Quantitative in vitro to in vivo extrapolation of genotoxicity data provides protective estimates of in vivo dose.

Autor: Beal MA; Bureau of Chemical Safety, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada., Audebert M; Toxalim UMR1331, Toulouse University, INRAE, Toulouse, France., Barton-Maclaren T; Existing Substances Risk Assessment Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario, Canada., Battaion H; Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario, Canada., Bemis JC; Litron Laboratories, Rochester, New York, USA., Cao X; Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas, USA., Chen C; Health and Environmental Sciences Institute, Washington, District of Columbia, USA., Dertinger SD; Litron Laboratories, Rochester, New York, USA., Froetschl R; Genetic and Reproductive Toxicology, BfArM, Bonn, Germany., Guo X; Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas, USA., Johnson G; Swansea University, Swansea, UK., Hendriks G; Toxys, Oegstgeest, Netherlands., Khoury L; PrediTox, Toulouse, France., Long AS; Existing Substances Risk Assessment Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario, Canada., Pfuhler S; Global Product Stewardship, Procter & Gamble, Cincinnati, Ohio, USA., Settivari RS; Mammalian Toxicology Center, Corteva Agriscience, Newark, Delaware, USA., Wickramasuriya S; Existing Substances Risk Assessment Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario, Canada., White P; Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario, Canada.
Jazyk: angličtina
Zdroj: Environmental and molecular mutagenesis [Environ Mol Mutagen] 2023 Feb; Vol. 64 (2), pp. 105-122. Date of Electronic Publication: 2022 Dec 22.
DOI: 10.1002/em.22521
Abstrakt: Genotoxicity assessment is a critical component in the development and evaluation of chemicals. Traditional genotoxicity assays (i.e., mutagenicity, clastogenicity, and aneugenicity) have been limited to dichotomous hazard classification, while other toxicity endpoints are assessed through quantitative determination of points-of-departures (PODs) for setting exposure limits. The more recent higher-throughput in vitro genotoxicity assays, many of which also provide mechanistic information, offer a powerful approach for determining defined PODs for potency ranking and risk assessment. In order to obtain relevant human dose context from the in vitro assays, in vitro to in vivo extrapolation (IVIVE) models are required to determine what dose would elicit a concentration in the body demonstrated to be genotoxic using in vitro assays. Previous work has demonstrated that application of IVIVE models to in vitro bioactivity data can provide PODs that are protective of human health, but there has been no evaluation of how these models perform with in vitro genotoxicity data. Thus, the Genetic Toxicology Technical Committee, under the Health and Environmental Sciences Institute, conducted a case study on 31 reference chemicals to evaluate the performance of IVIVE application to genotoxicity data. The results demonstrate that for most chemicals considered here (20/31), the PODs derived from in vitro data and IVIVE are health protective relative to in vivo PODs from animal studies. PODs were also protective by assay target: mutations (8/13 chemicals), micronuclei (9/12), and aneugenicity markers (4/4). It is envisioned that this novel testing strategy could enhance prioritization, rapid screening, and risk assessment of genotoxic chemicals.
(© 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 Canada. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)
Databáze: MEDLINE
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