Establishing a quantitative framework for regulatory interpretation of genetic toxicity dose-response data: Margin of exposure case study of 48 compounds with both in vivo mutagenicity and carcinogenicity dose-response data.

Autor: Chepelev N; Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario, Canada., Long AS; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada., Beal M; Existing Substances Risk Assessment Bureau, Health Canada, Ottawa, Ontario, Canada., Barton-Maclaren T; Existing Substances Risk Assessment Bureau, Health Canada, Ottawa, Ontario, Canada., Johnson G; Swansea University Medical School, Swansea University, Swansea, UK., Dearfield KL; Retired, Burke, Virginia, USA., Roberts DJ; Charles River Laboratories, Skokie, Illinois, USA., van Benthem J; National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands., White P; Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario, Canada.
Jazyk: angličtina
Zdroj: Environmental and molecular mutagenesis [Environ Mol Mutagen] 2023 Jan; Vol. 64 (1), pp. 4-15. Date of Electronic Publication: 2023 Jan 06.
DOI: 10.1002/em.22517
Abstrakt: Quantitative relationships between carcinogenic potency and mutagenic potency have been previously examined using a benchmark dose (BMD)-based approach. We extended those analyses by using human exposure data for 48 compounds to calculate carcinogenicity-derived and genotoxicity-derived margin of exposure values (MOEs) that can be used to prioritize substances for risk management. MOEs for 16 of the 48 compounds were below 10,000, and consequently highlighted for regulatory concern. Of these, 15 were highlighted using genotoxicity-derived (micronucleus [MN] dose-response data) MOEs. A total of 13 compounds were highlighted using carcinogenicity-derived MOEs; 12 compounds were overlapping. MOEs were also calculated using transgenic rodent (TGR) mutagenicity data. For 10 of the 12 compounds examined using TGR data, the results similarly revealed that mutagenicity-derived MOEs yield regulatory decisions that correspond with those based on carcinogenicity-derived MOEs. The effect of benchmark response (BMR) on MOE determination was also examined. Reinterpretation of the analyses using a BMR of 50% indicated that four out of 15 compounds prioritized using MN-derived MOEs based on a default BMR of 5% would have been missed. The results indicate that regulatory decisions based on in vivo genotoxicity dose-response data would be consistent with those based on carcinogenicity dose-response data; in some cases, genotoxicity-based decisions would be more conservative. Going forward, and in the absence of carcinogenicity data, in vivo genotoxicity assays (MN and TGR) can be used to effectively prioritize substances for regulatory action. Routine use of the MOE approach necessitates the availability of reliable human exposure estimates, and consensus regarding appropriate BMRs for genotoxicity endpoints.
(© 2022 His Majesty the King in Right of Canada and The Authors. Environmental and Molecular Mutagenesis published by Wiley Periodicals LLC on behalf of Environmental Mutagen Society. Reproduced with the permission of the Minister of Health.)
Databáze: MEDLINE
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