A poroposed role for silicates and protein in the proliferative effects of saccharin on the male rat urothelium

Cohen, Samuel M.; Cano, Martín; Earl, Robert A.; Carson, Steven D.; Garland, Emily M.

doi:10.1093/carcin/12.9.1551

Cited by 53 publications

(15 citation statements)

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“…Recently Cohen et al (7) hypothesized that a2u-globulin, which is synthesized in the male rat liver and excreted into the urine in large quantities, may be a necessary component for promotion of rat urinary bladder carcinogenesis. Indeed, it has been shown that NBR male rats that lack a2u-globulin-synthesizing ability do not demonstrate the expected increases in epithelial cell proliferation after sodium saccharin and Na-AsA treatment (26,49).…”

Section: Methodsmentioning

confidence: 99%

Dose-Dependent Amplification by L-Ascorbic Acid of NaHCO3 Promotion of Rat Urinary Bladder Carcinogenesis

et al. 1997

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The dose dependence of L-ascorbic acid (AsA) copromotion of urinary bladder carcinogenesis with continuous concomitant administration of NaHCO 3 was investigated. In the first experiment, 83 male F344 rats were all given 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 4 wk and then divided into 5 groups, which received basal diet (Oriental MF) containing AsA at 0, 1, 2, 3.5, or 5% plus 1.5% NaHCO 3 for 32 wk. Relative urinary bladder weights in the 5% AsA group were significantly increased as compared to the 0 or 1% group values due to the development of tumors. Both the incidence and number of microscopic urinary bladder lesions (tumors and preneoplastic lesions) showed dose-dependent increases. Furthermore, the sizes of the urinary bladder tumors (carcinomas and papillomas) were significantly increased with the highest dose. 5-bromo-2'-deoxyuridine labeling indices showed slightly increased proliferation in preneoplastic lesions of the urinary bladder epithelium with 5% AsA treatment. In a separate experiment, scanning electron microscopic observation revealed that administration of 5% AsA plus 1.5% NaHCO 3 for 8 wk, without BBN, altered the urinary bladder surface. Elevation of urinary bladder epithelium AsA content, as well as urinary AsA, was also noted. Ornithine decarboxylase (ODC) activity and ODC messenger RNA levels in urinary bladder epithelium of rats treated with 1.5% NaHCO 3 plus 5% AsA for 8 wk showed no statistically significant differences as compared to the control group. The results indicate that AsA amplifies the rat urinary bladder carcinogenesis promotion activity of NaHCO 3 and that its intensity of action depends on the dose, particularly at high dose.

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Section: Methodsmentioning

confidence: 99%

Dose-Dependent Amplification by L-Ascorbic Acid of NaHCO3 Promotion of Rat Urinary Bladder Carcinogenesis

et al. 1997

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“…As early as 8 days after the chemical was removed, light microscopic examination of urine collected on study day 79 from animals in the recovery group showed no evidence of the small round crystals found in the urine of the animals during treatment with 5,000 or 20,000 ppm sulfosulfuron. The only crystals present on urinary lters prepared from the same urine and examined by SEM and X-ray energy dispersive spectroscopy had the characteristic cof n-shaped morphology, and X-ray spectrum of ammonium magnesium phosphate crystals normally found in rat urine (9).…”

Section: Recovery Periodmentioning

confidence: 96%

Effect of Sulfosulfuron on the Urine and Urothelium of Male Rats

et al. 2001

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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.

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“…68,69 Saccharin is not genotoxic; the presumed mechanism of toxicity is the binding of saccharin to urinary proteins (not normally found in humans), creating a nidus for the formation of silicate crystals, which are cytotoxic to bladder epithelium. 70 Saccharin is an o-toluene sulfonamide derivative and causes similar dermatologic reactions. Crosssensitivity with sulfonamides has been demonstrated; therefore, children with "sulfa" allergy should also avoid saccharin.…”

Section: Saccharinmentioning

confidence: 99%

“Inactive” Ingredients in Pharmaceutical Products: Update (Subject Review)

1997

Pediatrics

141

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ABSTRACT. Because of an increasing number of reports of adverse reactions associated with pharmaceutical excipients, in 1985 the Committee on Drugs issued a position statement 1 recommending that the Food and Drug Administration mandate labeling of over-thecounter and prescription formulations to include a qualitative list of inactive ingredients. However, labeling of inactive ingredients remains voluntary. Adverse reactions continue to be reported, although some are no longer considered clinically significant, and other new reactions have emerged. The original statement, therefore, has been updated and its information expanded.ABBREVIATIONS. FDA, Food and Drug Administration; MDIs, metered-dose inhalers Pharmaceutical products often contain agents that have a variety of purposes, including improvement of the appearance, bioavailability, stability, and palatability of the product. Excipients (substances added to confer a suitable consistency or form to a drug, such as the vehicle, preservatives, or stabilizers) frequently make up the majority of the mass or volume of oral and parenteral drug products. These pharmaceutical adjuvants are usually considered to be inert and do not add to or affect the intended action of the therapeutically active ingredients.Some 773 chemical agents have been approved by the Food and Drug Administration (FDA) for use as inactive ingredients in drug products.2 Inasmuch as these compounds are classified as "inactive," no regulatory statutes require listing on product labeling. Pharmacopeial guidelines, enforceable under the Food, Drug, and Cosmetic Act, do require labeling of inactive ingredients for topical, ophthalmic, and parenteral preparations; orally administered products are currently exempt. Because of pressure from professional and consumer organizations asking the FDA to require complete disclosure of all ingredients, voluntary labeling was adopted by the two major pharmaceutical industry trade associations. These voluntary guidelines contain an exemption for "trade secret" components and do not require complete disclosure of all fragrance and flavoring ingredients.Current problems encountered with "inactive" ingredients include benzalkonium chloride-induced bronchospasm from antiasthmatic drugs, aspartameinduced headache and seizures, saccharin-induced cross-sensitivity reactions in children with sulfonamide allergy, benzyl alcohol toxicity in neonates receiving high-dose continuous infusion with preserved medications, dye-related cross-reactions in children with aspirin intolerance, lactose-induced diarrhea, and propylene glycol-induced hyperosmolality and lactic acidosis. Although many other excipients have been implicated in causing adverse reactions, these are the most significant in the pediatric population. ANTIASTHMATIC MEDICATIONSIt is readily appreciated that some percentage of asthmatic children will develop a "paradoxical" bronchospasm after they inhale their medication. Because many of these reactions were attributed to sulfite, which had been highly publicized ...

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A poroposed role for silicates and protein in the proliferative effects of saccharin on the male rat urothelium

Cited by 53 publications

References 0 publications

Dose-Dependent Amplification by L-Ascorbic Acid of NaHCO3 Promotion of Rat Urinary Bladder Carcinogenesis

Dose-Dependent Amplification by L-Ascorbic Acid of NaHCO3 Promotion of Rat Urinary Bladder Carcinogenesis

Effect of Sulfosulfuron on the Urine and Urothelium of Male Rats

“Inactive” Ingredients in Pharmaceutical Products: Update (Subject Review)

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