RAS PROTOONCOGENE ACTIVATION IN DICHLOROACETIC ACID-INDUCED, TRICHLOROETHYLENE-INDUCED AND TETRACHLOROETHYLENE-INDUCED LIVER-TUMORS IN B6C3F1 MICE

The frequency and mutation spectra of proto-oncogene activation in hep atocellular neoplasms induced by tetrachloroethylene, trichloroethylen e and dichloroacetic acid were examined to help define the molecular b asis for their carcinogenicity. H-ras codon 61 activation was not sign ificantly different among dichloroacetic acid-and trichloroethylene-in duced and combined historical and concurrent control hepatocellular tu mors (62%, 51% and 69% respectively). The mutation spectra of H-ras co don 61 mutations showed a significant decrease in AAA and increase in CTA mutations for dichloroacetic acid-and trichloroethylene-induced tu mors when compared to combined controls. The H-ras codon 61 mutation f requency for tetrachloroethylene-induced tumors was significantly lowe r (24%) than that of combined controls and also that of the two other chemicals. Mutations at codons 13 and 117 plus a second exon insert co ntributed 4% to the total H-vas frequencies for trichloroethylene and tetrachloroethylene. There was also a higher incidence of K-ras activa tion (13%) in tetrachloroethylene-induced tumors than in the other che mically induced or control tumors. Four liver tumors were found to con tain insertions of additional bases within the second exon of K- or H- ras. These findings suggest that exposure to dichloroacetic acid, tric hloroethylene and tetrachloroethylene provides a selective growth adva ntage to spontaneously occurring mutations in codon 61 of H-ras and, a t the same time, is responsible for a small number of unique molecular lesions suggestive of either a random genotoxic mode of action or a n on-specific result of secondary DNA damage. However, the absence of ra s activation in many of the liver neoplasms suggests that alternative mechanisms are also important in B6C3F1 mouse hepatocarcinogenesis.