Dose-response relationships in chemical carcinogenesis: from DNA adducts to tumor incidence.
Mechanistic possibilities responsible for nonlinear shapes of the dose-response relationship in chemical carcinogenesis are discussed. (i) Induction and saturation of enzymatic activation and detoxification processes and of DNA repair affect the relationship between dose and steady-state DNA adduct level; (ii) The fixation of DNA adducts in the form of mutations is accelerated by stimulation of the cell division, for instance due to regenerative hyperplasia at cytotoxic dose levels; (iii) The rate of tumor formation results from a superposition of the rates of the individual steps. It can become exponential with dose if more than one step is accelerated by the DNA damage exerted by the genotoxic carcinogen. The strongly sigmoidal shapes often observed for dose-tumor incidence relationships in animal bioassays supports this analysis. A power of four for the dose in the sublinear part of the curve is the maximum observed (formaldehyde). In contrast to animal experiments, epidemiological data in humans rarely show a significant deviation from linearity. The discrepancy might be explained by the fact that a large number of genes contribute to the overall sensitivity of an individual and to the respective heterogeneity within the human population. Mechanistic nonlinearities are flattened out in the presence of genetic and life-style factors which affect the sensitivity for the development of cancer. For a risk assessment, linear extrapolation from the high-dose incidence to the spontaneous rate can therefore be appropriate in a heterogeneous population even if the mechanism of action would result in a nonlinear shape of the dose-response curve in a homogeneous population.
Lutz
W K
WK
Institute of Toxicology, Swiss Federal Institute of Technology, Schwerzenbach.
D000818:Animals; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D004247:DNA / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000139:chemically induced; D012307:Risk Factors
D002273:Carcinogens; D004247:DNA