Investigating Mechanisms for Non-linear Genotoxic Responses, and Analysing Their Effects in Binary Combination

A recent shift by the scientiˆc and regulatory communi-ty, towards accepting the existence of non-linear doseresponses for certain DNA reactive genotoxic agents, hasunveiled a myriad of questions regarding their biologicalbasis. The mechanisms responsible for `genotoxic toler-ance' at low doses are wide ranging but poorly under-stood, yet this information is essential when analysingnon-linear dose responses for hazard and risk assessment.For DNA reactive genotoxins, non-linear dose responsescan arise from many diSerent biological mechanisms, in-cluding DNA repair. Recent work from our group exploredthe contributory role of DNA repair to nonlinear genotoxicdose responses, in human cells exposed alkylating agents.Here we discuss the involvement of the repair enzymesmethylpurine DNA-glycosylase and methyl-guaninemethyl-transferase in modulating the non-linear doseresponses observed in human cells exposed to ethylmethanesulfonate (EMS) and N-methyl-N-nitrosourea, re-spectively. We also discuss the exposure of binary mix-tures, and how combinations of the dissimilar actingagents Benomyl and EMS at their no observed genotoxiceSect levels, induce a signiˆcant increase in micronuclei.Key words: alkylating agents, thresholds, mode of action,DNA repair, mixtures