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Intact urothelial cells isolated from bladders of untreated inbred NZO/BIGd or NZC/BIGd mice and NZR/Gd rats activated dimethyl, diethyl, dipropyl, and dibutyl nitrosamines in a liquid culture mutagenesis fluctuation assay using Salmonella typhimurium TA100 as target organism. Rat and mouse urothelial cells were highly effective at 1.5 X 10(5) cells/ml, in O2 gas phase, and no cofactors were required. Relative mutagenic activities were estimated at equitoxic (LD50) concentrations of the 4 nitrosamines. Nitrosamines with odd-carbon chain substitutents were more active than the C-even compounds. Although dibutylnitrosamine is a powerful bladder carcinogen in both rats and mice while the other 3 compounds very rarely cause bladder tumours, the most active promutagens were dipropyl and dimethyl, followed by diethyl and dibutyl nitrosamines. None were active in absence of urothelial cells. Mouse bladder cells were more active than those from NZR rats. There were sex differences in the mice with NZC males and NZO females predominating, but in NZR rats urothelial cells from male and female animals were equally active. These dialkylnitrosamines are widely distributed in the environment, and our results indicate that direct mutagenic activation in the urothelium could be one factor contributing to the incidence of bladder cancer.

In NZO inbred mice a single dose of dimethylnitrosamine (DMN) induced kidney tumors in males only; females did not develop kidney tumors even when the dose of DMN was doubled. Orchiectomy before DMN injection abolished the kidney tumor response in male mice. These observations imply that androgens are essential for renal carcinogenesis by DMN in the NZO mouse.

Endocrine modulation of DMN carcinogenesis was studied in NZR/Gd rats preconditioned by starving 48 hr and then injected i.p. once with 20 mg DMN/kg. Intact rats developed kidney tumors (44% TBA), most of tubular epithelial type resembling human tumors rather than mesenchymal. Thyroidectomy (Tx) 45 days before DMN significantly enhanced DMN carcinogenesis, renal carcinoma incidence increasing to 69%. Renal carcinomas showed more signs of malignancy in Tx rats. Other neoplastic responses useful for further studies including tumors in nasal epithelium (13%), liver (18%, increased to 59% in Tx rats), and lung (40%): these tumors were rare or not previously reported in single-dose experiments in other rat strains. A sex difference in lung tumor incidence (male 70%, female 16%) was statistically significant and thyroidectomy reduced the sex-differential (to 54% and 39% respectively). The increased incidence of kidney and liver tumors could be due to altered metabolism of DMN in tissues of Tx rats.

Dimethylnitrosamine (DMN) induced a significant incidence (45.5%) of kidney epithelial tumors in adult male Balb/C mice. The proportion of mice with renal tumors orchiectomized after DMN injection was reduced to 25.6%; whereas the proportion of tumor bearing animals at other sites, such as lung, liver, and lymphatic tissue, increased compared to intact DMN treated animals and controls. This experiment confirms other studies in rats and mice showing that androgens play a role in initiation and progression of nitrosamine induced renal cancer, paralleling the finding of increased male susceptibility in human renal cancer.