MITOGENIC EFFECTS OF PROPOXUR ON MALE-RAT BLADDER UROTHELIUM

Propoxur produces bladder tumors in rats, but not other species. The h yperplastic and tumorigenic effects do not occur if urinary pH is lowe red by administering propoxur in a semi-synthetic diet or co-administe ring it with ammonium chloride (NH4Cl). We fed propoxur at 8000 p.p.m. in Altromin 1321 diet to male Wistar rats for 4 weeks, with or withou t NH4Cl as 10 000 p.p.m. of the diet. The urine of rats fed control di et with or without propoxur had a relatively high urinary pH (similar to 8); the addition of NH4Cl lowered the urinary pH by similar to 0.5- 1.0 units. There was no evidence of urinary calculi or amorphous preci pitate nor was there an increase in microcrystals or formation of diff erent crystal than occur in normal rat urine. Propoxur produced hyperp lasia of the urothelium, as observed by light and scanning electron mi croscopy, and increased the labeling index for proliferating cell nucl ear antigen. These effects were significantly inhibited by coadministr ation with NH4Cl. There was no evidence of urothelial necrosis. Thus, the hyperplasia appears to result from a direct mitogenic effect of pr opoxur or a metabolite on the urothelium, rather than from toxicity an d consequent regeneration. Based on the present study and previous inv estigations, the urothelial effects of propoxur in the rat are depende nt on high urinary pH and high administered doses, factors which need to be incorporated into any mechanistic model for the chemical and int o any extrapolation to potential effects in humans.