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.

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. 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.

Toxicity and carcinogenicity of the water disinfection byproduct, dibromoacetic acid, in rats and mice

“…The mechanism(s) of neoplasm induction by DBA or the related compound, DCA, are not known. For DCA, Carter et al (2003) suggested that the induction of liver tumors in mice is due to selective growth of a phenotypic cell-type that does not respond to mitoinhibitory homeostatic control mechanisms. Neither hepatocellular necrosis nor regenerative hyperplasia was associated with the development of preneoplastic lesions or liver tumors in DCA-treated or DBA-treated mice.…”

Helicobacter hepaticus–Induced Liver Tumor Promotion Is Associated with Increased Serum Bile Acid and a Persistent Microbial-Induced Immune Response

“…Histopathological evaluation was performed by a board-certified veterinary pathologist blinded to the identity of the samples. Liver sections were scored as previously described with minor modifications (14, 15). Briefly, hepatic lobular, portal and interface inflammation was graded on a scale of 0-4 and the number of lobes with ≥ 5 inflammatory foci was enumerated.…”

Physiologically based pharmacokinetic modeling of dibromoacetic acid in F344 rats

“…Comparing these internal dose predictions with tumor incidence data from rodent assays (Carter et al, 2003; Melnick et al, 2007; NTP, 2007; NTP, 2009), would allow stronger conclusions about the dose-response for the carcinogenicity of these chemicals. Possible hypotheses that can be examined are: 1) inactivation of GSTzeta by DHA may increase the concentrations of DHAs in the liver thus contributing to the liver alterations induced by DHAs; 2) inactivation of GSTzeta by DHA may disrupt the tyrosine catabolism pathway resulting in toxicity endpoints (Ammini et al, 2003; Cornett et al, 1999; Lantum et al, 2002); and 3) increased GXA or OXA concentrations in the liver as a result of DHA metabolism might impact a liver tumor response.…”