Possible Mechanisms Underlying Genotoxic Thresholds: DNA Repair and Translesion DNA Synthesis

Currently, chemical carcinogens are classified into two groups, that is, genotoxic carcinogens and nongenotoxic carcinogens. The former are chemicals that induce tumors through genotoxic mechanisms such as mutations, while the latter are those that induce tumors through nongenotoxic mechanisms such as hormonal effects or cell toxicity. This classification has strong implications in regulation of chemicals because neither thresholds nor acceptable daily intake levels are accepted for genotoxic carcinogens. However, this regulatory policy, that is, a linear no-threshold model for genotoxic carcinogens, has been challenged recently. Humans possess a number of self-defense mechanisms, which may suppress genotoxicity of chemicals at low doses to spontaneous levels, thereby establishing practical thresholds. In addition, it is not simple to distinguish genotoxic from nongenotoxic carcinogens. In this chapter, we argue the challenges in the identification of genotoxicity of chemicals and discuss possible roles of DNA repair and translesion DNA synthesis in the practical thresholds for genotoxicity.