Re-evaluation of the 2-year chloroform drinking water carcinogenicity bioassay in Osborne-Mendel rats supports chronic renal tubule injury as the mode of action underlying the renal tumor response

Chloroform, generally regarded as a non-genotoxic compound, is associated w ith the induction of liver and/or kidney tumors in laboratory mice and rats . In particular, chloroform produced renal tubule tumors in low incidence i n male Osborne-Mendel rats when administered by corn-oil gavage or in the d rinking water. There is a lack of data on intermediate endpoints that may b e linked to renal cancer development in this strain of rat, in contrast to mice. Specifically, evidence linking chloroform-induced liver and kidney tu mors in mice with cytotoxicity and regenerative cell proliferation is very strong, but weak in the rat. In the present study, kidney tissue from a car cinogenicity bioassay of chloroform in Osborne-Mendel rats was re-evaluated for histological evidence of compound-induced cytotoxicity and cell turnov er. 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 mi d to deep cortex indicative of chronic cytotoxicity. Tubule alterations spe cifically associated with chronic chloroform exposure included cytoplasmic basophilia, cytoplasmic vacuolation, and nuclear crowding consistent with s imple tubule hyperplasia. Occasional pyknotic cells, mitotic figures in pro ximal tubules, and prominent karyomegaly of the renal tubule epithelium wer e present. These alterations were not present in control groups or at the 2 00-ppm (19 mg/kg/day) or 400-ppm (38 mg/kg/day) dose levels. This new infor mation 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.