Guerard, Melanie, Baum, Matthias, Bitsch, Annette, Eisenbrand, Gerhard, Elhajouji, Azeddine, Epe, Bernd, Habermeyer, Michael, Kaina, Bernd, Martus, Hans-Joerg, Pfuhler, Stefan, Schmitz, Cordula, Sutter, Andreas, Thomas, Adam, Ziemann, Christina and Froetschl, Roland (2015) Threshold mechanisms for genotoxicity: assessment of relevant mechanisms and their impact on dose-response relationships. Mutation Research-Reviews.

Abstract

For many genotoxic endpoints, threshold-type dose-response relationships are being
reported for diverse genotoxins with different modes of action (MoA). In any case, convincing evidence for a biologically plausible mechanism is indispensable to postulate a non-linear dose-response relationship. We have identified that high-powered, statistically robust studies into the dose-response relationship at low doses of genotoxins, particularly with accompanying mechanistic data are sparse but emerging. Of those studies with sufficient mechanistic data, it is clear that careful consideration of MoA (e.g. reactive oxygen species -generation, topoisomerase inhibition or spindle disruption), potential detoxification pathways, pro-carcinogen activation, biomarkers of exposure and/or relevant DNA repair processes are as important as initial study design, dose spacing and dose-response modeling in order to assess the biological relevance of genotoxic thresholds.
Overall, experimental proof of a threshold is challenging and will not always be possible. There is,
however, convincing evidence for a number of MoAs that practical threshold for mutagenicity can be
assumed. We conclude that evaluation of the biological mechanism underlying a possible threshold for DNA damage is key and will require a case-specific testing approach.

Item Type:	Article
Date Deposited:	27 Feb 2025 00:47
Last Modified:	27 Feb 2025 00:47
URI:	https://oak.novartis.com/id/eprint/23697