TUMORIGENICITY OF SODIUM ASCORBATE IN MALE RATS

Sodium ascorbate, like other sodium salts such as saccharin, glutamate , and bicarbonate, produces urinary alterations when fed at high doses to rats, which results in mild superficial urothelial cytotoxicity an d regeneration but not tumors in a standard 2-year bioassay, Sodium sa ccharin was shown to produce a low incidence of bladder tumors in rats if administered in a two-generation bioassay, In the present study, w e evaluated sodium ascorbate in a two-generation bioassay that involve d feeding to the male and female parental F344 rats for 4 weeks before mating, feeding the dams during gestation and lactation, and then fee ding the weaned (at 28 days of age) male F-1 generation rats for the r emainder of their lifetime (up to 128 weeks of the experiment). Dietar y levels of 1.0, 5.0, and 7.0% sodium ascorbate were tested. At 5.0 an d 7.0% sodium ascorbate, there was an increase in urinary bladder urot helial papillary and nodular hyperplasia and the induction of a few pa pillomas and carcinomas. There was a dose-responsive increase in renal pelvic calcification and hyperplasia and inhibition of the aging neph ropathy of rats even at the level of 1% sodium ascorbate, Because the short-term urothelial effects of sodium ascorbate in rats are inhibite d by treatments producing urinary acidifi cation to pH < 6.0, we coadm inistered high doses of long-term NH4Cl to groups of rats with 5.0 or 7.0% sodium ascorbate to evaluate the longterm effects. The combinatio n of 7.0% sodium ascorbate plus 2.78% NH4Cl in the diet was toxic, and the group was terminated early during the course of the experiment. T he group fed 5.0% sodium ascorbate plus 2.04 NH4Cl showed complete inh ibition of the urothelial effects of sodium ascorbate and significant inhibition of its renal effects. We also demonstrated the presence of a calcium phosphate-containing urinary precipitate in rats fed sodium ascorbate at all doses, in a dose-responsive manner. The formation of the precipitate was inhibited by coadministration with NH4Cl. The prol iferative effects of sodium ascorbate on the male rat urinary tract in this study are similar to those seen with sodium saccharin when admin istered in a two-generation bioassay, Mechanistic information suggests that this is a high-dose, rat-specific phenomenon.