TRIBUTYL-PHOSPHATE EFFECTS ON URINE AND BLADDER EPITHELIUM IN MALE SPRAGUE-DAWLEY RATS

Tributyl phosphate (TBP) produces tumors of the bladder urothelium in rats at high doses (700 and 3000 ppm), with greater effects in males t han in females. TBP does not produce tumors in mice and it is nongenot oxic. The dose response of TBP effects on urine and urothelium was eva luated 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 pp m TBP plus 12,300 ppm NH4Cl to evaluate the effect of urinary acidific ation. An additional group of 10 rats received 12,300 ppm NH4Cl. A hig h-dose recovery group (10 weeks 3000 ppm TBP, then 10 weeks control di et) was included to evaluate reversibility. Urine chemistries for cont rol and TBP-treated animals were similar except for a slight decrease in osmolality and creatinine at the highest dose. Scanning electron mi croscopic examination of the urine of TBP-treated rats showed no incre ased or abnormal crystalluria, urinary precipitate, or calculi. The ur othelial effects were seen at the two highest doses, but were most sev ere at 3000 ppm TBP, with ulceration and hemorrhage into the bladder l umen 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 r egenerative hyperplasia which is reversible upon withdrawal of treatme nt. The cytotoxicity is likely due to the direct effect of TBP or its metabolites rather than an indirect consequence of urinary changes. (C ) 1997 Society of Toxicology.