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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.
This article was published in the following journal.
Name: Environmental and molecular mutagenesis
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The ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response.
The application of STATISTICS to biological systems and organisms involving the retrieval or collection, analysis, reduction, and interpretation of qualitative and quantitative data.
A specific immune response elicited by a specific dose of an immunologically active substance or cell in an organism, tissue, or cell.
The science concerned with the benefit and risk of drugs used in populations and the analysis of the outcomes of drug therapies. Pharmacoepidemiologic data come from both clinical trials and epidemiological studies with emphasis on methods for the detection and evaluation of drug-related adverse effects, assessment of risk vs benefit ratios in drug therapy, patterns of drug utilization, the cost-effectiveness of specific drugs, methodology of postmarketing surveillance, and the relation between pharmacoepidemiology and the formulation and interpretation of regulatory guidelines. (Pharmacoepidemiol Drug Saf 1992;1(1); J Pharmacoepidemiol 1990;1(1))
The relationship between the dose of administered radiation and the response of the organism or tissue to the radiation.