Melnick R L, Kohn M C, Portier C J
Laboratory of Quantitative and Computational Biology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Environ Health Perspect. 1996 Mar;104 Suppl 1(Suppl 1):123-34. doi: 10.1289/ehp.96104s1123.
Nongenotoxic carcinogens are chemicals that induce neoplasia without it or its metabolites reacting directly with DNA. Chemicals classified as nongenotoxic carcinogens have been assumed to act as tumor promoters and exhibit threshold tumor dose-responses. This is in contrast to genotoxic carcinogens that are DNA reactive, act as tumor initiators, and are assumed to exhibit proportional responses at low doses. In this perspective, we examine the basic tenets and utility of this classification for evaluating human cancer risk. Two classes of so-called nongenotoxic chemical carcinogens selected for review include cytotoxic agents that induce regenerative hyperplasia (trihalomethanes and inducers of alpha 2-microglobulin nephropathy) and agents that act via receptor-mediated mechanisms (peroxisome proliferators and dioxin). Major conclusions of this review include: a) many chemicals considered to be nongenotoxic carcinogens actually possess certain genotoxic activities, and limiting evaluations of carcinogenicity to their nongenotoxic effects can be misleading; b) some nongenotoxic activities may cause oxidative DNA damage and thereby initiate carcinogenesis; c) although cell replication is involved in tumor development, cytotoxicity and mitogenesis do not reliably predict carcinogenesis; d) a threshold tumor response is not an inevitable result of a receptor-mediated mechanism. There are insufficient data on the chemicals reviewed here to justify treating their carcinogenic effects in animals as irrelevant for evaluating human risk. Research findings that characterize the multiple mechanisms of chemical carcinogenesis should be used quantitatively to clarify human dose-response relationships, leading to improved scientifically based public health decisions. Excessive reliance on oversimplified classification schemes that do not consider all potential contributing effects of a toxicant can obscure the actual causal relationships between exposure and cancer outcome.
非遗传毒性致癌物是指那些诱导肿瘤形成，但本身或其代谢产物不直接与DNA发生反应的化学物质。被归类为非遗传毒性致癌物的化学物质被认为是肿瘤促进剂，并表现出阈值肿瘤剂量反应。这与遗传毒性致癌物形成对比，遗传毒性致癌物具有DNA反应性，作为肿瘤启动剂，并且被认为在低剂量下表现出成比例的反应。从这个角度出发，我们研究了这种分类在评估人类癌症风险方面的基本原理和实用性。选择进行综述的两类所谓非遗传毒性化学致癌物包括诱导再生性增生的细胞毒性剂（三卤甲烷和α2-微球蛋白肾病诱导剂）以及通过受体介导机制起作用的物质（过氧化物酶体增殖剂和二噁英）。本综述的主要结论包括：a）许多被认为是非遗传毒性致癌物的化学物质实际上具有一定的遗传毒性活性，将致癌性评估仅限于其非遗传毒性作用可能会产生误导；b）一些非遗传毒性活性可能导致氧化性DNA损伤，从而引发致癌作用；c）虽然细胞复制参与肿瘤发展，但细胞毒性和有丝分裂不能可靠地预测致癌作用；d）阈值肿瘤反应并非受体介导机制的必然结果。关于此处综述的化学物质，现有数据不足以证明将其在动物中的致癌作用视为与评估人类风险无关。应定量使用表征化学致癌多种机制的研究结果，以阐明人类剂量反应关系，从而做出更科学合理的公共卫生决策。过度依赖不考虑毒物所有潜在作用的过于简化的分类方案，可能会掩盖暴露与癌症结局之间的实际因果关系。
