in vivo Approaches to Identify Mutations and in vitro Research to Reveal Underlying Mechanisms of Genotoxic Thresholds

Abstract

In regulatory toxicology, it is assumed that genotoxic carcinogens, which induce cancer through genotoxic mechanisms, have no threshold for their action. However, humans possess a number of defense mechanisms against DNA damaging agents, which may reduce the genotoxic and cancer risk at low doses to the spontaneous levels. The defense mechanisms may constitute practical thresholds for genotoxic carcinogens. In fact, accumulating evidence with rodent carcinogenicity and genotoxicity assays suggest that some genotoxic compounds clearly exhibit threshold-like dose responses in vivo. These results challenge the paradigm that cancer risk induced by genotoxic compounds at high doses can be linearly extrapolated into low doses where people are exposed in daily life (linear non-threshold model). Here, we discuss two issues regarding the practical thresholds for genotoxic carcinogens. The first issue is how to define “genotoxicity” of chemicals. There are a number of genotoxicity assays in vitro and in vivo. Therefore, it is unclear what genotoxicity assay(s) should be employed to define whether the compound is genotoxic or not. The second issue is possible mechanisms underlying the practical thresholds. In particular, we emphasize the importance of DNA repair and translesion DNA synthesis as the underlying mechanisms of the practical thresholds. Finally, we discuss issues associated with low dose exposure to genotoxic carcinogens, i.e., risk assessment of exposure to multiple genotoxic chemicals.