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Environmental and Molecular Mutagenesis Aug 2019Styrene is an important high production volume chemical used to manufacture polymeric products. In 2018, International Agency for Research on Cancer classified styrene... (Review)
Review
Critical review of styrene genotoxicity focused on the mutagenicity/clastogenicity literature and using current organization of economic cooperation and development guidance.
Styrene is an important high production volume chemical used to manufacture polymeric products. In 2018, International Agency for Research on Cancer classified styrene as probably carcinogenic to humans; National Toxicology Program lists styrene as reasonably anticipated to be a human carcinogen. The genotoxicity literature for styrene and its primary metabolite, styrene 7,8-oxide (SO), begins in the 1970s. Organization of Economic Cooperation and Development (OECD) recently updated most genotoxicity test guidelines, making substantial new recommendations for assay conduct and data evaluation for the standard mutagenicity/clastogenicity assays. Thus, a critical review of the in vitro and in vivo rodent mutagenicity/clastogenicity studies for styrene and SO, based on the latest OECD recommendations, is timely. This critical review considered whether a study was optimally designed, conducted, and interpreted and provides a critical assessment of the evidence for the mutagenicity/clastogenicity of styrene/SO. Information on the ability of styrene/SO to induce other types of genotoxicity endpoints is summarized but not critically reviewed. We conclude that when styrene is metabolized to SO, it can form DNA adducts, and positive in vitro mutagenicity/clastogenicity results can be obtained. SO is mutagenic in bacteria and the in vitro mouse lymphoma gene mutation assay. No rodent in vivo mutation studies were identified. SO is clastogenic in cultured mammalian cells. Although the in vitro assays gave positive responses, styrene/SO is not clastogenic/aneugenic in vivo in rodents. In addition to providing updated information for styrene, this review demonstrates the application of the new OECD guidelines for chemicals with large genetic toxicology databases where published results may or may not be reliable. Environ. Mol. Mutagen. 2019. © 2019 Wiley Periodicals, Inc.
Topics: Animals; Carcinogens; DNA Damage; Humans; Mutagenesis; Mutagenicity Tests; Mutagens; Styrene
PubMed: 30786062
DOI: 10.1002/em.22278 -
Food and Chemical Toxicology : An... Oct 2023Although there are a number of guidance documents and frameworks for evaluation of carcinogenicity, none of the current methods fully reflects the state of the science....
Although there are a number of guidance documents and frameworks for evaluation of carcinogenicity, none of the current methods fully reflects the state of the science. Common limitations include the absence of dose-response assessment and not considering the impact of differing exposure patterns (e.g., intermittent, high peaks vs. lower, continuous exposures). To address these issues, we have developed a framework for risk assessment of dietary carcinogens. This framework includes an enhanced approach for weight of evidence (WOE) evaluation for genetic toxicology data, with a focus on evaluating studies based on the most recent testing guidance to determine whether a chemical is a mutagen. Included alongside our framework is a discussion of resources for evaluating tissue dose and the temporal pattern of internal dose, taking into account the chemical's toxicokinetics. The framework then integrates the mode of action (MOA) and associated dose metric category with the exposure data to identify the appropriate approach(es) to low-dose extrapolation and level of concern associated with the exposure scenario. This framework provides risk managers with additional flexibility in risk management and risk communication options, beyond the binary choice of linear low-dose extrapolation vs. application of uncertainty factors.
Topics: Humans; Carcinogens; Neoplasms; Mutagens; Risk Assessment
PubMed: 37716495
DOI: 10.1016/j.fct.2023.114022 -
Environmental and Molecular Mutagenesis Jan 2020We recently published a next generation framework for assessing the risk of genomic damage via exposure to chemical substances. The framework entails a systematic... (Review)
Review
We recently published a next generation framework for assessing the risk of genomic damage via exposure to chemical substances. The framework entails a systematic approach with the aim to quantify risk levels for substances that induce genomic damage contributing to human adverse health outcomes. Here, we evaluated the utility of the framework for assessing the risk for industrial chemicals, using the case of benzene. Benzene is a well-studied substance that is generally considered a genotoxic carcinogen and is known to cause leukemia. The case study limits its focus on occupational and general population health as it relates to benzene exposure. Using the framework as guidance, available data on benzene considered relevant for assessment of genetic damage were collected. Based on these data, we were able to conduct quantitative analyses for relevant data sets to estimate acceptable exposure levels and to characterize the risk of genetic damage. Key observations include the need for robust exposure assessments, the importance of information on toxicokinetic properties, and the benefits of cheminformatics. The framework points to the need for further improvement on understanding of the mechanism(s) of action involved, which would also provide support for the use of targeted tests rather than a prescribed set of assays. Overall, this case study demonstrates the utility of the next generation framework to quantitatively model human risk on the basis of genetic damage, thereby enabling a new, innovative risk assessment concept. Environ. Mol. Mutagen. 61:94-113, 2020. © 2019 The Authors. Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.
Topics: Animals; Benzene; Carcinogens; DNA Damage; Environmental Exposure; Humans; Leukemia; Mutagenesis; Mutagenicity Tests; Mutagens; Occupational Exposure; Risk Assessment
PubMed: 31709603
DOI: 10.1002/em.22346 -
International Journal of Molecular... Feb 2022The use of in silico toxicity prediction methods plays an important role in the selection of lead compounds and in ADMET studies since in vitro and in vivo methods are...
The use of in silico toxicity prediction methods plays an important role in the selection of lead compounds and in ADMET studies since in vitro and in vivo methods are often limited by ethics, time, budget and other resources. In this context, we present our new web tool VenomPred, a user-friendly platform for evaluating the potential mutagenic, hepatotoxic, carcinogenic and estrogenic effects of small molecules. VenomPred platform employs several in-house Machine Learning (ML) models developed with datasets derived from VEGA QSAR, a software that includes a comprehensive collection of different toxicity models and has been used as a reference for building and evaluating our ML models. The results showed that our models achieved equal or better performance than those obtained with the reference models included in VEGA QSAR. In order to improve the predictive performance of our platform, we adopted a consensus approach combining the results of different ML models, which was able to predict chemical toxicity better than the single models. This improved method was thus implemented in the VenomPred platform, a freely accessible webserver that takes the SMILES (Simplified Molecular-Input Line-Entry System) strings of the compounds as input and sends the prediction results providing a probability score about their potential toxicity.
Topics: Carcinogens; Computer Simulation; Drug-Related Side Effects and Adverse Reactions; Machine Learning; Mutagenesis; Mutagens; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Software
PubMed: 35216217
DOI: 10.3390/ijms23042105 -
Antimicrobial Agents and Chemotherapy Feb 2019We show that trimethoprim (TMP), an antibiotic in current use, displays a strong synergistic effect on mutagenesis in when paired with the base analog 2-aminopurine...
We show that trimethoprim (TMP), an antibiotic in current use, displays a strong synergistic effect on mutagenesis in when paired with the base analog 2-aminopurine (2AP), resulting in a 35-fold increase in mutation frequencies in the -Rif system. Combination therapies are often employed both as antibiotic treatments and in cancer chemotherapy. However, mutagenic effects of these combinations are rarely examined. An analysis of the mutational spectra of TMP, 2AP, and their combination indicates that together they trigger a response via an alteration in deoxynucleoside triphosphate (dNTP) ratios that neither compound alone can trigger. A similar, although less strong, response is seen with the frameshift mutagen ICR191 and 2AP. These results underscore the need for testing the effects on mutagenesis of combinations of antibiotics and chemotherapeutics.
Topics: 2-Aminopurine; Anti-Bacterial Agents; DNA-Directed RNA Polymerases; Drug Synergism; Escherichia coli; Escherichia coli Proteins; Mutagenesis; Mutagens; Trimethoprim
PubMed: 30509944
DOI: 10.1128/AAC.01577-18 -
Journal of Food Protection Jun 2022Roasting coffee results in not only the creation of carcinogens such as acrylamide, furan, and polycyclic aromatic hydrocarbons but also the elimination of carcinogens...
ABSTRACT
Roasting coffee results in not only the creation of carcinogens such as acrylamide, furan, and polycyclic aromatic hydrocarbons but also the elimination of carcinogens in raw coffee beans, such as endotoxins, preservatives, or pesticides, by burning off. However, it has not been determined whether the concentrations of these carcinogens are sufficient to make either light or dark roast coffee more carcinogenic in a living organism. An Ames test was conducted on light, medium, and dark roast coffee from three origins. We found that lighter roast coffee shows higher mutagenicity, which is reduced to the control level in dark roast coffee varieties, indicating that the roasting process is not increasing mutagenic potential but is beneficial to eliminating the existing carcinogens in raw coffee beans. This result suggests that dark roast coffee is safer and promotes further studies of the various carcinogens in raw coffee that have been burned off.
Topics: Acrylamide; Carcinogens; Coffee; Hot Temperature; Mutagens; Polycyclic Aromatic Hydrocarbons
PubMed: 35226750
DOI: 10.4315/JFP-21-427 -
Proceedings of the National Academy of... Jul 2018MutLα (MLH1-PMS2 heterodimer), which acts as a strand-directed endonuclease during the initiation of eukaryotic mismatch repair, has been postulated to function as a...
MutLα (MLH1-PMS2 heterodimer), which acts as a strand-directed endonuclease during the initiation of eukaryotic mismatch repair, has been postulated to function as a zinc-dependent enzyme [Kosinski J, Plotz G, Guarné A, Bujnicki JM, Friedhoff P (2008) 382:610-627]. We show that human MutLα copurifies with two bound zinc ions, at least one of which resides within the endonuclease active site, and that bound zinc is required for endonuclease function. Mutagenic action of the carcinogen cadmium, a known inhibitor of zinc-dependent enzymes, is largely due to selective inhibition of mismatch repair [Jin YH, et al. (2003) 34:326-329]. We show that cadmium is a potent inhibitor (apparent ∼ 200 nM) of MutLα endonuclease and that cadmium inhibition is reversed by zinc. We also show that inhibition of mismatch repair in cadmium-treated nuclear extract is significantly reversed by exogenous MutLα but not by MutSα (MSH2-MSH6 heterodimer) and that MutLα reversal depends on integrity of the endonuclease active site. Exogenous MutLα also partially rescues the mismatch repair defect in nuclear extract prepared from cells exposed to cadmium. These findings indicate that targeted inhibition of MutLα endonuclease contributes to cadmium inhibition of mismatch repair. This effect may play a role in the mechanism of cadmium carcinogenesis.
Topics: Cadmium; Carcinogens; DNA Mismatch Repair; Enzyme Inhibitors; Humans; MutL Proteins; Mutagens; Protein Multimerization
PubMed: 29941579
DOI: 10.1073/pnas.1807319115 -
Environmental Health Perspectives Nov 1986Data on raw water quality, disinfection treatment practices, and the resulting mutagenic properties of the treated water were compiled from pilot- and full-scale...
Data on raw water quality, disinfection treatment practices, and the resulting mutagenic properties of the treated water were compiled from pilot- and full-scale treatment experiments to evaluate that parameter which might produce variability in the results of a mutagenic study. Analysis of the data and comparison of treatment practices indicated that the measured mutagenic activity is strongly related to the characteristics of the organic matter in the raw water, the methodology used to sample and detect mutagens, the scale of the study both in terms of treatment flow and period of study, and the point at which and the conditions under which oxidants are added during treatment. Conclusions regarding disinfection systems in full-scale water treatment plants include the following: When raw water is pretreated and high concentrations of organics are present in the raw water, both ozonation and chlorination increased mutagenic activity. However, no significant difference in mutagenicity was found between the two oxidants. Both in the case of a nitrified groundwater and a clarified surface water, the mutagenic activity of the water after ozonation was related to its mutagenic activity before ozonation. With ozonation, mutagenic activity decreased after granular activated carbon (GAC) filtration. Thus, when GAC filtration follows ozone disinfection, early addition of oxidants may not be deleterious to the finished water quality. When chlorine or chlorine dioxide is added after GAC filtration, chlorine dioxide was found to produce a less mutagenic water than chlorine. Although these conclusions suggest means of controlling mutagenic activity during treatment, it must be stressed that the measurement of mutagenicity is a presumptive index of contamination level.
Topics: Carbon; Chlorine; Disinfectants; Disinfection; Mutagenicity Tests; Mutagens; Ozone; Pilot Projects; Water Supply
PubMed: 3816721
DOI: 10.1289/ehp.8669165 -
Mutation Research. Genetic Toxicology... 2022The development of new drugs based on metal complexes requires a detailed analysis of their biological endpoints. In this study, we report the genotoxic profile and...
The development of new drugs based on metal complexes requires a detailed analysis of their biological endpoints. In this study, we report the genotoxic profile and influence on cell proliferation and death of the oxovanadium(IV) complex with orotic acid ([VO(CHNO)], VO(oro)). Human hepatocellular carcinoma cells (HepG2) were the most sensitive tumor cells to VO(oro), which interfered with the integrity of cell membranes and proliferative capacity in a dose-dependent manner, inducing cell death by apoptosis. Regarding genotoxicity, VO(oro) did not induce considerable levels of DNA damage in HepG2 cells (comet test) and gene mutations (Ames test). However, it caused a statistically significant increase in the frequency of micronuclei at the highest concentration tested (12.5 µmol.L), indicating aneuploidy and clastogenicity. The data presented here provide information on various biological aspects of the VO(oro) complex, which may allow the elucidation of its mechanism of action as a possible therapeutic agent.
Topics: Humans; Orotic Acid; DNA Damage; Mutagens; Mutation; Cell Death
PubMed: 36462797
DOI: 10.1016/j.mrgentox.2022.503558 -
Ciencia & Saude Coletiva Aug 2020Malathion has been widely used worldwide in arbovirus control programs. In 2015, it was classified by the International Agency for Research on Cancer (IARC) as a...
Malathion has been widely used worldwide in arbovirus control programs. In 2015, it was classified by the International Agency for Research on Cancer (IARC) as a probable carcinogen to humans. This work aimed to systematize the evidence of the carcinogenic and mutagenic effects associated with the exposure of malathion and its analogs, malaoxon and isomalathion. The search was carried out in Toxline, PubMed and Scopus databases for original papers published from 1983 to 2015. In all, 73 papers were selected from a total of 273 eligible papers. The results of in vitro and in vivo studies showed mainly genetic and chromosomal damages caused by malathion. The epidemiological studies evidenced significant positive associations for thyroid, breast, and ovarian cancers in menopausal women. This evidence of the carcinogenic effect of malathion should be considered before its use in arbovirus control programs.
Topics: Female; Humans; Malathion; Mutagens
PubMed: 32785560
DOI: 10.1590/1413-81232020258.10672018