A 2-Year Dose-Response Study of Lesion Sequences during Hepatocellular Carcinogenesis in the Male B6C3[F.Sub.1] Mouse Given the Drinking Water Chemical Dichloroacetic Acid. (Research)

Article excerpt

Dichloroacetic acid (DCA) is carcinogenic to the B6C3[F.sub.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 noninvolved liver were related to this neoplastic progression. A lesion sequence for carcinogenesis in male B6C3[F.sub.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. Key words: B6C3[F.sub.1] mice, dichloracetic acid, drinking water disinfection by-products, hepatocarcinogenicity, histopathology, liver toxicity. Environ Health Perspect 111:53-64 (2003). [Online 2 December 2002] doi:10.1289/ehp.5442 available via http://dx.doi.org/


The reauthorization of the Safe Drinking Water Act of 1996 requires the U.S. Environmental Protection Agency (EPA) to develop a priority list of chemicals present in drinking water and to conduct research into the modes and mechanisms of action by which they produce adverse effects (Safe Drinking Water Act Amendments of 1996). Disinfection by-products are included in the priority list. The haloacetic acids, along with the trihalomethanes and haloacetonitriles, are the disinfection by-products found at the highest concentrations in drinking water after chlorine disinfection of surface waters (Krasner et al. 1989). Dichloroacetic acid (DCA) may occur in drinking water at concentrations > 100 [micro]g/L (Uden and Miller 1983) and has median concentrations in the 15-19 [micro]g/L range (Fair 1996; Krasner at al. 1989).

The carcinogenicity of DCA in the liver of the male and female B6C3[F.sub.1] mouse and the F344 male rat has been well demonstrated (Bull et al. 1990; Daniel et al. 1992; DeAngelo et al. 1991, 1996, 1999; Herren-Freund et al. 1987; Pereira 1996). The question arose whether DCA was promoting the outgrowth of initiated cells already present in the liver because the male B6C3[F.sub.1] mouse has a high rate of spontaneous liver tumor formation, and prior initiation with a genotoxic carcinogen was not required for DCA-induced liver tumor formation (DeAngelo et al. 1991). More recent data for the female B6C3[F.sub.1] mouse and for the C3H and C57BL parental strains revealed a biphasic dose-response curve for the number of carcinomas (CAs) per liver (DeAngelo 2000b; DeAngelo et al. 1996, 1999, unpublished oberservations). There was an increase in the number of CAs for the male B6C3[F.sub.1] and C3H mouse, strains with high spontaneous tumor rates, when animals were given 0.5 g/L DCA. In contrast, no increase in the number of CAS was seen at 0.5 g/L in animals with a low-background spontaneous CA rate (male C57BL mouse and female B6C3[F. …