A 2-year dose-response study of lesion sequences during hepatocellular carcinogenesis in the male B6C3F(1) mouse given the drinking water chemical dichloroacetic acid.
A 2-year dose-response study of lesion sequences during hepatocellular carcinogenesis in the male B6C3F(1) mouse given the drinking water chemical dichloroacetic acid.
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DOI：
10.1289/ehp.5442
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发表时间：
2003-01
影响因子：
10.4
通讯作者：
DeAngelo, Anthony B
中科院分区：
文献类型：
--
作者：
Carter, Julia H;Carter, Harry W;Deddens, James A;Hurst, Bernadette M;George, Michael H;DeAngelo, Anthony B
二氯乙酸（DCA）对B6C3F(1)小鼠和F344大鼠具有致癌性。鉴于DCA在啮齿动物肝脏中的致癌潜力以及饮用水中该化合物的已知浓度，需要可靠的基于生物学的模型来减少人类暴露于DCA的风险评估的不确定性。这种模型的发展需要识别和量化癌前肝病变，确定这些病变发生的剂量，并确定这些病变发展为癌症的可能性。在这项研究中，我们测定了暴露于DCA (0.05-3.5 g/L) 26-100周的小鼠肝脏发生的组织病理学变化的剂量反应。病变分为小于一个肝小叶的细胞改变灶（肝灶改变；AHF）、大于一个肝小叶的细胞改变灶（大细胞改变灶；LFCA）、腺瘤（ADs）或癌（CAs）。598例癌前病变的组织病理学分析显示：(a)每一类病变都有一个显性表型；(b)随着时间的推移，AHF、LFCA和AD表现出肿瘤进展；(c)独立于DCA剂量和暴露时间的影响，非受累肝脏的一些毒性/适应性变化与这种肿瘤进展有关。已经提出了雄性B6C3F(1)小鼠肝脏癌变的病变序列，这将使DCA的生物学基础数学模型的发展成为可能。由于在低剂量和高剂量下均发现了所有类型的癌前病变和ca，因此这些数据与结论一致，即在未观察到DCA遗传毒性的低剂量下，非遗传毒性机制（如负选择）与DCA致癌有关。
Dichloroacetic acid (DCA) is carcinogenic to the B6C3F(1) mouse and the F344 rat. Given the carcinogenic potential of DCA in rodent liver and the known concentrations of this compound in drinking water, reliable biologically based models to reduce the uncertainty of risk assessment for human exposure to DCA are needed. Development of such models requires identification and quantification of premalignant hepatic lesions, identification of the doses at which these lesions occur, and determination of the likelihood that these lesions will progress to cancer. In this study we determined the dose response of histopathologic changes occurring in the livers of mice exposed to DCA (0.05-3.5 g/L) for 26-100 weeks. Lesions were classified as foci of cellular alteration smaller than one liver lobule (altered hepatic foci; AHF), foci of cellular alteration larger than one liver lobule (large foci of cellular alteration; LFCA), adenomas (ADs), or carcinomas (CAs). Histopathologic analysis of 598 premalignant lesions revealed that (a)) each lesion class had a predominant phenotype; (b)) AHF, LFCA, and AD demonstrated neoplastic progression with time; and (c)) independent of DCA dose and length of exposure effects, some toxic/adaptive changes in non-involved liver were related to this neoplastic progression. A lesion sequence for carcinogenesis in male B6C3F(1) mouse liver has been proposed that will enable development of a biologically based mathematical model for DCA. Because all classes of premalignant lesions and CAs were found at both lower and higher doses, these data are consistent with the conclusion that nongenotoxic mechanisms, such as negative selection, are relevant to DCA carcinogenesis at lower doses where DCA genotoxicity has not been observed.