Evaluation of Dichloroacetic Acid for Carcinogenicity in Genetically Modified Tg.AC Hemizygous and p53 Haploinsufficient Mice

There has been considerable interest in the use of geneticallymodified mice for detecting potential environmental carcinogens.For this reason, the National Toxicology Program has been evaluatingTg.AC hemizygous and p53 haploinsufficient mice as models todetect potential carcinogens. It was reasoned that these mousemodels might also prove more effective than standard rodentmodels in evaluating the numerous disinfection byproducts thatare found in low concentrations in drinking water. Dichloroaceticacid (DCA) is one of the most frequently found disinfectionbyproducts and DCA has been consistently shown to cause hepatocellulartumors in rats and mice in standard rodent studies. Tg.AC hemizygousand p53 haploinsufficient mice were exposed in the drinkingwater to DCA for up to 41 weeks. In a second study Tg.AC micewere subjected to dermal DCA exposure for up to 39 weeks. Increasedincidences and severity of cytoplasmic vacuolization of hepatocyteswere seen in the p53 mice, but there was no evidence of carcinogenicactivity at exposures of up to 2000 mg/l in the drinking water.Increased incidences and severity of cytoplasmic vacuolizationof hepatocytes were seen in the drinking water study with Tg.ACmice and a modest non-dose-related increase in pulmonary adenomaswas observed in males exposed to 1000 mg/l in the drinking water.Dermal exposure up to 500 mg/kg for 39 weeks resulted in increaseddermal papillomas at the site of application in Tg.AC mice.No significant increase in papillomas under the same study conditionswas seen in the 26-week study. For DCA under these study conditions,the p53 and Tg.AC mice appear less sensitive to hepatocarcinogenesisthan standard rodent models. These results suggest caution forthe use of Tg.AC and p53 mice to screen unknown chemicals indrinking water for potential carcinogenicity.