Opportunities to integrate new approaches in genetic toxicology: An ILSI-HESI workshop report

Genetic toxicity tests currently used to identify and characterize potential human mutagens and carcinogens rely on measurements of primary DNA damage, gene mutation, and chromosome damage in vitro and in rodents. The International Life Sciences Institute Health and Environmental Sciences Institute (ILSI-HESI) Committee on the Relevance and Follow-up of Positive Results in In Vitro Genetic Toxicity Testing held an April 2012 Workshop in Washington, DC, to consider the impact of new understanding of biology and new technologies on the identification and characterization of genotoxic substances, and to identify new approaches to inform more accurate human risk assessment for genetic and carcinogenic effects. Workshop organizers and speakers were from industry, academe, and government. The Workshop focused on biological effects and technologies that would potentially yield the most useful information for evaluating human risk of genetic damage. Also addressed was the impact that improved understanding of biology and availability of new techniques might have on genetic toxicology practices. Workshop topics included (1) alternative experimental models to improve genetic toxicity testing, (2) Biomarkers of epigenetic changes and their applicability to genetic toxicology, and (3) new technologies and approaches. The ability of these new tests and technologies to be developed into tests to identify and characterize genotoxic agents; to serve as a bridge between in vitro and in vivo rodent, or preferably human, data; or to be used to provide dose response information for quantitative risk assessment was also addressed. A summary of the workshop and links to the scientific presentations are provided.International Life Sciences Institute/Health and Environmental Sciences Institute Committe

Méthodes d'étude de l'écotoxicité : application à l'évaluation de l'impact potentiel des eaux résiduaires d'incendie sur les écosystèmes aquatiques

National audienceL'ecotoxicite d'une substance chimique, d'un effluent industriel ou de tout rejet a l'environnement peut etre evaluee a l'aide de diverses techniques regroupees schematiquement en deux categories, les etudes de laboratoire d'une part et les etudes en milieu naturel d'autre par

Evaluation du potentiel génotoxique du phénobarbital dans le foie de rat à l'aide du test des comètes in vivo (comparaison de deux protocoles de traitement court terme (3 jours) versus long terme (29 jours))

LYON1-BU Santé (693882101) / SudocSudocFranceF

Utilisation de mésocosmes comme outils d'aide à l'évaluation des risques écotoxicologiques

National audienceLa réglementation européenne concernant la mise sur le marché et/ou l'utilisation de substances chimiques nécessite la caractérisation de l'écotoxicité et du devenir de ces substances dans l'environnement (Directive 92/32/CEE) afin de réaliser, dans la mesure où la substance est classée dangereuse pour l'environnement, une évaluation des risques pour l'environnement liés à l'utilisation de ces produits (Directive 93/67/CEE). A l'heure actuelle, cette évaluation, tant du comportement que de l'écotoxicité est réalisée à partir des résultats d'essais normalisés de laboratoire (Directive 92/32/CEE). Les mésocosmes, en permettant de coupler les études de comportement et de caractérisation de l'ecotoxicité des substances chimiques représentent un niveau d'intégration supérieur à celui des essais de laboratoire et permettent donc une évaluation plus réaliste des risques résultant d'une éventuelle contamination des milieux aquatiques. Ces outils ont d'ailleurs fait l'objet de diverses études, en particulier aux Etats-Unis, notamment pour évaluer l'impact des pesticides sur les écosystèmes aquatiques (Touart, 1994; Urban 1994). L'objectif des études menées dans le cadre du Programme PNETOX est de recueillir les informations nécessaires permettant à terme de réaliser des simplifications des écosystèmes artificiels tant lotiques que lentiques de sorte que la variabilité soit réduite et que des mécanismes essentiels puissent être isolés, sans pour autant invalider les conclusions et les prédictions qui pourraient être tirées

Effects of ethylene glycol ethers on the reproduction of Ceriodaphnia dubia

International audienceSeven-day static renewal tests with Ceriodaphnia dubia were used to document the chronic toxicity of ethylene glycol ethers and acetates to this invertebrate. The 7-d EC10 (effective concentrations inducing an inhibition of 10% of the reproduction of the tested organisms) values ranged from 0.06 to 1025 mg/l. While a survey of the literature showed that the acute toxicity of these chemicals appeared negligible, our results clearly revealed the potential chronic effects of some of them to this organism occupying an important trophic level in the aquatic ecosystems. The usefulness of this kind of test to better estimate the adverse effects of glycol ethers was stressed

Ecotoxicity of ethylene glycol monomethyl ether and its acetate

International audienceEthylene glycol monomethyl ether (EGME) and ethylene glycol monomethyl ether acetate (EGMEA) have been tested for their acute and chronic toxicity to various organisms occupying different trophic levels in the aquatic ecosystems. The results obtained in this study and those collected from the literature clearly reveal that EGME does not present short- or long-term ecotoxic effects in the ranges of concentrations likely to be found in aquatic environments. Indeed, in general, concentrations of 1000 to 10,000 mg/L of EGME are necessary before significant adverse effects can be observed in aquatic species. Conversely, acute toxicity occurs in fish at about 50 mg/L of EGMEA, and reproduction of Ceriodaphnia dubia is affected by 0.06 mg/L of this chemical. A teratogenic effect-with a specific malformation of the eyes-occurs in Xenopus laevis in the presence of 75 mg/L of EGMEA

Performance and data interpretation of the in vivo comet assay in pharmaceutical industry: EFPIA survey results

This paper summarizes a survey suggested by the Safety Working Party of European Medicines Agency (EMA), and conducted by the European Federation of Pharmaceutical Industries and Associations (EFPIA) to investigate experience accumulated in European pharmaceutical companies with the conduct of the in vivo comet assay for regulatory purpose. The objective was to evaluate better the details of results obtained, and to identify potential on difficulties encountered with the interpretation of study data. In total 147 studies have been conducted (in-house or outsourced) and the conclusion on the comet assay response was shared for 136 studies. Most of the studies were negative (118/136). Only about 10% (14/136 studies) of the comet assays showed a positive response. None of the positive comet assay results were clearly associated with organ toxicity indicating that the positive responses are not due to cytotoxic effects of the compound in the tissue examined. The number of comet assays with an equivocal or inconclusive response are rare, respectively <1% (1/147 studies) and 2% (3/147 studies). In case additional information (e.g. repeat assay, organ toxicity, metabolism, tissue exposure) would have been available for evaluation, a final conclusion could most probably have been drawn for most of these studies. All negative in vivo comet assays that were submitted in conjunction with a negative in vivo micronucleus assay (46/97) were accepted by the regulatory authorities to mitigate a positive in vitro mammalian cell assay following the current ICH S2 guidance. The survey results demonstrate the robustness of the comet and the regulatory acceptance of the current ICH S2 guidance