Chloroform, generally regarded as a non-genotoxic compound, is associated with the induction of liver and/or kidney
tumors in laboratory mice and rats. In particular,
chloroform produced renal tubule
tumors in low incidence in male Osborne-Mendel rats when administered by
corn-oil gavage or in the
drinking water. There is a lack of data on intermediate endpoints that may be linked to
renal cancer development in this strain of rat, in contrast to mice. Specifically, evidence linking
chloroform-induced liver and kidney
tumors in mice with cytotoxicity and regenerative cell proliferation is very strong, but weak in the rat. In the present study, kidney tissue from a carcinogenicity bioassay of
chloroform in Osborne-Mendel rats was re-evaluated for histological evidence of compound-induced cytotoxicity and cell turnover. All rats treated with 1800 ppm (160 mg/kg/day, high-dose group) in the
drinking water for 2 years and half the rats treated with 900 ppm (81 mg/kg/day) had mild to moderate changes in proximal convoluted tubules in the mid to deep cortex indicative of chronic cytotoxicity. Tubule alterations specifically associated with chronic
chloroform exposure included cytoplasmic basophilia, cytoplasmic vacuolation, and nuclear crowding consistent with simple tubule
hyperplasia. Occasional pyknotic cells, mitotic figures in proximal tubules, and prominent karyomegaly of the renal tubule epithelium were present. These alterations were not present in control groups or at the 200-ppm (19 mg/kg/day) or 400-ppm (38 mg/kg/day) dose levels. This new information adds substantially to the weight of evidence that the key events in
chloroform-induced carcinogenicity in rat kidney include sustained cellular toxicity and chronic regenerative
hyperplasia.