Hepatocarcinogenicity in the Male B6c3f1 Mouse Following a Lifetime Exposure to Dichloroacetic Acid in the Drinking Water: Dose-Response Determination and Modes of Action

Abstract

Male B6C3F, 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 1 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.

Use of mechanism-based structure-activity relationships analysis in carcinogenic potential ranking for drinking water disinfection by-products.

“…Dichloroacetaldehyde has been given a moderate concern because it is a potential cross-linking agent. It can also be readily oxidized to dichloroacetic acid, which has been shown to be a rodent carcinogen with multiple mechanisms of action (43)(44)(45). Dibromonitromethane has been given a moderate concern because the corresponding dichloronitromethane is believed to be the proximate mutagen of chloropicrin (46).…”

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.

“…The question arose whether DCA was promoting the outgrowth of initiated cells already present in the liver because the male B6C3F 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 . More recent data for the female B6C3F 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 1996DeAngelo et al , 1999. There was an increase in the number of CAs for the male B6C3F 1 and C3H mouse, strains with high spontaneous tumor rates, when animals were given 0.5 g/L DCA.…”

“…The carcinogenicity of DCA in the liver of the male and female B6C3F 1 mouse and the F344 male rat has been well demonstrated Daniel et al 1992;DeAngelo et al 1991DeAngelo et al , 1996DeAngelo et al , 1999Herren-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 B6C3F 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 .…”

“…Concentrations ≥ 0.5 g/L resulted in a steeper dose-response curve. At the highest concentrations tested, 3.5-5 g/L DCA, there were no differences between strains or sexes in the CA multiplicity respective of the spontaneous tumor background rate (DeAngelo 2000b;DeAngelo et al , 1999. Although high concentrations (> 2 g/L) of DCA induced gene mutations and chromosomal damage (clastogenesis) in several in vivo and in vitro test systems (DeMarini et al 1994;Fuscoe et al 1995;Harrington-Brock et al 1998;Leavitt et al 1997), the role of genotoxicity in the DCA-induced carcinogenic process in vivo has not been clearly defined (Chang et al 1992;Fox et al 1996;Giller et al 1997;Kopfler et al 1985).…”

“…To begin addressing these questions, the present histopathologic analysis includes classification, quantification, and statistical analysis of hepatic lesions arising in male B6C3F 1 mice receiving DCA at doses as low as 0.05 g/L for 100 weeks and at 0.5, 1.0, 2.0, and 3.5 g/L for between 26 and 100 weeks (DeAngelo et al 1999). As recently recommended (Harada et al 1999), the analysis includes a separation of preneoplastic and benign hepatic lesions into subtypes as well as a grouping of subtypes.…”