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A true threshold dose in chemical carcinogenesis cannot be defined for a population, irrespective of the mode of action

Department of Toxicology, University of Wuerzburg, 9 Versbacher Strasse, Wuerzburg D-97078, Germany

Strongly sigmoidal (S-shaped) dose-cancer incidence relationships are often observed in animal bioassays for carcinogenicity. If a genotoxic contribution is not plausible, an epigenetic mode of carcinogen action is proposed and a thresholded low dose-response suggested. In a strictsense, a threshold implies a no-yes situation, i.e., no effect up to the threshold dose and an effect above the threshold dose. A convincing explanation ofthe discontinuity ofthe gradient of the dose-response curve at the threshold dose is not available to me. However, the existence of a threshold is accepted for an individual. The threshold dose is the dose required for the manifestation of the tumor in an individual exactly at the end of a defined period of observation (for instance, 2 years in an animal bioassay, 75 years in humans). Because of genetic and lifestyle-dependent susceptibility differences, each animal or human has his individual threshold dose. For a group, no single threshold dose can be defined, irrespective of the mode of carcinogen action. Furthermore, in view of the stochastic elements in the process of carcinogenesis, the exact threshold dose can only be defined after tumor incidence and cannot be predicted.

Key Words: carcinogens • dose response • genetics • predisposition • risk • time factors

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