THE ROLE OF DICHLOROACETATE IN THE HEPATOCARCINOGENICITY OF TRICHLOROETHYLENE

The induction of hepatic tumors in B6C3F1 mice treated with trichloroe thylene (TRI) has been attributed to its metabolism to trichloroacetat e (TCA). Trichloroacetate is an effective peroxisome proliferator in m ice at blood concentrations that are readily achieved with carcinogeni c doses of TRI. Recent data has demonstrated that both TCA and dichlor oacetate (DCA) are capable of inducing liver tumors in B6C3F1 mice. Al though long recognized as a metabolite of TRI, little attention has fo cussed on the role DCA might play in the hepatocarcinogenic effects of TRI. There are significant differences in the effects of DCA and TCA on the liver of B6C3F1 mice. Trichloroacetate treatment induces peroxi some proliferation, increases lipid deposition, and results in a marke d accumulation of lipofuscin in the liver with long-term exposures. Di chloroacetate induces a markedly enlarged liver associated with a cyto megaly and large accumulations of glycogen. The cytomegaly is associat ed with the development of focal areas of recurrent liver necrosis whi ch in tum lead to high levels of cell proliferation in the area surrou nding these lesions. Induction of peroxisomes with DCA is transitory a nd the accumulation of lipofuscin is much less evident than with TCA t reatment. Studies of TRI metabolism demonstrate that blood levels of D CA produced are sufficient to account for the hepatocarcinogenic effec ts of TRI. The rather low concentrations of DCA found in the urine of mice treated with TRI relative to TCA concentrations are due to the mu ch more rapid and complete metabolism of DCA. These data do not suppor t the conclusion that the hepatocarcinogenic effects of TRI are simply related to peroxisome proliferation.