Evaluation of dichloroacetic acid for carcinogenicity in genetically modified Tg.AC hemizygous and p53 haploinsufficient mice

Abstract

There has been considerable interest in the use of genetically modified mice for detecting potential environmental carcinogens. For this reason, the National Toxicology Program has been evaluating Tg.AC hemizygous and p53 haploinsufficient mice as models to detect potential carcinogens. It was reasoned that these mouse models might also prove more effective than standard rodent models in evaluating the numerous disinfection byproducts that are found in low concentrations in drinking water. Dichloroacetic acid (DCA) is one of the most frequently found disinfection byproducts and DCA has been consistently shown to cause hepatocellular tumors in rats and mice in standard rodent studies. Tg.AC hemizygous and p53 haploinsufficient mice were exposed in the drinking water to DCA for up to 41 weeks. In a second study Tg.AC mice were subjected to dermal DCA exposure for up to 39 weeks. Increased incidences and severity of cytoplasmic vacuolization of hepatocytes were seen in the p53 mice, but there was no evidence of carcinogenic activity at exposures of up to 2000 mg/l in the drinking water. Increased incidences and severity of cytoplasmic vacuolization of hepatocytes were seen in the drinking water study with Tg.AC mice and a modest non-dose-related increase in pulmonary adenomas was observed in males exposed to 1000 mg/l in the drinking water. Dermal exposure up to 500 mg/kg for 39 weeks resulted in increased dermal papillomas at the site of application in Tg.AC mice. No significant increase in papillomas under the same study conditions was seen in the 26-week study. For DCA under these study conditions, the p53 and Tg.AC mice appear less sensitive to hepatocarcinogenesis than standard rodent models. These results suggest caution for the use of Tg.AC and p53 mice to screen unknown chemicals in drinking water for potential carcinogenicity.

FIG. 1.

Mean body weights (g) of male and female Tg.AC hemizygous and p53 haploinsufficient mice exposed to DCA in drinking water for 41 weeks. Mean body weights of 500, 1000, and 2000 mg/l Tg.AC males were less than those of controls after weeks 35, 8, and 11, respectively (A); mean body weights of 500, 1000, and 2000 mg/l Tg.AC females were less than those of controls after weeks 27, 28, and 26, respectively (B). Mean body weights of 500, 1000, 2000 mg/l p53 hemizygous male mice were less than those of controls after 4, 3, and 1 weeks, respectively (C); mean body weights of 500, 1000, 2000 mg/l p53 hemizygous female mice were less than those of controls after 27, 9, and 9 weeks, respectively (D).

FIG. 2.

Liver tumor incidences (%) from studies of DCA in B6C3F₁ mice. The length of exposure ranged from 31 weeks (Pereira et al., 2001) to 104 weeks (Daniel et al., 1992), with most studies lasting at least 52 weeks. In all studies, the incidence of liver tumors increased with increasing concentration of DCA. Also see Table 6.