Department of Pathology, New York Medical College, Valhalla, NY, 10595, USA.
Department of Pathology, New York Medical College, Valhalla, NY, 10595, USA.
Chem Biol Interact. 2019 Mar 1;301:88-111. doi: 10.1016/j.cbi.2018.11.011. Epub 2019 Feb 11.
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.
在多年来对化学致癌性阈值问题的审议中，主导范式一直是线性无阈值（LNT）模型，该模型源自辐射诱变概念。基于与辐射的类比，评估化学诱导致癌性的剂量-效应的关键机制假设是，任何剂量，无论多么低，都可能导致突变的诱导，从而导致肿瘤发生的某些风险。然而，LNT 假设从未有很好的依据，并且其在化学致癌物中的应用不能考虑它们的处置或作用机制的差异。这些机制包括 DNA 反应性和表观遗传效应，这是由于致癌剂具有非常不同的性质，导致不同的剂量效应。对长期重复给药的化学致癌物的剂量效应研究进行了综述，结果表明，只有一些涉及现在被认为是 DNA 反应性致癌剂的实验，对肿瘤的诱导产生了与不存在阈值一致的剂量效应（对于 6/14 种化学物质）。然而，这些研究都没有包括不会产生遗传或其他细胞毒性的低剂量，这些毒性是致癌性的基础。否则，大多数剂量效应实验，包括所有涉及表观遗传剂的实验（7），都没有观察到肿瘤的无效应水平，表明存在阈下剂量。基于包括相关机制数据在内的高度信息性实验数据，得出结论，对于致癌物诱导的前体效应和肿瘤形成，都存在无效应水平。因此，我们得出结论，在非毒性剂量下，所有类型的致癌剂诱导实验性癌症都存在阈值。
