IN-VIVO CHCL3 BIOACTIVATION, TOXICOKINETICS, TOXICITY, AND INDUCED COMPENSATORY CELL-PROLIFERATION IN B6C3F1 MALE-MICE

Chloroform carcinogenicity has often been associated with acute tissue damage and consequent compensatory cell proliferation. However, avail able data do not fully support this hypothesis, and other biological f actors may play a role in the tumor induction by chloroform. The purpo se of this study was to characterize the in vivo CHCl3 metabolism and the time course of toxic effects and of cell proliferation in the live r and kidney of B6C3F1 male mice dosed ip or by gavage with 150 mg CHC l3/kg body wt. Microsomal phospholipid adducts attributed to (CHCl3)-C -14 metabolism by both oxidative and reductive pathways were detected in both liver and kidney. The levels and composition of the adducts we re similar in the liver and kidney of treated animals. In the liver, a lthough no necrosis was histologically detectable, a transient cell pr oliferation was found starting at 24 and peaking at 48 hr post-treatme nt. Kidney toxicity was evident by biochemical and cytochemical method s at 5 hr after dosing and progressed to severe necrosis at 48 and 96 hr. An intense kidney cell regeneration began 48 hr after CHCl3 treatm ent, became maximal at 96 hr, and was sustained for at least the follo wing 3 days. These observations raise questions about the purely epige netic action of chloroform in tumor induction since bioassays have fou nd tumors in liver but not kidneys of CHCl3-treated B6C3F1 mice. (C) 1 996 Academic Press, Inc.