Differences in rat liver enzyme-altered foci produced by chlorinated aliphatics and phenobarbital

Abstract

Nine chlorinated aliphatics (CAs)--1,1-dichloroethane, 1,2-dichloroethane, 1,1,1-trichloroethane, 1,1,2-trichloroethane, trichloroethylene, tetrachloroethylene, 1,1,1,2-tetrachloroethane, 1,1,2,2-tetrachloroethane, and hexachloroethane--were examined in a rat liver foci assay for evidence of initiating and promoting potential. Young adult male Osborne-Mendel rats (ten/group) were given partial hepatectomies, followed 24 hr later by a single i.p. dose of either diethylnitrosamine (30 mg/kg body weight) or CA, 1 wk later either a diet containing 0.05% (w/w) phenobarbital or daily oral gavage (5 X/wk) of CA in corn oil for 7 weeks, and sacrificed 1 wk later. Putative preneoplastic markers monitored were foci with increased gamma-glutamyltranspeptidase activity [GGT(+)]. CAs were without significant effect in the initiation protocol at the maximum tolerated dose. In the promotion protocol, 1,1-dichloroethane, 1,1,2-trichloroethane, tetrachloroethylene, 1,1,2,2-tetrachloroethane, and hexachloroethane induced significant increases in GGT(+) foci above control levels. Two variants of GGT(+) foci were distinguishable, one associated predominantly with phenobarbital promotion, resembling preneoplastic foci in other models, and the other associated with CA promotion, which was less intensely stained and exhibited branching, resembling foci undergoing redifferentiation. The marked differences in response may relate to differences in cytotoxic potential or mechanism of action of the two types of agents.