Assessment of mechanisms driving non-linear dose-response relationships in genotoxicity testing

Mutation Research. Reviews in Mutation Research
M GuérardR Froetschl

Abstract

In genetic toxicology, risk assessment has traditionally adopted linear dose-responses for any compound that causes genotoxic effects. Increasing evidence of non-linear dose-responses, however, suggests potential cellular tolerance to low levels of many genotoxicants with diverse modes of action. Such putative non-linear dose-responses need to be substantiated by strong mechanistic data that identifies the mechanisms responsible for the tolerance to low doses. This can be achieved by experimental demonstration of cytoprotective mechanisms and by providing experimental support for the existence of tolerance mechanisms against low dose effects. By highlighting key experiments into low dose mechanisms, this review aims to clarify which mechanistic data are required to support the use of non-linear dose-response models in risk assessment. Such key experiments are presented and discussed for alkylating agents, oxidants, particulate matter, nucleoside analogues, topoisomerase inhibitors and aneugens and exemplify the use of gene knockout models or transgenic models as well as chemical modulators of key effectors of relevant pathways and their impact on dose-response relationships. In vitro studies are particularly valuable to elucida...Continue Reading

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Citations

May 22, 2016·Toxicological Sciences : an Official Journal of the Society of Toxicology·Ester Lovsin BarleHans-Joerg Martus
Oct 4, 2016·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Jörg Fahrer, Bernd Kaina
Sep 27, 2018·Risk Analysis : an Official Publication of the Society for Risk Analysis·Maria A Spassova
Jul 14, 2019·Environmental and Molecular Mutagenesis·Joanna Klapacz, B Bhaskar Gollapudi
Jul 28, 2016·Clinical and Translational Medicine·Maria Longauer BanholzerLucette Doessegger
Mar 16, 2017·Environmental and Molecular Mutagenesis·Melanie GuérardTessier Yann
Dec 16, 2020·Carcinogenesis·Federica ChiaraAndrea Trevisan
Sep 18, 2020·Toxicology Letters·Colin M NorthStephen D Williams
Dec 18, 2015·Journal of Veterinary Medical Education·Michael D Lairmore, Jan Ilkiw
Aug 30, 2019·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Natacha AllgayerMauricio Lehmann
Dec 21, 2019·Chemical Research in Toxicology·Andreas ZellerSimone Schadt

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