National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
Mutat Res. 2009 Sep-Dec;682(2-3):94-109. doi: 10.1016/j.mrrev.2009.07.002. Epub 2009 Jul 22.
It is well established that cancer is a multi-step process which involves initiation, promotion and progression. Chemical carcinogens can alter any of these processes to induce their carcinogenic effects. The presence of multiple mutations in critical genes is a distinctive feature of cancer cells and supports the contention that cancer arises through the accumulation of irreversible DNA damage. In the majority of instances, chemical carcinogens, directly or after xenobiotic metabolism, induce DNA damage and act in a 'genotoxic' manner. There is, however, a group of carcinogens that induce cancer via non-genotoxic mechanisms. Non-genotoxic carcinogens have been shown to act as tumor promoters (1,4-dichlorobenzene), endocrine-modifiers (17beta-estradiol), receptor-mediators (2,3,7,8-tetrachlorodibenzo-p-dioxin), immunosuppressants (cyclosporine) or inducers of tissue-specific toxicity and inflammatory responses (metals such as arsenic and beryllium). The diversity of modes of action of non-genotoxic carcinogens, the tissue and species specificity, and the absence of genotoxicity makes predicting their carcinogenic potential extremely challenging. In order to better understand the mechanisms of known human non-genotoxic carcinogens and to illustrate the importance of a weight of evidence approach when evaluating their carcinogenic potential, we will (1) evaluate the proportion of non-genotoxic carcinogens among known, probable and possible human carcinogens classified by the International Agency for Research on Cancer (IARC), (2) estimate the risk of exposure of human non-genotoxic carcinogens through margin of exposure (MOE) evaluation, and (3) discuss potential alternative methods for their detection. Our analysis demonstrated that human non-genotoxic carcinogens were present in 12% (45/371) of IARC's Groups 1, 2A and 2B carcinogens and that a potential hazard was associated with 27% (12/45) of them. Consequently, it is suggested that for all genotoxic chemicals, the mode of action is investigated for hazard and risk evaluation. Further, if negative genotoxic compounds have putative non-genotoxic modes of action, appropriate risk measures should be implemented.
已经证实，癌症是一个多步骤的过程，涉及起始、促进和进展。化学致癌物可以改变这些过程中的任何一个来诱导其致癌作用。关键基因的多个突变的存在是癌细胞的一个显著特征，并支持这样一种观点，即癌症是通过不可逆转的 DNA 损伤的积累而产生的。在大多数情况下，化学致癌物，直接或经过外源性代谢后，诱导 DNA 损伤，并以“遗传毒性”的方式起作用。然而，有一组致癌物通过非遗传毒性机制诱导癌症。已经表明，非遗传毒性致癌物可以作为肿瘤促进剂（1,4-二氯苯）、内分泌调节剂（17β-雌二醇）、受体介导剂（2,3,7,8-四氯二苯并-p-二恶英）、免疫抑制剂（环孢菌素）或诱导组织特异性毒性和炎症反应的物质（如砷和铍等金属）。非遗传毒性致癌物作用方式的多样性、组织和物种特异性以及缺乏遗传毒性使得预测其致癌潜力极具挑战性。为了更好地了解已知人类非遗传毒性致癌物的机制，并说明在评估其致癌潜力时采用证据权重方法的重要性，我们将：(1) 评估国际癌症研究机构 (IARC) 分类的已知、可能和可能的人类致癌物中非遗传毒性致癌物的比例；(2) 通过暴露边际评估 (MOE) 评估人类非遗传毒性致癌物的暴露风险；(3) 讨论用于检测它们的潜在替代方法。我们的分析表明，人类非遗传毒性致癌物存在于 IARC 第 1、2A 和 2B 组的 12%（45/371）致癌物中，其中 27%（12/45）可能与潜在危害有关。因此，建议对所有遗传毒性化学物质，都应调查其作用模式以进行危害和风险评估。此外，如果具有潜在非遗传毒性作用模式的阴性遗传毒性化合物，应采取适当的风险措施。
