Green T
Zeneca Central Toxicology Laboratory, Macclesfield, Cheshire, UK.
Hum Exp Toxicol. 1997 Jan;16(1):3-13. doi: 10.1177/0960327197016001021.
B6C3F1 mice exposed to high dose levels of methylene chloride by inhalation for 2 years had an elevated incidence of liver and lung tumours. These tumours were not increased in rats or hamsters exposed under the same or similar conditions. This paper gives an overview of research conducted over the last 10 years into the mechanism of action of methylene chloride as a mouse carcinogen and into the relevance of the mouse data to humans exposed to this chemical. Data are presented on the comparative metabolism and pharmacokinetics of methylene chloride in mice, rats, hamsters and humans, on the toxicity of methylene chloride to the target organs in the mouse, and on the genotoxicity of methylene chloride in vitro and in vivo. The enzyme which activates methylene chloride to its carcinogenic form has been isolated, sequenced, and cloned, and its distribution studied within cells, organs and between species. Evidence has been obtained to show the methylene chloride caused cancer in mice as a result of interactions between metabolites of the glutathione S-transferase pathway and DNA. Damage to mouse lung Clara cells and increased cell division are believed to have influenced the development of the lung tumours. The species specificity was a direct consequence of the very high activity and specific cellular and nuclear localisation of a theta class glutathione S-transferase enzyme which was unique to the mouse. Consequently, DNA damage was not detectable in rats in vivo, or in hamster and human hepatocytes exposed to cytotoxic dose levels of methylene chloride in vitro. These results provide evidence that the mouse is unique in its response to methylene chloride and that it is an inappropriate model for human health assessment.
通过吸入高剂量二氯甲烷暴露2年的B6C3F1小鼠，肝脏和肺部肿瘤的发生率有所升高。在相同或相似条件下暴露的大鼠或仓鼠中，这些肿瘤并未增加。本文概述了过去10年中对二氯甲烷作为小鼠致癌物的作用机制以及小鼠数据与接触该化学物质的人类的相关性的研究。文中呈现了二氯甲烷在小鼠、大鼠、仓鼠和人类体内的比较代谢和药代动力学数据、二氯甲烷对小鼠靶器官的毒性以及二氯甲烷在体外和体内的遗传毒性数据。激活二氯甲烷成为其致癌形式的酶已被分离、测序和克隆，并对其在细胞、器官内以及物种间的分布进行了研究。已获得证据表明，二氯甲烷在小鼠体内致癌是由于谷胱甘肽S -转移酶途径的代谢物与DNA之间的相互作用。对小鼠肺克拉拉细胞的损伤和细胞分裂增加被认为影响了肺部肿瘤的发展。物种特异性是小鼠特有的θ类谷胱甘肽S -转移酶具有非常高的活性以及特定的细胞和细胞核定位的直接结果。因此，在体内大鼠中或在体外暴露于细胞毒性剂量二氯甲烷的仓鼠和人类肝细胞中均未检测到DNA损伤。这些结果提供了证据，表明小鼠对二氯甲烷的反应具有独特性，并且它不是用于人类健康评估的合适模型。
