Susceptibility differences in chemical carcinogenesis linearize the dose–response relationship: threshold doses can be defined only for individuals

Abstract

The debate on thresholds in dose–response relationships for chemical carcinogenesis concentrates on the question of mechanisms of action that come into play only at dose levels that overwhelm compensatory control mechanism, such as DNA repair or regulation of cell proliferation and death. In this article, individual susceptibility differences are introduced. It is postulated that one single threshold dose cannot be defined for a heterogeneous population because both the background rate of carcinogenesis and specific exposure-related effects differ between individuals. A threshold dose can therefore be defined only on an individual basis and for a given organ. Expressed as a time-to-tumor, the threshold dose results in tumor manifestation at exactly the end of the specified observation period. For those individuals who do not have cancer by the end of this period, the dose was below their individual threshold dose, for those who do have cancer, the dose was above their threshold dose. Based on this concept, a distinction between genotoxic and non-genotoxic carcinogens is no longer required; both types modulate time-to-tumor. Although the present analysis does not allow to define a threshold dose for a population, the setting of a “limit value” for regulatory purposes can be considered if regulators are aware of the fact that this splits a population at some percentile into a group for which the chosen standard is protective and a group for which it might not be. Investigation of factors that confer particular susceptibility to individuals is the key to an understanding of the dose–response relationship at low dose.