Effect of Carcinogen Release Rate on the Incidence of Preneoplastic and Neoplastic Lesions of the Respiratory Tract Epithelium in Rats23

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Abstract
Inbred F344 rat tracheal transplants were exposed to 7,12-dimethylbenz[α ]anthracene (DMBA) delivered at different release rates from intraluminal pellets made of various matrices to study the effect of carcinogen dose rate on the induction of lesions in the epithelium. These matrices were beeswax, beeswax-stearyl alcohol, and beeswax-cholesterol. In addition, DMBA adsorbed onto carbon particles was dispersed in beeswax-stearyl alcohol. The fastest release was obtained from beeswax pellets from which 99% of the carcinogen (198 μg) was released in 4 weeks, and the slowest release was from DMBA adsorbed on carbon at a ratio of 1:9 from which only 56% (113 μg) was released in 16 weeks. Morphometry of histologic sections showed marked differences in the percentage of luminal surface covered by dysplastic-neoplastic epithelium (i.e., 7.5% in the tracheas exposed to the fastest releasing pellets and 46.3% in the tracheas exposed to the slowest releasing pellets). An inverse linear correlation was found between the cumulative amount of DMBA released from the different pellet matrices at 2 weeks and the incidence of dysplastic plus neoplastic lesions of tracheal epithelium at 16 weeks. The results indicate that lower doses of carcinogen delivered slowly are more effective in producing dysplastic plus neoplastic lesions than higher doses delivered rapidly.