Hepatocarcinogenicity in the male B6C3F1 mouse following a lifetime exposure to dichloroacetic acid in the drinking water:: Dose-response determination and modes of action
Hepatocarcinogenicity in the male B6C3F1 mouse following a lifetime exposure to dichloroacetic acid in the drinking water:: Dose-response determination and modes of action
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DOI：
10.1080/009841099157115
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发表时间：
1999-12-24
影响因子：
2.6
通讯作者：
House, DE
中科院分区：
文献类型：
--
作者：
DeAngelo, AB;George, MH;House, DE
将雄性B6 C3 F（1）小鼠暴露于饮用水中的二氯乙酸（DCA），以建立诱导肝细胞癌的剂量反应，并检查致癌过程的几种作用模式。将各组动物暴露于对照组、0.05、0.5、1、2或3.5 g/L DCA饮用水中90-100 wk。计算的DCA平均日剂量（MDD）为8、84、168、315和429 mg/kg/d。与对照组（26%）相比，1 g/L（71%）、2 g/L（95%）和3.5 g/L（100%）给药组中肝细胞癌（HC）的患病率（动物百分比）显著增加。与对照组（0.28）相比，所有DCA处理（0.05 g/L（0.58）、0.5 g/L（0.68）、1 g/L（1.29）、2 g/L（2.47）和3.5 g/L（2.90））均显着增加HC多样性（肿瘤/动物）。基于HC多重性，无法确定肝致癌性的无明显作用水平（诺埃尔）。肝过氧化物酶体增殖显着增加，只有3.5 g/L的DCA治疗在26周，并没有与肝脏肿瘤的反应。肝毒性的严重程度随着DCA浓度的增加而增加。严重指数和血清乳酸脱氢酶活性证明，低于1 g/L时，肝毒性为轻度且短暂。广义肝细胞增殖分析反映了轻度肝毒性，并证明对增殖性病变外肝细胞标记指数无显著治疗效应。因此，DCA诱导肝癌似乎不依赖于过氧化物酶体诱导或化学持续的细胞增殖。肝毒性，特别是在较高剂量下，可能对致癌过程产生重要影响。
Male B6C3F(1) mice were exposed to dichloroacetic acid (DCA) in the drinking water in order to establish a dose response for the induction of hepatocellular cancer and to examine several modes of action for the carcinogenic process. Groups of animals were exposed to control, 0.05, 0.5, 1, 2, or 3.5 g/L DCA in the drinking water for 90-100 wk. Mean daily doses (MDD) of 8, 84, 168, 315, and 429 mg/kg/d of DCA were calculated. The prevalence (percent of animals) with hepatocellular carcinoma (HC) was significantly increased in the 1-g/L (71%), 2-g/L (95%), and 3.5-g/L (100%) treatment groups when compared to the control (26%). HC multiplicity (tumors/animal) was significantly increased by all DCA treatments-0.05 g/L (0.58), 0.5 g/L (0.68), 1 g/L (1.29), 2 g/L (2.47), and 3.5 g/L (2.90)-compared to the control group (0.28). Based upon HC multiplicity, a no-observed-effect level (NOEL) for hepatocarcinogenicity could not be determined. Hepatic peroxisome proliferation was significantly increased only for 3.5 g/L DCA treatment at 26 wk and did not correlate with the liver tumor response. The severity of hepatotoxicity increased with DCA concentration. Below I g/L, hepatotoxicity was mild and transient as demonstrated by the severity indices and serum lactate dehydrogenase activity. An analysis of generalized hepatocyte proliferation reflected the mild hepatotoxicity and demonstrated no significant treatment effects on the labeling index of hepatocytes outside proliferative lesions. Consequently, the induction of liver cancer by DCA does not appear to be conditional upon peroxisome induction or chemically sustained cell proliferation. Hepatotoxicity, especially at the higher doses, may exert an important influence on the carcinogenic process.