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A TWO-YEAR DOSE-RESPONSE STUDY OF LESION SEQUENCES DURING HEPATOCELLULAR CARCINOGENESIS IN THE MALE B6C3F1 MOUSE GIVEN THE DRINKING WATER CHEMICAL DICHLOROACETIC ACID
Citation:
Carter, J. H., H. W. Carter, J. A. Deddens, B. M. Hurst, M H. George, AND A B. DeAngelo. A TWO-YEAR DOSE-RESPONSE STUDY OF LESION SEQUENCES DURING HEPATOCELLULAR CARCINOGENESIS IN THE MALE B6C3F1 MOUSE GIVEN THE DRINKING WATER CHEMICAL DICHLOROACETIC ACID. ENVIRONMENTAL HEALTH PERSPECTIVES 111(1):53-64, (2001).
Description:
ABSTRACT
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. This study determined the dose response of histopathologic changes occurring in the livers of mice exposed to DCA (0.05 g/L ? 3.5 g/L) for 26 to 100 weeks. Lesions were classified as foci of cellular alteration smaller than 1 liver lobule (altered hepatic foci, AHF), foci of cellular alteration larger than 1 liver lobule (large foci of cellular alteration, LCFA), adenoinas (AD), or
carcinomas (CA). Histopathologic analysis of 598 premalignant lesions revealed: 1) that each lesion class had a predominant phenotype; 2) that AHF, LFCA and AD demonstrated neoplastic progression with time; and 3) that 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 B6C3F1 mouse liver has been proposed that will enable development of a biologically based mathematical model for DCA. Since all classes of premalignant lesions and CA were found at both lower and higher doses, these data are consistent with the conclusion that non-genotoxic mechanisms, such as negative selection, are relevant to DCA carcinogenesis at lower doses where DCA genotoxicity has not been observed.