Liteplo R G, Long G W, Meek M E
Health Canada, Environmental Health Centre, Ottawa, Ontario, Canada.
Hum Exp Toxicol. 1998 Feb;17(2):84-7. doi: 10.1177/096032719801700202.
Considerable research has been conducted to identify possible mechanisms of the carcinogenicity of methylene chloride in rodents, and to ascertain whether the observed increased incidences of liver and lung tumours in mice exposed to this substance, are relevant in assessing the potential hazards and risks to human health. On the basis of a study that purported to show qualitative differences between murine and human tissues, in the subcellular localization of the Theta-class glutathione S-transferase enzyme responsible for converting methylene chloride to a putative highly unstable, but reactive genotoxic metabolite, it was suggested that the mouse is an inappropriate model for human health risk assessment. However, other studies conducted in vitro with intact cells do not support the hypothesis that a putatively reactive metabolite of methylene chloride must be generated only within the nucleus in order to be able to interact with genomic DNA. Moreover, investigations employing semi-quantitative methods of mRNA hybridization are not convincing in identifying the subcellular localization of active Theta class glutathione S-transferase, and do not support the hypothesis of the differential subcellular localization of this enzyme within the nucleus of mouse, but not human cells. There is therefore, insufficient evidence to support the view that qualitative differences between humans and mice in the subcellular distribution of Theta-class glutathione S-transferase, renders carcinogenicity studies conducted with mice irrelevant in human hazard identification and risk assessment.
已经开展了大量研究，以确定二氯甲烷在啮齿动物中的致癌机制，并确定在接触该物质的小鼠中观察到的肝脏和肺部肿瘤发病率增加，是否与评估对人类健康的潜在危害和风险相关。基于一项声称显示小鼠和人类组织在负责将二氯甲烷转化为一种假定的高度不稳定但具有反应性的遗传毒性代谢物的θ类谷胱甘肽S-转移酶的亚细胞定位上存在质的差异的研究，有人认为小鼠不是评估人类健康风险的合适模型。然而，其他用完整细胞进行的体外研究并不支持这样的假设，即二氯甲烷的一种假定的反应性代谢物必须仅在细胞核内产生才能与基因组DNA相互作用。此外，采用mRNA杂交半定量方法的研究在确定活性θ类谷胱甘肽S-转移酶的亚细胞定位方面并不令人信服，也不支持该酶在小鼠细胞核而非人类细胞核内存在亚细胞定位差异的假设。因此，没有足够的证据支持这样的观点，即人类和小鼠在θ类谷胱甘肽S-转移酶的亚细胞分布上的质的差异，使得用小鼠进行的致癌性研究与人类危害识别和风险评估无关。
