in inhibiting the viability of human A549 lung cancer cells at higher concentrations of 100 μg mL -1 . The morphological changes in the MPPE-AuNPs treated A549 lung cancer cells were visualized under phase-contrast microscopy. Furthermore, the ecotoxicity of MPPE-AuNPs on the freshwater micro crustacean Ceriodaphnia cornuta were evaluated. Notably, no mortality was recorded in MPPE-AuNPs treated C. cornuta at 250 μg mL -1 . This study concludes that MPPE-AuNPs are non-toxic, eco-friendly and act as a multipurpose potential biomaterial for biomedical applications. Copyright © 2016 Elsevier Ltd. All rights reserved.

Oximes in organophosphate poisoning: 60 years of hope and despair.

PubMed

Worek, Franz; Thiermann, Horst; Wille, Timo

2016-11-25

The high number of annual fatalities following suicidal poisoning by organophosphorus (OP) pesticides and the recent homicidal use of the chemical warfare nerve agent sarin against civilian population in Syria underlines the continuous threat by these highly toxic agents. The need for an effective treatment of OP poisoning resulted in the implementation of a combination therapy with the muscarinic receptor antagonist atropine and an oxime for the reactivation of OP-inhibited acetylcholinesterase (AChE). Since the invention of the first clinically used oxime pralidoxime (2-PAM) in the 1950s ongoing research attempted to identify more effective oximes. In fact, several thousand oximes were synthesized in the past six decades. These include charged and non-charged compounds, mono- and bispyridinium oximes, asymmetric oximes, oximes with different substitutes and more recently non-oxime reactivators. Multiple in vitro and in vivo studies investigated the potential of oximes to reactivate OP-inhibited AChE and to reverse OP-induced cholinergic signs. Depending on the experimental model, the investigated species and the tested OP largely variable results were obtained by different laboratories. These findings and the inconsistent effectiveness of oximes in the treatment of OP-pesticide poisoned patients led to a continuous discussion on the value of oximes. In order to provide a forward-looking evaluation of the significance of oximes in OP poisoning multiple aspects, including intrinsic toxicity, in vitro reactivation potency, efficacy and pharmacokinetics, as well as the impact of the causative OP have to be considered. The different influencing factors in order to define the benefit and limitations of oximes in OP poisoning will be discussed. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Recent advances in occupational and environmental health hazards of workers exposed to gasoline compounds.

PubMed

Ekpenyong, Christopher E; Asuquo, Asuquo E

2017-02-21

The impact of health and environmental hazards, associated with the constituents of gasoline, on occupationally exposed workers has been recorded over the past few decades. However, the scientific literature on their pathogenic potential remains incomplete, which could affect the current understanding of the associated health risks. This review provides current information based on recently improved research techniques to evaluate gasoline toxicity profiles for humans. Our current knowledge provides insight into the intricate mechanism of gasoline-induced adverse effects, including the formation of reactive metabolites via bio-activation and subsequent generation of reactive oxygen species (ROS) and oxidative stress, which are involved in multiple mechanisms that are central to the aetiology of gasoline-induced toxicity. These mechanisms include covalent binding to deoxyribonucleic acid (DNA), leading to oxidative damage, tumor-suppression gene activity, and activation of pro-oncogenes. Furthermore, it results in induction of autoimmunity and local inflammatory responses, disruption of multiple neurotransmitters and immune cell function, derangement of various enzyme activities (e.g., sodiumpotassium adenosine triphosphate (Na+/K+/ATPase) activity, cytochrome P450 (CYP450), nitric oxide synthase (NOS), antioxidant enzyme activities, etc.), conjugation of bile, and non-specific cell membrane interaction, leading to damage of the membrane lipid bilayer and proteins. Available data suggests that exposure to gasoline or gasoline constituents have the potential to cause different types of illnesses. The data highlights the need to maintain safety measures via suitable research, medical surveillance, regulatory control, life style modification, early detection, and intervention to minimize exposure and manage suspected cases. They also present novel opportunities to design and develop effective therapeutic strategies against gasoline-induced detrimental effects. Int J Occup Med Environ Health 2017;30(1):1-26. This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.

Towards more ecological relevance in sediment toxicity testing with fish: Evaluation of multiple bioassays with embryos of the benthic weatherfish (Misgurnus fossilis).

PubMed

Schreiber, Benjamin; Fischer, Jonas; Schiwy, Sabrina; Hollert, Henner; Schulz, Ralf

2018-04-01

The effects of sediment contamination on fish are of high significance for the protection of ecosystems, human health and economy. However, standardized sediment bioassays with benthic fish species, that mimic bioavailability of potentially toxic compounds and comply with the requirements of alternative test methods, are still scarce. In order to address this issue, embryos of the benthic European weatherfish (Misgurnus fossilis) were exposed to freeze-dried sediment (via sediment contact assays (SCA)) and sediment extracts (via acute fish embryo toxicity tests) varying in contamination level. The extracts were gained by accelerated solvent extraction with (i) acetone and (ii) pressurized hot water (PHWE) and subsequently analyzed for polycyclic aromatic hydrocarbons, polychlorinated biphenyls and polychlorinated dibenzodioxins and dibenzofurans. Furthermore, embryos of the predominately used zebrafish (Danio rerio) were exposed to extracts from the two most contaminated sediments. Results indicated sufficient robustness of weatherfish embryos towards varying test conditions and sensitivity towards relevant sediment-bound compounds. Furthermore, a compliance of effect concentrations derived from weatherfish embryos exposed to sediment extracts (96h-LC 50 ) with both measured gradient of sediment contamination and previously published results was observed. In comparison to zebrafish, weatherfish embryos showed higher sensitivity to the bioavailability-mimicking extracts from PHWE but lower sensitivity to extracts gained with acetone. SCAs conducted with weatherfish embryos revealed practical difficulties that prevented an implementation with three of four sediments tested. In summary, an application of weatherfish embryos, using bioassays with sediment extracts from PHWE might increase the ecological relevance of sediment toxicity testing: it allows investigations using benthic and temperate fish species considering both bioavailable contaminants and animal welfare concerns. Copyright © 2017 Elsevier B.V. All rights reserved.

Absorption of Bupivacaine after Administration of a Lozenge as Topical Treatment for Pain from Oral Mucositis.

PubMed

Mogensen, Stine; Sverrisdóttir, Eva; Sveinsdóttir, Kolbrún; Treldal, Charlotte; Jensen, Kenneth; Jensen, Anders Bonde; Kristensen, Claus Andrup; Jacobsen, Jette; Kreilgaard, Mads; Petersen, Janne; Andersen, Ove

2017-01-01

The aim was to investigate systemic exposure after administration of a novel bupivacaine lozenge in healthy individuals with normal mucosa and in head and neck cancer (HNC) patients with oral mucositis. A lozenge containing 5, 10, 25 and 50 mg bupivacaine, respectively, was administered as single dose to 10 healthy individuals, and a lozenge containing 25 mg bupivacaine was administered as single dose to 10 HNC patients with oral mucositis and as multiple doses to five patients with HNC. Blood samples were collected for 6 hr from the healthy individuals and 3 hr from the patients with HNC, respectively, after administration. The plasma concentration-time profiles of bupivacaine were fitted to pharmacokinetic models using nonlinear mixed-effects modelling, evaluating demographics and health status as covariates. The population pharmacokinetics (PK) of bupivacaine lozenge was best described by a two-compartment distribution model with absorption transit compartments. All the observed plasma concentrations were well below the bupivacaine concentrations (2000-2250 ng/ml) which have caused toxic symptoms. The PK model suggested that relative bioavailability was two times higher in HNC patients with oral mucositis grade 1-2 and three times higher in HNC patients with oral mucositis grade 3-4 than in the healthy individuals. Simulations showed that the plasma concentrations would be below the toxic limit after repeated dosing every second hour with 25 mg bupivacaine for five days. The 25-mg bupivacaine lozenges were safe without systemic toxic levels of bupivacaine or risk of side effects. Based on PK simulations of repeated doses of 25 mg every two hours for 16 hr a day, the lozenges can be administered with minimum risk of exceeding the toxic limit. © 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Multiple mitigation mechanisms: Effects of submerged plants on the toxicity of nine insecticides to aquatic animals.

PubMed

Brogan, William R; Relyea, Rick A

2017-01-01

Understanding the processes that regulate contaminant impacts in nature is an increasingly important challenge. For insecticides in surface waters, the ability of aquatic plants to sorb, or bind, hydrophobic compounds has been identified as a primary mechanism by which toxicity can be mitigated (i.e. the sorption-based model). However, recent research shows that submerged plants can also rapidly mitigate the toxicity of the less hydrophobic insecticide malathion via alkaline hydrolysis (i.e. the hydrolysis-based model) driven by increased water pH resulting from photosynthesis. However, it is still unknown how generalizable these mitigation mechanisms are across the wide variety of insecticides applied today, and whether any general rules can be ascertained about which types of chemicals may be mitigated by each mechanism. We quantified the degree to which the submerged plant Elodea canadensis mitigated acute (48-h) toxicity to Daphnia magna using nine commonly applied insecticides spanning three chemical classes (carbamates: aldicarb, carbaryl, carbofuran; organophosphates: malathion, diazinon, chlorpyrifos; pyrethroids: permethrin, bifenthrin, lambda-cyhalothrin). We found that insecticides possessing either high octanol-water partition coefficients (log K ow ) values (i.e. pyrethroids) or high susceptibility to alkaline hydrolysis (i.e. carbamates and malathion) were all mitigated to some degree by E. canadensis, while the plant had no effect on insecticides possessing intermediate log K ow values and low susceptibility to hydrolysis (i.e. chlorpyrifos and diazinon). Our results provide the first general insights into which types of insecticides are likely to be mitigated by different mechanisms based on known chemical properties. We suggest that current models and mitigation strategies would be improved by the consideration of both mitigation models. Copyright © 2016 Elsevier Ltd. All rights reserved.

Neurotoxic properties of the anabolic androgenic steroids nandrolone and methandrostenolone in primary neuronal cultures.

PubMed

Caraci, Filippo; Pistarà, V; Corsaro, A; Tomasello, Flora; Giuffrida, Maria Laura; Sortino, Maria Angela; Nicoletti, Ferdinando; Copani, Agata

2011-04-01

Anabolic-androgenic steroid (AAS) abuse is associated with multiple neurobehavioral disturbances. The sites of action and the neurobiological sequels of AAS abuse are unclear at present. We investigated whether two different AASs, nandrolone and methandrostenolone, could affect neuronal survival in culture. The endogenous androgenic steroid testosterone was used for comparison. Both testosterone and nandrolone were neurotoxic at micromolar concentrations, and their effects were prevented by blockade of androgen receptors (ARs) with flutamide. Neuronal toxicity developed only over a 48-hr exposure to the steroids. The cell-impermeable analogues testosterone-BSA and nandrolone-BSA, which preferentially target membrane-associated ARs, were also neurotoxic in a time-dependent and flutamide-sensitive manner. Testosterone-BSA and nandrolone-BSA were more potent than their parent compounds, suggesting that membrane-associated ARs were the relevant sites for the neurotoxic actions of the steroids. Unlike testosterone and nandrolone, toxicity by methandrostenolone and methandrostenolone-BSA was insensitive to flutamide, but it was prevented by the glucocorticoid receptor (GR) antagonist RU-486. Methandrostenolone-BSA was more potent than the parent compound, suggesting that its toxicity relied on the preferential activation of putative membrane-associated GRs. Consistently with the evidence that membrane-associated GRs can mediate rapid effects, a brief challenge with methandrostenolone-BSA was able to promote neuronal toxicity. Activation of putative membrane steroid receptors by nontoxic (nanomolar) concentrations of either nandrolone-BSA or methandrostenolone-BSA became sufficient to increase neuronal susceptibility to the apoptotic stimulus provided by β-amyloid (the main culprit of AD). We speculate that AAS abuse might facilitate the onset or progression of neurodegenerative diseases not usually linked to drug abuse. Copyright © 2011 Wiley-Liss, Inc.

A mir-231-Regulated Protection Mechanism against the Toxicity of Graphene Oxide in Nematode Caenorhabditis elegans

PubMed Central

Yang, Ruilong; Ren, Mingxia; Rui, Qi; Wang, Dayong

2016-01-01

Recently, several dysregulated microRNAs (miRNAs) have been identified in organisms exposed to graphene oxide (GO). However, their biological functions and mechanisms of the action are still largely unknown. Here, we investigated the molecular mechanism of mir-231 in the regulation of GO toxicity using in vivo assay system of Caenorhabditis elegans. We found that GO exposure inhibited the expression of mir-231::GFP in multiple tissues, in particular in the intestine. mir-231 acted in intestine to regulate the GO toxicity, and overexpression of mir-231 in intestine caused a susceptible property of nematodes to GO toxicity. smk-1 encoding a homologue to mammalian SMEK functioned as a targeted gene for mir-231, and was also involved in the intestinal regulation of GO toxicity. Mutation of smk-1 gene induced a susceptible property to GO toxicity, whereas the intestinal overexpression of smk-1 resulted in a resistant property to GO toxicity. Moreover, mutation of smk-1 gene suppressed the resistant property of mir-231 mutant to GO toxicity. In nematodes, SMK-1 further acted upstream of the transcriptional factor DAF-16/FOXO in insulin signaling pathway to regulate GO toxicity. Therefore, mir-231 may encode a GO-responsive protection mechanism against the GO toxicity by suppressing the function of the SMK-1 - DAF-16 signaling cascade in nematodes. PMID:27558892

Demonstration of toxicity to fish and to mammalian cells by Pfiesteria species: Comparison of assay methods and strains

PubMed Central

Burkholder, JoAnn M.; Gordon, Andrew S.; Moeller, Peter D.; Law, J. Mac; Coyne, Kathryn J.; Lewitus, Alan J.; Ramsdell, John S.; Marshall, Harold G.; Deamer, Nora J.; Cary, S. Craig; Kempton, Jason W.; Morton, Steven L.; Rublee, Parke A.

2005-01-01

Toxicity and its detection in the dinoflagellate fish predators Pfiesteria piscicida and Pfiesteria shumwayae depend on the strain and the use of reliable assays. Two assays, standardized fish bioassays (SFBs) with juvenile fish and fish microassays (FMAs) with larval fish, were compared for their utility to detect toxic Pfiesteria. The comparison included strains with confirmed toxicity, negative controls (noninducible Pfiesteria strains and a related nontoxic cryptoperidiniopsoid dinoflagellate), and P. shumwayae strain CCMP2089, which previously had been reported as nontoxic. SFBs, standardized by using toxic Pfiesteria (coupled with tests confirming Pfiesteria toxin) and conditions conducive to toxicity expression, reliably detected actively toxic Pfiesteria, but FMAs did not. Pfiesteria toxin was found in fish- and algae-fed clonal Pfiesteria cultures, including CCMP2089, but not in controls. In contrast, noninducible Pfiesteria and cryptoperidiniopsoids caused no juvenile fish mortality in SFBs even at high densities, and low larval fish mortality by physical attack in FMAs. Filtrate from toxic strains of Pfiesteria spp. in bacteria-free media was cytotoxic. Toxicity was enhanced by bacteria and other prey, especially live fish. Purified Pfiesteria toxin extract adversely affected mammalian cells as well as fish, and it caused fish death at environmentally relevant cell densities. These data show the importance of testing multiple strains when assessing the potential for toxicity at the genus or species level, using appropriate culturing techniques and assays. PMID:15728353

A mir-231-Regulated Protection Mechanism against the Toxicity of Graphene Oxide in Nematode Caenorhabditis elegans

NASA Astrophysics Data System (ADS)

Yang, Ruilong; Ren, Mingxia; Rui, Qi; Wang, Dayong

2016-08-01

Recently, several dysregulated microRNAs (miRNAs) have been identified in organisms exposed to graphene oxide (GO). However, their biological functions and mechanisms of the action are still largely unknown. Here, we investigated the molecular mechanism of mir-231 in the regulation of GO toxicity using in vivo assay system of Caenorhabditis elegans. We found that GO exposure inhibited the expression of mir-231::GFP in multiple tissues, in particular in the intestine. mir-231 acted in intestine to regulate the GO toxicity, and overexpression of mir-231 in intestine caused a susceptible property of nematodes to GO toxicity. smk-1 encoding a homologue to mammalian SMEK functioned as a targeted gene for mir-231, and was also involved in the intestinal regulation of GO toxicity. Mutation of smk-1 gene induced a susceptible property to GO toxicity, whereas the intestinal overexpression of smk-1 resulted in a resistant property to GO toxicity. Moreover, mutation of smk-1 gene suppressed the resistant property of mir-231 mutant to GO toxicity. In nematodes, SMK-1 further acted upstream of the transcriptional factor DAF-16/FOXO in insulin signaling pathway to regulate GO toxicity. Therefore, mir-231 may encode a GO-responsive protection mechanism against the GO toxicity by suppressing the function of the SMK-1 - DAF-16 signaling cascade in nematodes.

Experimental Analysis of Exhaust Manifold with Ceramic Coating for Reduction of Heat Dissipation

NASA Astrophysics Data System (ADS)

Saravanan, J.; Valarmathi, T. N.; Nathc, Rajdeep; Kumar, Prasanth

2017-05-01

Exhaust manifold plays an important role in the exhaust system, the manifold delivers the waste toxic gases to a safe distance and it is used to reduce the sound pollution and air pollution. Exhaust manifold suffers with lot of thermal stress, due to this blow holes occurs in the surface of the exhaust manifold and also more noise is developed. The waste toxic gases from the multiple cylinders are collected into a single pipe by the exhaust manifold. The waste toxic gases can damage the material of the manifold. In this study, to prevent the damage zirconia powder has been coated in the inner surface and alumina (60%) combined with titania (40%) has been used for coating the outer surface of the exhaust manifold. After coating experiments have been performed using a multiple-cylinder four stroke stationary petrol engine. The test results of hardness, emission, corrosion and temperature of the coated and uncoated manifolds have been compared. The result shows that the performance is improved and also emission is reduced in the coated exhaust manifold.

Gastric Lavage in Acute Organophosphorus Pesticide poisoning (GLAOP) – a randomised controlled trial of multiple vs. single gastric lavage in unselected acute organophosphorus pesticide poisoning

PubMed Central

Li, Yi; Yu, XueZhong; Wang, Zhong; Wang, HouLi; Zhao, XiangHuai; Cao, YuPing; Wang, WeiZhan; Eddleston, Michael

2006-01-01

Background Organophosphorus (OP) pesticide poisoning is the most common form of pesticide poisoning in many Asian countries. Guidelines in western countries for management of poisoning indicate that gastric lavage should be performed only if two criteria are met: within one hour of poison ingestion and substantial ingested amount. But the evidence on which these guidelines are based is from medicine overdoses in developed countries and may be irrelevant to OP poisoning in Asia. Chinese clinical experience suggests that OP remains in the stomach for several hours or even days after ingestion. Thus, there may be reasons for doing single or multiple gastric lavages for OP poisoning. There have been no randomised controlled trials (RCTs) to assess this practice of multiple lavages. Since it is currently standard therapy in China, we cannot perform a RCT of no lavage vs. a single lavage vs. multiple lavages. We will compare a single gastric lavage with three gastric lavages as the first stage to assess the role of gastric lavage in OP poisoning. Methods/Design We have designed an RCT assessing the effectiveness of multiple gastric lavages in adult OP self-poisoning patients admitted to three Chinese hospitals within 12 hrs of ingestion. Patients will be randomised to standard treatment plus either a single gastric lavage on admission or three gastric lavages at four hour intervals. The primary outcome is in-hospital mortality. Analysis will be on an intention-to-treat basis. On the basis of the historical incidence of OP at the study sites, we expect to enroll 908 patients over three years. This projected sample size provides sufficient power to evaluate the death rate; and a variety of other exposure and outcome variables, including particular OPs and ingestion time. Changes of OP level will be analyzed in order to provide some toxic kinetic data. Discussion the GLAOP study is a novel, prospective cohort study that will explore to the toxic kinetics of OP and effects of gastric lavage on it. Given the poor information about the impact of gastric lavage on clinical outcomes for OP patients, this study can provide important information to inform clinical practice. PMID:17049100

Removal of 2,4-dichlorophenoxyacetic acid in aqueous solution by pulsed corona discharge treatment: Effect of different water constituents, degradation pathway and toxicity assay.

PubMed

Singh, Raj Kamal; Philip, Ligy; Ramanujam, Sarathi

2017-10-01

A multiple pin-plane corona discharge reactor was used to generate plasma for the degradation of 2,4 dichlorophenoxyacetic acid (2,4-D) from the aqueous solution. The 2,4-D of concentration 1 mg/L was completely removed within 6 min of plasma treatment. Almost complete mineralization was achieved after the treatment time of 14 min for a 2,4-D concentration of 10 mg/L. Effects of different water constituents such as carbonates, nitrate, sulphate, chloride ions, natural organic matter (humic acids) and pH on 2,4-D degradation was studied. A significant antagonistic effect of carbonate and humic acid was observed, whereas, the effects of other ions were insignificant. A higher first order rate constant of 1.73 min -1 was observed, which was significantly decreased in the presence of carbonate ions and humic acids. Also, a higher degradation of 2,4-D was observed in acidic pH conditions. Different 2,4-D intermediates were detected and the degradation pathway of 2,4-D in plasma treatment process was suggested. The toxicity of 10 mg/L 2,4-D was completely eradicated after 10 min of plasma treatment. Copyright © 2017 Elsevier Ltd. All rights reserved.