There is increasing evidence for non-linear relationships for gene mutations, chromosomal aberrations and even tumor incidences in response to low doses of genotoxic carcinogens. To attain the biological relevance of such non-linear responses, there is a need to identify the underlying defense mechanisms that allow tolerance to low doses of genotoxicants. This communication discusses presumptive cancer prevention mechanisms that may contribute to thresholds, i.e. points of departure, for each endpoint, from initial DNA lesion to tumor formation. We discuss a sequential order of genome protection during carcinogenesis where genotoxicant scavenging, cellular efflux, DNA repair, elimination of damaged cells by apoptosis, autophagy, silencing by DNA damage-triggered replicative senescence, and finally, elimination of transformed (premalignant) cells by the immune system are thought to be responsible for a threshold in tumor formation. We highlight DNA repair, for which experimental evidence has been recently provided to dictate a role in PoDs. In conclusion, from a theoretical perspective it is reasonable to posit that tolerance to low dose levels exists for each requisite step of tumor formation and these tolerance mechanisms are critical in determining thresholds in chemical carcinogenesis.

中文翻译：

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化学致癌阈值的理论考虑。

越来越多的证据表明，低剂量的遗传毒性致癌物对基因突变，染色体畸变甚至肿瘤发生率具有非线性关系。为了获得此类非线性反应的生物学相关性，需要确定潜在的防御机制，以允许对低剂量的遗传毒性剂产生耐受性。该交流讨论了推测性的癌症预防机制，这些机制可能会导致从初始DNA损伤到肿瘤形成的每个终点的阈值（即出发点）。我们讨论了癌变过程中的基因组保护的顺序，其中包括遗传毒性清除剂，细胞外排，DNA修复，通过凋亡消除受损细胞，自噬，通过DNA损伤触发的复制衰老来沉默，最后，免疫系统消除转化的（癌变前）细胞被认为是导致肿瘤形成的阈值。我们重点介绍了DNA修复，最近已提供了实验证据来证明其在PoD中的作用。总之，从理论的角度出发，有理由认为对肿瘤形成的每个必要步骤都存在对低剂量水平的耐受性，并且这些耐受性机制对于确定化学致癌的阈值至关重要。