DOSE-RESPONSE RELATIONSHIP FOR CHEMICAL CARCINOGENESIS BY GENOTOXIC AGENTS

Formation and repair of DNA adducts from genotoxic carcinogens is expected to be proportional to dose as long as the rates of the enzymatic and non-enzymatic activation and inactivation reactions are all proportional to the substrate concentration. Deviations from linearity are expected in situations of induced and saturated kinetics. A sublinear shape of the dose-response curve is always expected at toxic dose levels when regenerative hyperplasia accelerates the fixation and accumulation of mutations resulting from the DNA adducts. In a heterogeneous population, however, a nonlinear dose-response curve is linearized when genetic and life-style factors result in individual variability in the rates of the activation and inactivation pathways. Finally, in the light of the endogenous and therefore partly unavoidable nature of genetic damage, it is proposed that the cancer risk from exposure to an exogenous carcinogen should be expressed as a reduction of tumor-free life span rather than in absolute terms of additional cases.