Hepatocarcinogenicity of Chioral Hydrate, 2-Chloroacetaldehyde, and Dichioroacetic Acid in the Male B6C3F1 Mouse

The chlorinated acetaldehydes, chloral hydrate (CH) and 2-chloroacetaldehyde(CAA), have been identified as chlorination by-products in finisheddrinking water supplies. Although both chemicals are genotoxic,their potential for carcinogenicity had not been adequatelyexplored. The studies reported here are chronic bioassays conductedwith male B6C3F1 mice exposed to levels of 1 g/liter CH and0.1 g/liter CAA via the drinking water for 104 weeks. Distilledwater (H₂O) served as the untreated control and dichloroaceticacid (DCA; 0.5 g/liter), another chlorine disinfection by-product,was included. The mean daily ingested doses were approximately166 mg/kg/day for CH, 17 mg/kg/day for CAA, and 93 mg/kg/dayfor DCA. Evaluations included mortality, body weight, organweights, gross pathology, and histopathology. The primary targetorgan was the liver as the organ weights and pathological changesin the other organs (spleen, kidneys, and testes) were comparablebetween the treated groups and the H₂O control group. Liverweights were increased for all three test chemicals at the terminaleuthanasia with the greatest increase seen in the CH and DCAgroups. Hepatocellular necrosis was induced by all three testchemicals, and it was also most prevalent and severe in theCH and DCA groups. A significant increase in the prevalenceof liver tumors was seen for all three chemicals. The strongestresponse was with DCA, in which 63% of the 104-week survivorshad hepatocellular carcinomas (carcinomas) and 42% possessedhepatocellular adenomas (adenomas) and the combined prevalencefor carcinomas plus adenoma was 75%. The corresponding prevalencerate for carcinomas, adenomas, and combined tumors were 46,29, and 71% 31, 8, and 38% and 10, 5, and 15% for CH, CAA, andH₂O, respectively. In addition to the tumors we evaluated theprevalence of a possible preneoplastic lesion, the hepatocellularhyperplastic nodule (nodules), a lesion which occurred in allthree treated groups but not in the H₂O group.