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Sulprofos, disulfoton, azinphos-methyl, methamidophos, trichlorfon, and tebupirimphos were screened for neurotoxic potential, in accordance with U.S. EPA (FIFRA) requirements. Each organophosphate was administered through the diet for 13 weeks to separate groups of Fischer 344 rats at four dose levels, including a vehicle control. For each study, 12 rats/sex/dietary level were tested using a functional observational battery (FOB), automated measures of activity (figure-8 maze), and detailed clinical observations, with half of the animals perfused at term for microscopic examination of neural and muscle tissues. Separate groups of satellite animals (6/sex/dietary level) were used to measure the effect of each treatment on plasma, erythrocyte (RBC), and brain cholinesterase (ChE) activity. The results show that measures of ChE activity were consistently the most sensitive indices of exposure and assisted in the interpretation of findings. All treatment-related neurobehavioral findings were ascribed to cholinergic toxicity, occurring only at dietary levels that produced more than 20% inhibition of plasma, RBC, and brain ChE activity. Neurobehavioral tests provided no evidence of additional cumulative toxicity after 8 weeks of treatment. The FOB and motor activity findings did not alter the conclusions and generally did not reduce the neurobehavioral no-observed-effect level (NOEL) for any of the six compounds, relative to the results from detailed clinical observations as conducted in these studies. The one exception occurred with tebupirimphos, where the NOEL for motor activity was one dose level lower than the NOEL for the FOB and clinical observations. These results support the value of detailed clinical observations to screen for the neurotoxic potential of organophosphates and a general standard of more than 20% inhibition of brain ChE activity for cholinergic neurotoxicity. © 1997 society of Toxicoio g5 .

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 ammonium 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 10,000 p.p.m. of the diet. The urine of rats fed control diet with or without propoxur had a relatively high urinary pH (approximately 8); the addition of NH4Cl lowered the urinary pH by approximately 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 nuclear antigen. These effects were significantly inhibited by co-administration 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 urothelium, 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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