Effect of Regenerative Hyperplasia on the Urinary Bladder: Carcinogenicity of Sodium Saccharin and N-[4-(5-Nitro-2-furyl)-2-thiazolyl]formamide¹

The effect of ulceration of the urinary bladder on bladder carcinogenesis induced by N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) or sodium saccharin was evaluated in 5-week-old F344 rats which were all killed 2 years after the start of the experiment. The results indicate that long-term feeding of sodium saccharin, a nonmutagen, appears to be capable of inducing bladder tumors if administered to a rat with a proliferating bladder mucosa even without FANFT “initiation.” Ulceration was induced by freezing. FANFT was fed at a level of 0.2% of the diet for 2 weeks, and sodium saccharin was fed as 5% of the diet for 102 or 104 weeks. Ulceration followed immediately by FANFT administration and then by control diet for 102 weeks did not result in bladder tumors, whereas FANFT administration followed by ulceration and then control diet for a similar period induced bladder tumors. Ulceration followed by FANFT administration and then by 102 weeks of sodium saccharin feeding induced bladder tumors, but ulceration followed by 2 weeks of control diet followed by 102 weeks of sodium saccharin feeding induced a similar incidence of tumors. Ulceration followed immediately by sodium saccharin (fed for 104 weeks) induced a slightly lower incidence of tumors. FANFT followed by sodium saccharin without ulceration induced a single bladder carcinoma, but either chemical alone did not induce bladder tumors. Ulceration of the urinary bladder produced by a single i.p. injection of cyclophosphamide (100 mg/kg) gave similar results as ulceration by freezing. Ulceration alone induced by freezing or cyclophosphamide was followed by a reversible, regenerative nodular and papillary hyperplasia, and the bladder mucosa returned to normal in 3 to 4 weeks after ulceration and remained normal through 2 years. The lack of enhancing effect of FANFT, a potent mutagen, compared to control diet and ulceration induced by cyclophosphamide, a mutagenic alkylating agent, compared to ulceration induced by freezing support the hypothesis of carcinogenesis occurring without mutation. These results may also help to explain the carcinogenicity of sodium saccharin in two-generation and pellet implantation experiments and may assist in the identification of populations with increased susceptibility to bladder cancer.