Lai David Y
Office of Pollution Prevention and Toxics, Risk Assessment Division, US Environmental Protection Agency, Washington, DC 20460, USA.
J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2004 May;22(1):37-55. doi: 10.1081/GNC-120038005.
A variety of substances such as hypolipidemic drugs, phthalate ester plasticizers, pesticides, and industrial solvents have been shown to increase the size and number of peroxisomes in rats and mice. They are grouped under the generic term peroxisome proliferators (PP) because of their unique property of inducing peroxisome proliferation. There are marked species differences in response to PP. Rats and mice are most sensitive, and hamsters show an intermediate response while guinea pigs, monkeys, and humans appear to be relatively insensitive or non-responsive at dose levels that produce a marked response in rodents. Out of over 100 PP identified to date, about 30 have been adequately tested and shown to be carcinogenic, inducing tumors (primarily in the liver) upon chronic administration to rats and/or mice; hence, chemicals which induce the proliferations of peroxisomes have formed a unique class of chemical carcinogens. It is not well documented that activation of the "peroxisome proliferator-activated receptor alpha" (PPARalpha) is involved in PP-induced liver growth and carcinogenesis in rodents. PPARalpha is also present in human cells; however, the levels reported are about 10% of those found in the liver of rodents. The human relevance of rodent tumors induced by PP has been the subject of debate over the last decade. Review of the existing evidence on PPAR-alpha agonists by a recent International Life Science Institute (ILSI) workgroup following a human relevance mode of action (MOA) framework has concluded that despite the presence of similar pathways in humans, it is unlikely that the proposed MOA for rodent tumors is plausible in humans, taking into account kinetic and dynamic factors. The data, however, did not permit a definitive conclusion that the animal MOA is not plausible in humans. While these agents appear unlikely to be hepatocarcinogens in humans at expected levels of human exposure, it remains uncertain to some experts in the field whether there is no possibility of carcinogenic potential under any circumstances of PP exposure, and if the potential human carcinogenicity of these chemicals can be summarily ignored. A number of remaining issues on human relevance of rodent tumors induced by PP are discussed.
多种物质，如降血脂药物、邻苯二甲酸酯类增塑剂、农药和工业溶剂，已被证明可增加大鼠和小鼠过氧化物酶体的大小和数量。由于它们具有诱导过氧化物酶体增殖的独特特性，它们被归为过氧化物酶体增殖剂（PP）这一通用术语之下。对PP的反应存在明显的物种差异。大鼠和小鼠最为敏感，仓鼠表现出中等反应，而豚鼠、猴子和人类在对啮齿动物产生明显反应的剂量水平下似乎相对不敏感或无反应。在迄今确定的100多种PP中，约30种已得到充分测试，并显示具有致癌性，长期给大鼠和/或小鼠施用后会诱发肿瘤（主要在肝脏）；因此，诱导过氧化物酶体增殖的化学物质形成了一类独特的化学致癌物。“过氧化物酶体增殖物激活受体α”（PPARα）的激活是否参与PP诱导的啮齿动物肝脏生长和致癌作用，目前尚无充分文献记载。PPARα也存在于人类细胞中；然而，报告的水平约为啮齿动物肝脏中发现水平的10%。在过去十年中，PP诱导的啮齿动物肿瘤与人类的相关性一直是争论的主题。最近一个国际生命科学研究所（ILSI）工作组按照人类相关性作用模式（MOA）框架对PPAR-α激动剂的现有证据进行审查后得出结论，尽管人类中存在类似途径，但考虑到动力学和动态因素，啮齿动物肿瘤的拟议MOA在人类中不太可能合理。然而，这些数据并不能得出动物MOA在人类中不合理的明确结论。虽然在预期的人类接触水平下，这些物质似乎不太可能成为人类肝癌致癌物，但该领域的一些专家仍然不确定，在任何PP接触情况下是否都没有致癌潜力，以及这些化学物质对人类的潜在致癌性是否可以一概忽略。本文讨论了关于PP诱导的啮齿动物肿瘤与人类相关性的一些遗留问题。
