Dose-response relationships in chemical carcinogenesis reflect differences in individual susceptibility. Consequences for cancer risk assessment, extrapolation, and prevention.
The shape of the dose-cancer incidence curve observed in an animal bioassay for carcinogenicity of a chemical is the result of a superposition of various mechanisms contributing to the process of carcinogenesis. For genotoxic carcinogens, for instance, a sublinear (convex; up-bent) shape could be the result of a saturation of DNA repair or of a higher rate of cell turnover associated with high-dose cytotoxicity and regenerative hyperplasia. In human cancer epidemiology, the situation is more complex. The human population is very heterogeneous with respect to both genetic and life-style factors that modulate the process of tumor formation. Therefore, individuals are expected to show widely variable susceptibility to carcinogenic factors, and the dose-response curve is in fact a reflection of the tolerance distribution. Each modulating factor divides the population up into subpopulations of different susceptibility so that nonlinearities that could be present in a homogeneous population are flattened out. A linear extrapolation of a human cancer risk to low dose might therefore be appropriate under certain conditions even if the dose-response curve in animals has a strongly sigmoidal shape. For cancer prevention, the investigation of susceptibility factors is expected to be of great value. The elimination of concurrent risk factors in high-risk subpopulations or individuals might be more effective than a minor general reduction of a tolerable exposure level.
Lutz
W K
WK
Department of Toxicology, University of Wuerzburg, Versbacher St. 9, Wuerzburg D-97078, Germany.
D000818:Animals; D002273:Carcinogens / Q000008:administration & dosage* / Q000009:adverse effects*; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004781:Environmental Exposure / Q000009:adverse effects / Q000032:analysis; D020022:Genetic Predisposition to Disease; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000139:chemically induced* / Q000235:genetics* / Q000517:prevention & control; D018570:Risk Assessment; D013269:Stochastic Processes
D002273:Carcinogens