Review of the evidence for thresholds for DNA-Reactive and epigenetic experimental chemical carcinogens

In the deliberations over many years on the question of thresholds for the carcinogenicity of chemicals, the dominant paradigm has been the linear no-threshold (LNT) model, derived from concepts formulated in radiation mutagenicity. Based on the analogy with radiation, the key mechanistic assumption underlying the assessment of the dose-effect of chemical-induced carcinogenicity has been that any dose, no matter how low, can lead to induction of mutations, which will result in some risk of neoplasia. The LNT assumption, however, was never well founded and, its application to chemical carcinogens, does not allow for differences in their disposition or mechanisms of action. These mechanisms include DNA-reactivity and epigenetic effects, resulting from very different properties of carcinogens, leading to different dose effects. This review of the research on dose effects of chemical carcinogens administered by repeat dosing for long duration reveals that only some experiments involving what are now recognized as DNA-reactive carcinogens yielded dose effects for induction of tumors which were consistent with the absence of a threshold (for 6/14 chemicals). None of these studies, however, included low doses documented not to produce genetic or other cellular toxicities that underlie carcinogenicity. Otherwise, most dose-effect experiments, including all with epigenetic agents (7), revealed no-observed-effect-levels for tumors, indicative of subthreshold doses. Based on highly informative experimental data, including relevant mechanistic data, it is concluded that no-effect-levels exist for both carcinogen-induced precursor effects and neoplasia. Accordingly, we conclude that, at non-toxic dosages, thresholds exist for the induction of experimental cancer by all types of carcinogens.