A Quantitative Dosing Schedule for the Induction of Transitional Cell Carcinomas in Female F344 Rats With the Use of N-Butyl-N-(4-hydroxybutyl)nitrosamine2

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Abstract
Transitional cell carcinomas (TCC) of the urinary bladder were induced in female F344 rats by gastric intubation of N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN) with the use of a quantitative dosing schedule. Animals received 100, 150, or 200 mg OH-BBN per intubation two times each week for 6 weeks, i.e., a total dose of 1,200, 1,800, or 2,400 mg OH-BBN, respectively. The diagnosis of TCC was based on the presence of invasion of the underlying connective tissue or smooth muscle. Varying degrees of squamous and/or glandular metaplasia were observed in many of the TCC. Proliferative epithelial lesions included noninvasive papillomas and discrete hyperplastic lesions that did not meet the diagnostic criteria necessary for classification as carcinomas. At 6 months after the first carcinogen intubation, 50%, 40%, and 40% of the animals exhibited discrete proliferative lesions with atypical epithelium (cellular atypia score, +2 or greater), and 20%, 60%, and 60% presented with TCC at the respective OH-BBN doses. At 1 year, 10%, 10%, and 13% of the animals presented with discrete proliferative lesions with atypical epithelium (cellular atypia score, +2 or greater), and a 90%, 80%, and 100% incidence of TCC was observed, respectively. These data suggest that discrete proliferative lesions with atypical epithelium observed at 6 months progressed to TCC by 1 year. This model results in invasive lesions similar to the human counterpart but has the advantage of a short latency of cancer appearance. The use of females also avoids the complication of bladder stones, which are more frequent in males.

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