Acrolein initiates rat urinary bladder carcinogenesis.

Acrolein, a reactive, alpha,beta-unsaturated aldehyde which is ubiquitous in the environment, forms DNA adducts, is mutagenic, and is teratogenic. However, studies have not indicated a carcinogenic effect in rodent bioassays. Since it is present in cigarette smoke and is the toxic metabolite of cyclophosphamide with respect to the urinary tract, we investigated the possibility that acrolein might have carcinogenic activity toward the rat urinary bladder. We also evaluated whether it possessed initiating and/or promoting activity. To evaluate initiating activity, acrolein was administered at a dose of 2 mg/kg i.p. twice a week for 6 weeks followed by uracil as 3% of the diet for 20 weeks and then control diet for 6 weeks. N-[4-(5-Nitro-2-furyl)-2-thiazolyl]formamide (FANFT) as 0.2% of the diet followed by uracil was used as a positive control, and a negative control group was administered solvent control (water) i.p. during the 6-week initiation period followed by uracil. Acrolein followed by uracil produced an incidence of 18 of 30 rats (60%) with papilloma compared to 8 of 30 rats (27%) treated with solvent control followed by uracil. FANFT followed by uracil produced an incidence of 70% carcinomas and 30% papillomas, clearly indicating that it is a much more potent initiating agent than acrolein. Acrolein for 6 weeks followed by control diet produced no tumors. To evaluate promoting activity, groups of rats were fed FANFT for 6 weeks followed by acrolein. Acrolein administered during the initial 6 weeks and continued for the second phase of the experiment (to evaluate complete carcinogenic activity) resulted in severe toxicity. Administration of acrolein had to be terminated after 21 weeks of the experiment. The animals were maintained for 53 weeks of the experiment without further chemical treatment, and there was no evidence of papilloma or carcinoma development. This study clearly indicates that acrolein has initiating activity for the urinary bladder when administered by i.p. injection to the male F344 rat, but toxicity precluded evaluation of its promoting or complete carcinogenic activity.