Melnick R L, Kohn M C, Dunnick J K, Leininger J R
Environmental Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Toxicol Appl Pharmacol. 1998 Jan;148(1):137-47. doi: 10.1006/taap.1997.8302.
Chloroform (TCM), a water disinfection by-product, induced liver tumors in female mice when administered by gavage in corn oil but not when given in drinking water at comparable daily doses. Because short-term studies showed that the gavage doses also induced liver toxicity, it has been suggested that the liver tumor response occurs secondary to cytotoxicity and consequent regenerative hyperplasia induced by oxidative metabolism of TCM to the toxic dihalocarbonyl intermediate. This study compares dose-response relationships of gavage-administered chlorinated/brominated trihalomethanes for hepatotoxicity, replicative DNA synthesis, and hepatocarcinogenicity in female B6C3F1 mice. The liver tumor data were obtained from previously published studies. Because bromine is a better leaving group than chlorine, metabolism of bromodichloromethane (BDCM) should produce the same intermediates as would be formed from TCM. Hence, the toxicity and carcinogenicity of BDCM was expected to be qualitatively similar to that of TCM. Dose responses for liver weight, serum sorbitol dehydrogenase and alanine aminotransferase (ALT) activities, hepatocyte degeneration, and hepatocyte labeling index (LI, a measure of replicative DNA synthesis) in female mice were similar following 3 weeks of gavage administration (once per day, 5 days per week) with TCM, BDCM, or chlorodibromomethane (CDBM). Fits of composite data for these trihalomethanes to a Hill equation model revealed sigmoidal dose responses for ALT activity and hepatocyte LI and a nearly linear low-dose response for liver tumor incidence. For this family of chemicals, the mouse liver tumor response was not associated with an elevated hepatocyte LI at doses of approximately 1 mmol/kg or less. High incidences of liver tumors were observed with BDCM and CDBM at doses that had a marginal effect or no effect on the hepatocyte LI. Thus, the carcinogenic effects of trihalomethanes are not simply a consequence of cytotoxicity and regenerative hyperplasia. The possible contributions from other activation pathways, including GSH conjugation and reductive metabolism, need to be considered in assessments of the carcinogenicity of the trihalomethanes.
氯仿（TCM）是一种水消毒副产物，当以玉米油灌胃方式给予雌性小鼠时可诱发肝肿瘤，但以相当的日剂量给予饮用水时则不会。由于短期研究表明灌胃剂量也会诱发肝脏毒性，因此有人提出肝脏肿瘤反应是由TCM氧化代谢为有毒二卤代羰基中间体所诱导的细胞毒性及随后的再生性增生继发产生的。本研究比较了灌胃给予氯化/溴化三卤甲烷对雌性B6C3F1小鼠肝毒性、复制性DNA合成和肝癌发生的剂量-反应关系。肝脏肿瘤数据来自先前发表的研究。由于溴是比氯更好的离去基团，溴二氯甲烷（BDCM）的代谢应产生与TCM形成的相同中间体。因此，预计BDCM的毒性和致癌性在性质上与TCM相似。在以TCM、BDCM或氯二溴甲烷（CDBM）进行3周灌胃给药（每天一次，每周5天）后，雌性小鼠的肝脏重量、血清山梨醇脱氢酶和丙氨酸转氨酶（ALT）活性、肝细胞变性以及肝细胞标记指数（LI，复制性DNA合成的一种度量）的剂量反应相似。这些三卤甲烷的综合数据拟合到希尔方程模型显示，ALT活性和肝细胞LI呈S形剂量反应，而肝脏肿瘤发生率呈近似线性的低剂量反应。对于这一类化学物质，在剂量约为1 mmol/kg或更低时，小鼠肝脏肿瘤反应与肝细胞LI升高无关。在对肝细胞LI有轻微影响或无影响的剂量下，观察到BDCM和CDBM有高发生率的肝脏肿瘤。因此，三卤甲烷的致癌作用并非仅仅是细胞毒性和再生性增生的结果。在评估三卤甲烷的致癌性时，需要考虑其他活化途径（包括谷胱甘肽结合和还原代谢）可能做出的贡献。
