Department of Environmental and Occupational Health, Indiana University School of Public Health, Bloomington, IN, USA.
Department of Pathology, Microbiology, and Immunology and the Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
Crit Rev Toxicol. 2024 Oct;54(9):634-658. doi: 10.1080/10408444.2024.2377208. Epub 2024 Jul 30.
Dieldrin is an organochlorine insecticide that was widely used until 1970 when its use was banned because of its liver carcinogenicity in mice. Several long-term rodent bioassays have reported dieldrin to induce liver tumors in in several strains of mice, but not in rats. This article reviews the available information on dieldrin liver effects and performs an analysis of mode of action (MOA) and human relevance of these liver findings. Scientific evidence strongly supports a MOA based on CAR activation, leading to alterations in gene expression, which result in increased hepatocellular proliferation, clonal expansion leading to altered hepatic foci, and ultimately the formation of hepatocellular adenomas and carcinomas. Associative events include increased liver weight, centrilobular hypertrophy, increased expression of Cyp2b10 and its resulting increased enzymatic activity. Other associative events include alterations of intercellular gap junction communication and oxidative stress. Alternative MOAs are evaluated and shown not to be related to dieldrin administration. Weight of evidence shows that dieldrin is not DNA reactive, it is not mutagenic, and it is not genotoxic in general. Furthermore, activation of other pertinent nuclear receptors, including PXR, PPARα, AhR, and estrogen are not related to dieldrin-induced liver tumors nor is there liver cytotoxicity. In previous studies, rats, dogs, and non-human primates did not show increased cell proliferation or production of pre-neoplastic or neoplastic lesions following dieldrin treatment. Thus, the evidence strongly indicates that dieldrin-induced mouse liver tumors are due to CAR activation and are specific to the mouse, which are qualitatively not relevant to human hepatocarcinogenesis. Thus, there is no carcinogenic risk to humans. This conclusion is also supported by a lack of positive epidemiologic findings for evidence of liver carcinogenicity. Based on current understanding of the mode of action of dieldrin-induced liver tumors in mice, the appropriate conclusion is that dieldrin is a mouse specific liver carcinogen and it does not pose a cancer risk to humans.
狄氏剂是一种有机氯杀虫剂，曾被广泛使用，直到 1970 年因其在小鼠体内的肝致癌性而被禁用。几项长期啮齿动物生物测定报告称，狄氏剂可诱导几种小鼠品系的肝脏肿瘤，但不能诱导大鼠产生肝脏肿瘤。本文综述了有关狄氏剂肝脏效应的现有信息，并对这些肝脏发现的作用机制（MOA）和与人类的相关性进行了分析。科学证据强烈支持基于 CAR 激活的 MOA，导致基因表达改变，从而导致肝细胞增殖增加、克隆扩展导致肝灶改变，最终形成肝细胞腺瘤和癌。相关事件包括肝重增加、中央小叶肥大、Cyp2b10 表达增加及其导致的酶活性增加。其他相关事件包括细胞间缝隙连接通讯和氧化应激的改变。替代的 MOA 也进行了评估，表明与狄氏剂给药无关。证据表明，狄氏剂不具有 DNA 反应活性、致突变性和一般遗传毒性。此外，其他相关核受体（包括 PXR、PPARα、AhR 和雌激素）的激活与狄氏剂诱导的肝脏肿瘤无关，也没有肝脏细胞毒性。在以前的研究中，大鼠、狗和非人类灵长类动物在接受狄氏剂治疗后没有显示出细胞增殖增加或前肿瘤或肿瘤病变的产生。因此，证据强烈表明，狄氏剂诱导的小鼠肝脏肿瘤是由于 CAR 激活引起的，并且仅在小鼠中发生，与人类肝癌发生在质上不相关。因此，对人类没有致癌风险。这一结论也得到了缺乏阳性流行病学证据表明肝脏致癌性的支持。基于对狄氏剂诱导的小鼠肝脏肿瘤作用机制的当前理解，适当的结论是，狄氏剂是一种特定于小鼠的肝脏致癌物，不会对人类构成癌症风险。
