SITE-SPECIFIC CELL-PROLIFERATION IN RENAL TUBULAR CELLS BY THE RENAL TUBULAR CARCINOGEN TRIS(2,3-DIBROMOPROPYL)PHOSPHATE

Our laboratory has been examining the mechanisms whereby chemicals are mutagenic in short-term in-vitro assays yet are not carcinogenic in a -year rodent bioassays. Previous studies indicated that mutagenic carc inogens increased the amount of cell turnover in the target organ, but that mutagenic noncarcinogens failed to do so. The present study comp ares the incidence of cell proliferation in specific regions of the ki dney, which is the site of carcinogenicity, with cell proliferation in duced in a nontarget tissue, the liver, by the mutagenic renal tubular carcinogen tris(2,3-dibromopropyl)phosphate (TRIS). Renal tubular ade nocarcinoma induced by TRIS was the only tumor type identified in male F344 rats, and it was localized in the outer medulla. Male F344 rats were fed a diet containing 0, 50, or 100 ppm TRIS for 14 days. These d oses were identical to the doses given in the National Toxicology Prog ram cancer bioassay. Replicating cells were labeled with bromodeoxyuri dine administered by an osmotic minipump and identified in tissue sect ions from liver and kidney using immunohistochemical techniques. Exami nation of liver sections showed no chemically related increases in cel l proliferation above control for either dose group. However, in the k idney, TRIS induced significant cell proliferation that was localized in the renal outer medulla region, the target area for carcinogenesis. The labeling index (number of labeled cells/total number of cells cou nted) in the kidneys of TRIS-exposed rats was increased approximately 4-fold in the outer medulla and was not increased in the cortex or inn er medulla. The results of this study suggest an association between t he chemically-induced renal cell proliferation and the renal carcinoge nicity of TRIS.