Quantitative approaches for assessing dose–response relationships in genetic toxicology studies

Genetic toxicology studies are required for the safety assessment of chemicals. Data from these studies have historically been interpreted in a qualitative, dichotomous ‘‘yes’’ or ‘‘no’’ manner without analysis of dose– response relationships. This article is based upon the work of an international multi-sector group that examined how quantitative dose–response relationships for in vitro and in vivo genetic toxicology data might be used to improve human risk assessment. The group examined three quantitative approaches for analyzing dose–response curves and deriving point-of-departure (POD) metrics (i.e., the no-observed-genotoxic-effectlevel (NOGEL), the threshold effect level (Td), and the benchmark dose (BMD)), using data for the induction of micronuclei and gene mutations by methyl methanesulfonate or ethyl methanesulfonate in vitro and in vivo. These results suggest that the POD descriptors obtained using the different approaches are within the same order of magnitude, with more variability observed for the in vivo assays. The different approaches were found to be complementary as each has advantages and limitations. The results further indicate that the lower confidence limit of a benchmark response rate of 10%