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Quantitative Interpretation of Genetic Toxicity Dose-Response Data for Risk Assessment and Regulatory Decision-making: Current Status and Emerging Priorities.

07:00 EST 3rd December 2019 | BioPortfolio

Summary of "Quantitative Interpretation of Genetic Toxicity Dose-Response Data for Risk Assessment and Regulatory Decision-making: Current Status and Emerging Priorities."

The screen-and-bin approach for interpretation of genotoxicity data is predicated on three false assumptions: that genotoxicants are rare, that genotoxicity dose-response functions do not contain a low-dose region mechanistically characterized by zero-order kinetics, and that genotoxicity is not a bona fide toxicological endpoint. Consequently, there is a need to develop and implement quantitative methods to interpret genotoxicity dose-response data for risk assessment and regulatory decision-making. Standardized methods to analyze dose-response data, and determine PoD (point-of-departure) metrics, have been established; the most robust PoD is the BMD (Benchmark Dose). However, there are no standards for regulatory interpretation of mutagenicity BMDs. Although 5-10% is often used as a CES (Critical Effect Size) for BMD determination, values for genotoxicity endpoints have not been established. Use of BMDs to determine Health-based Guidance Values (HBGVs) requires AFs (assessment factors) to account for inter-species differences and variability in human sensitivity. Default AFs used for other endpoints may not be appropriate for interpretation of in vivo mutagenicity BMDs. Analyses of published dose-response data showing the effects of compensatory pathway deficiency indicate that AFs for sensitivity differences should be in the range 2-20. Additional analyses indicate that the AF to compensate for short treatment durations should be in the range 5-15. Future work should use available data to empirically determine endpoint-specific CES values; similarly, to determine AF values for BMD adjustment. Future work should also evaluate the ability to use in vitro dose-response data for risk assessment, and the utility of probabilistic methods for determination of mutagenicity HBGVs. This article is protected by copyright. All rights reserved.

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Name: Environmental and molecular mutagenesis
ISSN: 1098-2280
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