It has been reported that chloroform administered to male B6C3F1 mice at doses of 138 and 277 mg/kg/day in corn oil by gavage 5 days/week for 2 years resulted in incidences of hepatocellular carcinomas of 36 and 98% relative to an incidence in controls of 6%. Cytotoxicity and regenerative cell proliferation have been implicated in the tumorigenic process for this non-genotoxic compound. Although chloroform is known to be nephrotoxic in the male mouse, no treatment-related increase was observed in the frequency of kidney tumors. To better understand the relationship of these endpoints, this study evaluated chloroform-induced cytotoxicity and cell proliferation in the liver and kidney under conditions of the cancer study. B6C3F1 mice were administered oral doses of 0, 34, 90, 138, or 277 mg/kg/day of chloroform dissolved in corn oil for 4 days or 5 days/week for 3 weeks. Bromo-2'-deoxyuridine (BrdU) was administered via osmotic pumps implanted 3.5 days prior to necropsy to label cells in S-phase. Cell proliferation was evaluated in tissue sections immunohistochemically as the percentage of cells in S-phase (nuclear labeling index; LI). Mice given 34 and 90 mg/kg/day by gavage had mild degenerative changes in centrilobular hepatocytes after 4 days of treatment, which was absent at 3 weeks. Centrilobular necrosis was observed in mice given 138 or 277 mg/kg chloroform for 4 days, with increased severity of necrosis at 3 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)