This research will address the major hypothesis that inhaled, highly lipophilic compounds, including some procarcinogens, are metabolized to a much greater extent in the respiratory tract than are less lipophilic ones and that metabolism in thick epithelia is much more extensive than in thin epithelia. It is proposed, based on theoretical considerations, that highly lipophilic compounds, including some procarcinogens, will attain high concentrations within the thick epithelia of the lung bronchi and, perhaps, of the nasal cavity, while less lipophilic compounds will attain much lower concentrations in these tissues. In turn, the clearance of highly lipophilic compounds from thick epithelia will depend in large part upon metabolism, with possible attendant activation of procarcinogens to genotoxicants. Clearance of less lipophilic compounds from thick epithelia will be mainly by transport of the parent compound in the blood and will involve relatively little metabolism. Clearance of both highly lipophilic and less lipophilic compounds from the thin epithelia of the peripheral lung will be mainly by transport of parent molecules in the blood. By implication, if the major hypothesis is correct, the carcinogenicity of inhaled procarcinogens in the respiratory tract may be greatest in thick epithelia and highly lipophilic inhaled procarcinogens, will be metabolized in the lung, with possible activation, to a greater extent than relatively less lipophilic ones. The major hypothesis will be tested by experimentally determining in the peripheral lung, the bronchi and the nasal respiratory and olfactory epithelia of the Beagle dog, the in vivo metabolism and clearance rates of instilled benzo(a)pyrene (BaP), a highly lipophilic procarcinogen that causes lung and nasal tumors following inhalation, and of an instilled nitrosamine, NNK, a relatively less lipophilic procarcinogen that causes lung and nasal cancer following systemic administration. Limited experiments with two additional compounds, highly-lipophilic dotriacontane (DTC) and water-miscible nicotine, will be carried out to test the generality of the results obtained using BaP and NNK and limited experiments in the rat will be used to test the generality of results obtained in the dog. The results will be used to validate a mathematical model suitable for modeling the fate of inhaled organic compounds in people by inputting the relevant human physiological constants.
