Tributyl phosphate (TBP) produces tumors of the bladder urothelium in rats at high doses (700 and 3000 ppm), with greater effects in males than in females. TBP does not produce tumors in mice and it is nongenotoxic. The dose response of TBP effects on urine and urothelium was evaluated in male Sprague-Dawley rats at 0, 200, 700, and 3000 ppm of the diet, 10 rats per group, for 10 weeks. Another group received 3000 ppm TBP plus 12,300 ppm NH4Cl to evaluate the effect of urinary acidification. An additional group of 10 rats received 12,300 ppm NH4Cl. A high-dose recovery group (10 weeks 3000 ppm TBP, then 10 weeks control diet) was included to evaluate reversibility. Urine chemistries for control and TBP-treated animals were similar except for a slight decrease in osmolality and creatinine at the highest dose. Scanning electron microscopic examination of the urine of TBP-treated rats showed no increased or abnormal crystalluria, urinary precipitate, or calculi. The urothelial effects were seen at the two highest doses, but were most severe at 3000 ppm TBP, with ulceration and hemorrhage into the bladder lumen and consequent diffuse papillary and nodular hyperplasia. Dietary NH4Cl acidified the urine but did not prevent the urothelial toxicity and regeneration. The bladder epithelial changes were reversible, but the ulcer repair process was accompanied by submucosal fibrosis. TBP at high doses appears to produce urothelial cytotoxicity with marked regenerative hyperplasia which is reversible upon withdrawal of treatment. The cytotoxicity is likely due to the direct effect of TBP or its metabolites rather than an indirect consequence of urinary changes.
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