Investigation of the Role of Saccharin and Its Physiological Effects in the Genesis of Morphological Lesions and the Promotion of Neoplastic Development in the Rat Urothelium

摘要

Saccharin has been reported to induce urinary bladder tumors in certain multi-generation fat feeding studies, to promote bladder carcinogenesis in rats initiated with known bladder carcinogens, and to cause marked changes in the urine composition of animals. These effects have been noted only at levels of administration near or exceeding the maximum tolerated dose. Information was needed on the appropriateness of the high doses of saccharin used in previous studies, and whether these levels may have indirectly, through physiological disturbances caused or promoted neoplastic development. To examine the dose-dependent effects of saccharin on the putatively related changes in urine composition and on tumor promotion, sodium saccharin was administered at six levels in the diet (5.0, 2.5, 1.0, 0.5, 0.1 and 0%) to female Sprague-Dawley rats which had received, by urethral instillation into the bladder, either a single dose of saline or an initiating dose of N-methyl-N-nitrosourea (MNU), a potent direct-acting carcinogen. Additional groups with and without MNU treatment received: (1) sodium saccharin (2%) in the drinking water; (2) acid-saccharin (5%) in the diet; or (3) MNU, four weekly doses, as a positive control.