Hengstler J G, Bogdanffy M S, Bolt H M, Oesch F
Institute of Toxicology, University of Mainz, D-55131 Mainz, Germany.
Annu Rev Pharmacol Toxicol. 2003;43:485-520. doi: 10.1146/annurev.pharmtox.43.100901.140219. Epub 2002 Jan 10.
Although many questions remain unanswered, the general principle of the sequence of events leading to cancer after exposure to genotoxic carcinogens has become increasingly clear. This helps to understand the parameters that influence the shape of the dose-effect curve for carcinogenesis, including metabolic activation and inactivation of carcinogens, DNA repair, cell cycle control, apoptosis, and control by the immune system. A linear dose-response relationship with no observable threshold seems to be a conservative but adequate description for the carcinogenic activity of many genotoxic carcinogens, such as aflatoxin B1, the tobacco-specific nitrosoketone NNK, and probably N,N-diethylnitrosamine. However, extrapolation models connecting the high-level risk to the zero intercept have clearly resulted in overestimations of risk. Vinyl acetate is an example that is discussed extensively in this review. At extremely high and toxic doses, vinyl acetate is carcinogenic in rats and mice and causes chromosomal aberrations. In tissues of contact, vinyl acetate is converted to acetic acid and acetaldehyde. Only when threshold levels are achieved do critical steps in the mechanism ultimately leading to cancer become active, namely pH reduction in exposed cells of more than 0.15 units leading to cytotoxicity, damage to DNA, and regenerative proliferation. Consistent with the known exposure to endogenous acetic acid and acetaldehyde, tissues sustain a certain level of exposure without adverse effects. Physiological modeling shows that the conditions necessary for carcinogenesis are in place only when threshold levels of vinyl acetate are exceeded. The example of vinyl acetate underlines the importance of toxicological research that unequivocally identifies genotoxic carcinogens acting through a threshold process.
尽管许多问题仍未得到解答，但接触遗传毒性致癌物后导致癌症的一系列事件的一般原则已越来越清晰。这有助于理解影响致癌作用剂量-效应曲线形状的参数，包括致癌物的代谢活化和失活、DNA修复、细胞周期控制、细胞凋亡以及免疫系统的调控。对于许多遗传毒性致癌物，如黄曲霉毒素B1、烟草特有的亚硝基酮NNK以及可能的N,N-二乙基亚硝胺，无明显阈值的线性剂量-反应关系似乎是一种保守但充分的致癌活性描述。然而，将高剂量风险外推至零截距的模型显然导致了风险的高估。醋酸乙烯酯就是本综述中广泛讨论的一个例子。在极高的毒性剂量下，醋酸乙烯酯在大鼠和小鼠中具有致癌性并导致染色体畸变。在接触组织中，醋酸乙烯酯会转化为乙酸和乙醛。只有当达到阈值水平时，最终导致癌症的机制中的关键步骤才会激活，即暴露细胞的pH值降低超过0.15个单位，从而导致细胞毒性、DNA损伤和再生性增殖。与已知的内源性乙酸和乙醛暴露情况一致，组织在一定水平的暴露下不会产生不良影响。生理模型表明，只有当醋酸乙烯酯超过阈值水平时，致癌所需的条件才会具备。醋酸乙烯酯的例子强调了毒理学研究的重要性，该研究能明确识别通过阈值过程起作用的遗传毒性致癌物。
