Pathogenesis of toxic and neoplastic renal lesions induced by the flame retardant tris (2,3-dibromopropyl)phosphate in F344 rats, and development of colonic adenomas after prolonged oral administration.

Male F344 rats, 4 weeks old, were given tris (2,3-dibromopropyl)phosphate (TBP) via stomach tube at a dosage level of 100 mg. per kg. of body weight per day. Treatment was given 5 days per week and continued for 4 or 52 weeks. Representative treated and control animals were killed at predetermined time intervals and the histomorphology and ultrastructure of the kidneys investigated. Twenty-four hours after the first TBP treatment, the epithelial cells at the corticomedullary junction developed increased nucleus to cytoplasm ratios, cytomegaly, and nuclear vacuolization and pleomorphism. These changes increased in severity to a toxic tubular nephrosis as treatment continued, and extended to the peripheral cortex by 52 weeks. Electron microscopy showed loss of microvilli and polarity in the epithelium of the proximal convoluted tubules. The development of adenocarcinomas from hyperplastic areas at these sites were studied. At the ultrastructural level, the cytoplasm of the neoplastic cells was poorly differentiated, and in many areas, the surfaces of the cells were covered by microvilli. In one group of rats, treatment was terminated after 4 weeks. In these animals, a gradual but incomplete restoration of the tubular epithelia to nearly normal morphology was observed. Nuclear changes persisted after cytoplasmic abnormalities had disappeared. At 52 weeks, three of five surviving rats given TBP throughout the experiment were found to have polypoid adenomas of the descending colon.