Mitogenic effects of propoxur on male rat bladder urothelium

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Abstract
Propoxur produces bladder tumors in rats, but not other species. The hyperplastic and tumorigenic effects do not occur if urinary pH is lowered by administering propoxur in a semi-synthetic diet or co-administering it with ammonlum chloride (NH4Cl) We fed propoxur at 8000 p.p.m. in Altromin 1321 diet to male Wistar rats for 4 weeks, with or without NH4Cl as 10000 p.p.m. of the diet. The urine of rats fed control diet with or without propoxur had a relatively high urinary pH (∼8); the addition of NH4Cl lowered the urinary pH by ∼0.5–1.0 units. There was no evidence of urinary calculi or amorphous precipitate nor was there an increase in microcrystals or formation of different crystals than occur in normal rat urine. Propoxur produced hyperplasia of the urothelium, as observed by light and scanning electron microscopy, and increased the labeling index for proliferating cell nudear antigen. These effects were signilicantly inhibited by coadministration with NH4Cl. There was no evidence of urothelial necrosis. Thus, the hyperplasia appears to result from a direct mitogenic effect of propoxur or a metabolite on the urothellum, rather than from toxicity and consequent regeneration. Based on the present study and previous investigations, the urothelial effects of propoxur in the rat are dependent on high urinary pH and high administered doses, factors which need to be incorporated into any mechanistic model for the chemical and into any extrapolation to potential effects in humans.

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