The carcinogenicity of trichloroethylene and its metabolites, trichloroacetic acid and dichloroacetic acid, in mouse liver.
Trichloroethylene (TCE) has previously been shown to be carcinogenic in mouse liver when administered by daily gavage in corn oil. The metabolism of TCE results, in part, in the formation of trichloroacetic acid (TCA) as a major metabolite and dichloroacetic acid (DCA) as a minor metabolite. These chlorinated acetic acids have not been shown to be genotoxic, although they have been shown to induce peroxisome proliferation. Therefore, we determined the ability they have been shown to induce peroxisome proliferation. Therefore, we determined the ability of TCE, TCA, or DCA to act as tumor promoters in mouse liver. Male B6C3F1 mice were administered intraperitoneally 0, 2.5, or 10 micrograms/g body wt ethylnitrosourea (ENU) on Day 15 of age. At 28 days of age, the mice were placed on drinking water containing either TCE (3 or 40 mg/liter), TCA (2 or 5 g/liter), or DCA (2 or 5 g/liter). All drinking waters were neutralized with NaOH to a final pH of 6.5-7.5. The animals were killed after 61 weeks of exposure to the treated drinking water (65 weeks of age). Both DCA and TCA at a concentration of 5 g/liter were carcinogenic without prior initiation with ENU, resulting in hepatocellular carcinomas in 81 and 32% of the animals, respectively. DCA and TCA also increased the incidence of animals with adenomas and the number of adenomas/animal in those animals that were not initiated with ENU. While 2.5 micrograms/g body wt ENU followed by NaCl in the drinking water resulted in only 5% of the animals with hepatocellular carcinomas, 2.5 micrograms/g body wt ENU followed with 2 or 5 g/liter DCA resulted in a 66 or 78% incidence of carcinoma, respectively, or, followed with 2 or 5 g/liter TCA, resulted in a 48% incidence at either concentration. None of the untreated animals had hepatocellular carcinomas. Therefore our results demonstrate that DCA and TCA are complete hepatocarcinogens in B6C3F1 mice.
D000085:Acetates / Q000633:toxicity*; D000236:Adenoma / Q000139:chemically induced; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003999:Dichloroacetic Acid / Q000633:toxicity*; D004357:Drug Synergism; D005038:Ethylnitrosourea; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D010634:Phenobarbital / Q000633:toxicity; D014238:Trichloroacetic Acid / Q000633:toxicity*; D014241:Trichloroethylene / Q000633:toxicity*
D000085:Acetates; D014241:Trichloroethylene; D014238:Trichloroacetic Acid; D003999:Dichloroacetic Acid; D005038:Ethylnitrosourea; D010634:Phenobarbital