DNA Repair and its influence on points of departure for alkylating agent genotoxicity

Answering the question of whether low doses of DNA-reactive genotoxicants are of negligible concern has become a global effort due to its central importance in human health risk assessments. As a result, a huge amount of data exists suggesting that low doses can be tolerated, and do not increase the mutagenic or carcinogenic load. Investigations have turned to the source of this tolerance and have examined cytoprotective mechanisms, which may prevent mutagenesis and cancer at low doses and contribute to a point of departure (PoD). DNA repair has received the most attention, particularly in relation to the PoD for alkylating agents. Data using repair knockout models highlight the protective role of DNA repair at low doses. In models where DNA repair has been abrogated, the PoD is either absent (linear dose-response) or is significantly reduced. In this chapter, we examine the influence of DNA repair on PoD for alkylating agent genotoxicity.