Dose-response relationships for carcinogens

Abstract

Biotransformation of chemical carcinogens involves both metabolic activation and detoxication. The molecular dose present on DNA as adducts represents a balance between these two pathways (formation) and DNA repair. All of these are enzymatic processes subject to saturation. When none of the pathways is saturated, linear molecular dosimetry is expected, whereas if metabolic activation is saturated, a supralinear response occurs. If detoxication or DNA repair is saturated, a sublinear response occurs. With chronic exposure, steady-state concentrations of DNA adducts develop and these follow the same patterns. With several alkylating agents, multiple adducts are formed. The extent of formation is chemically defined, but different DNA repair pathways can be involved for different adducts. By understanding the molecular dose and biology of each adduct and comparing these to the dose-response for tumor induction, it may be possible to identify the most appropriate biomarkers for risk assessment. Recently, endogenous DNA adducts identical to those induced by known human carcinogens have been identified. These endogenously formed adducts may play an important role in human carcinogenesis.