Effect of Sulfosulfuron on the Urine and Urothelium of Male Rats

Abstract

Sulfosulfuron, developed as a herbicide, caused increased microcrystalluria and the formation of urinary tract calculi when fed to male and female rats in a chronic 2-year study at doses of 5,000 ppm and 20,000 ppm. Hyperplasi a was also seen in urinary bladders at 5,000 ppm and 20,000 ppm, almost exclusively in the presence of observabl e calculi/microcalculi. Urinary bladder tumors were found in 2 females in the 5000 ppm group, both in the presence of calculi. No increased microcrystalluria, calculi, or tumors were found at doses of 500 ppm and lower. In the current study, 5 groups of male Sprague-Dawley rats were fed sulfosulfuron at doses of 50, 500, 5,000, and 20,000 ppm for 10 weeks. Ten animals were co-administered 5,000 ppm sulfosulfuron with 12,300 ppm NH 4 Cl to determine if inhibition of the formation of calculi would prevent any urothelial effects of treatment with sulfosulfuron. Ten animals in the control group and in the high-dose sulfosulfuron group were fed only basal diet for an additional 10 weeks to determine if the effects of sulfosulfuron on the bladder epithelium were reversible. There was an increased incidence of microcrystalluria observed at 5,000 and 20,000 ppm. There was no increase in microcrystalluria observed in the urine of rats co-administered sulfosulfuron and NH 4 Cl. Urinary bladder calculi were found in the bladder of 1 animal fed 20,000 ppm. Examination by light microscopy showed diffuse papillary/nodular hyperplasia of the bladder epithelium in this animal. No increased microcrystalluria was observed after withdrawal of the chemical from the diet and the bladder epithelium was normal by light microscopy. The hyperplastic effects associated with the feeding of high doses of sulfosulfuron occur only with the appearance of urinary tract calculi. Based on these results and anatomical differences between rats and humans, it may be concluded that the hyperplastic and carcinogenic effects of sulfosulfuron in rats are high-dose, threshold phenomen a that are not likely to occur in humans under environmentall y relevant exposures.

Commercial AHAS-inhibiting herbicides are promising drug leads for the treatment of human fungal pathogenic infections

“…The SUs, including CE, and most AHAS-inhibiting herbicides show a pH-dependent solubility in aqueous solutions, with these compounds becoming insoluble at low pH. We therefore hypothesize the weaker effect of CE in reducing the fungal burden in the kidneys could be due to precipitation of the compound in urine (40).…”

Commercial AHAS-inhibiting herbicides are promising drug leads for the treatment of human fungal pathogenic infections

“…The SUs, including CE, and most AHAS-inhibiting herbicides show a pH-dependent solubility in aqueous solutions, with these compounds becoming insoluble at low pH. We therefore hypothesize the weaker effect of CE in reducing the fungal burden in the kidneys could be due to precipitation of the compound in urine (40).…”

Mammalian toxicology overview and human risk assessment for sulfosulfuron

“…In a study designed to determine if the rat urinary bladder carcinogenesis was indeed the result of calculus formation, groups of male Sprague-Dawley rats were fed sulfosulfuron at doses of 0, 50, 500, 5000, and 20,000 ppm for 10 weeks (Arnold et al, 2001). Ten animals were co-administered 5000 ppm sulfosulfuron with 12,300 ppm NH 4 Cl to determine if inhibition of the formation of calculi would prevent any urothelial effects of treatment with sulfosulfuron.…”

“…With one exception (Arnold et al, 2001), the information from the studies that comprise this database has not been previously published in the open literature. All of the details and findings of the studies described in this paper have been peer reviewed and extensively evaluated by scientists and others from international regulatory agencies, however, and, in addition, were conducted according to U.S., European, and Japanese regulatory testing guidelines and Good Laboratory Practices.…”

Investigations of Rodent Urinary Bladder Carcinogens: Collection, Processing, and Evaluation of Urine and Bladders

“…Bar = 10 μm. Originally published in Arnold et al (2001).…”

Commercial AHAS-inhibiting herbicides are promising drug leads for the treatment of human fungal pathogenic infections

“…The SUs, including CE, and most AHAS-inhibiting herbicides show a pH-dependent solubility in aqueous solutions, with these compounds becoming insoluble at low pH. We therefore hypothesize the weaker effect of CE in reducing the fungal burden in the kidneys could be due to precipitation of the compound in urine (40).…”

Mammalian toxicology overview and human risk assessment for sulfosulfuron

“…In a study designed to determine if the rat urinary bladder carcinogenesis was indeed the result of calculus formation, groups of male Sprague-Dawley rats were fed sulfosulfuron at doses of 0, 50, 500, 5000, and 20,000 ppm for 10 weeks (Arnold et al, 2001). Ten animals were co-administered 5000 ppm sulfosulfuron with 12,300 ppm NH 4 Cl to determine if inhibition of the formation of calculi would prevent any urothelial effects of treatment with sulfosulfuron.…”

“…With one exception (Arnold et al, 2001), the information from the studies that comprise this database has not been previously published in the open literature. All of the details and findings of the studies described in this paper have been peer reviewed and extensively evaluated by scientists and others from international regulatory agencies, however, and, in addition, were conducted according to U.S., European, and Japanese regulatory testing guidelines and Good Laboratory Practices.…”

Investigations of Rodent Urinary Bladder Carcinogens: Collection, Processing, and Evaluation of Urine and Bladders

“…Bar = 10 μm. Originally published in Arnold et al (2001).…”

Commercial AHAS-inhibiting herbicides are promising drug leads for the treatment of human fungal pathogenic infections

“…The SUs, including CE, and most AHAS-inhibiting herbicides show a pH-dependent solubility in aqueous solutions, with these compounds becoming insoluble at low pH. We therefore hypothesize the weaker effect of CE in reducing the fungal burden in the kidneys could be due to precipitation of the compound in urine (40).…”

Mammalian toxicology overview and human risk assessment for sulfosulfuron

“…In a study designed to determine if the rat urinary bladder carcinogenesis was indeed the result of calculus formation, groups of male Sprague-Dawley rats were fed sulfosulfuron at doses of 0, 50, 500, 5000, and 20,000 ppm for 10 weeks (Arnold et al, 2001). Ten animals were co-administered 5000 ppm sulfosulfuron with 12,300 ppm NH 4 Cl to determine if inhibition of the formation of calculi would prevent any urothelial effects of treatment with sulfosulfuron.…”

“…With one exception (Arnold et al, 2001), the information from the studies that comprise this database has not been previously published in the open literature. All of the details and findings of the studies described in this paper have been peer reviewed and extensively evaluated by scientists and others from international regulatory agencies, however, and, in addition, were conducted according to U.S., European, and Japanese regulatory testing guidelines and Good Laboratory Practices.…”

Investigations of Rodent Urinary Bladder Carcinogens: Collection, Processing, and Evaluation of Urine and Bladders

“…Bar = 10 μm. Originally published in Arnold et al (2001).…”