Acute Hepatotoxic and Nephrotoxic Effects of Chloroform in Male F-344 Rats and Female B6C3F1 Mice

Previous studies demonstrated that chloroform given by oralgavage in corn oil caused an increased incidence of liver tumorsin male and female mice and kidney tumors in male rats, whileadministration in drinking water resulted in an increased tumorincidence only in the kidneys of the male rats. The tumorigenicityof this nongenotoxic agent has been postulated to be linkedwith cytolethality and cell proliferation. This study examinedthe organ-specific toxicity of acute doses of chloroform. MaleF-344 rats were given chloroform by gavage in corn oil at thebioassay doses of chloroform of 0 and 180 mg/kg body wt as wellas 34 and 477 mg/kg and necropsied 24 hr later. Additional ratswere given a single dose of 180 mg chloroform/kg and administeredbromodeoxyuridine (BRDU) 2 hr prior to necropsy at 0.5, 1, 2,4, and 8 days after chloroform treatment. Female B6C3F1 micewere given chloroform by gavage at the bioassay doses of 0,238, and 477 mg/kg as well as 34 mg/kg and necropsied at 24hr after treatment. Additional mice were given a single doseof 350 mg chloroform/kg, labeled with BRDU, and necropsied at0.5, 1, 2, 4, and 8 days after treatment. The kidneys of malerats administered 34, 180, and 477 mg chloroform/kg exhibitedmild to severe proximal tubular necrosis in a dose-dependentmanner. A 20-fold increase in the labeling index (LI, the percentageof nuclei in S-phase) in the proximal tubule cells was observed2 days after treatment with the bioassay dose of 180 mg/kg.The livers of male rats exhibited only slight to moderate multifocalcentrilobular necrosis at 180 and 477 mg/kg. A 10-fold increasein the LI was observed in the liver of male rats given 477 mg/kg,but no increase was observed at the bioassay dose of 180 mg/kg.In contrast to male rats, female mice developed a dose-dependentcentrilobular hepatic necrosis at 238 and 477 mg/kg. No renallesions were observed in female mice at any dose. A peak increasein LI of 38-fold was observed in hepa-tocytes in the liversof female mice 2 days after treatment with 350 mg chloroform/kg,with only a 2-fold increase in LI observed in the kidneys. Thesedata indicate that acute chloroform-induced cytolethality leadsto increased cell proliferation and that the organ-specificpattern of toxicity is the same as the organ-specific patternof tumor formation. These observations are suggestive of a rolefor induced cell proliferation in tumor formation and indicatethat more extensive cell proliferation Studies are Warranted.