Considerations concerning the murine hepatocarcinogenicity of selected chlorinated hydrocarbons

Of the chlorinated hydrocarbons discussed above, all six are associated with induction of hepatocellular neoplasia in mice. None of the six is considered to be potent mutagen and most are without any significant genotoxic activity as assessed by conventional in vitro testing schemes. Although some of the agents have biological effects in common (see Figure 4), there is no single biological response (mode of action) that they all share to provide a mechanistic basis for the observed murine hepatocarcinogenicity. Based upon the information currently available for each of the chlorinated hydrocarbons discussed above, it is probable that some modes of action may be more contributory to the rodent carcinogenic response than others; however, no mode of action, pathway, or mechanism should be considered to be mutually exclusive. The murine hepatocarcinogenic effect of TriCE is most probably contingent upon its species-specific metabolism to trichloroacetic acid and DCA. There is fairly consistent evidence that cytotoxicity and reparative hyperplasia are associated with doses of TriCE that cause induction of liver neoplasms. The possibility that peroxisome proliferation is playing a role in the induction of mouse hepatocellular neoplasia remains a tempting explanation, since higher intracellular steady states of H2O2 production would be consistent with observed enhanced cellular proliferation as well as the possibility of in vivo DNA damage. The mouse hepatocarcinogenicity associated with TetCE most probably is associated with species-specific metabolic production of trichloroacetic acid. As with TriCE, cytotoxicity and reparative hyperplasia may represent a potential mode of action for the observed hepatocarcinogenicity. Once again, the potential for enhanced peroxisome proliferation is consistent with enhanced cell proliferation and oxygen radical damage would help explain the random point mutations in ras proto-oncogenes documented in DNA from TetCE-induced mouse liver tumors. DCA-induced mouse hepatocellular neoplasia is probably influenced by cytotoxicity and reparative hyperplasia, but there is also recent evidence that DCA may directly damage DNA, implying an in vivo genotoxic mechanism may be operational. Likewise, altered expression of several genes suggests that subversion of signal transduction may play a role in the induction or progression of liver tumor development. As with TetCE and TriCE, a role for peroxisome proliferation is still a consideration, although the liver tumor response is obvious at doses too low to cause peroxisome proliferation.(ABSTRACT TRUNCATED AT 400 WORDS)