Disposition of polycyclic aromatic hydrocarbons in the respiratory tract of the beagle dog. III. Mechanisms of the dosimetry.

The disposition of polycyclic aromatic hydrocarbons (PAHs) in the respiratory tract of the Beagle dog was measured and presented in two previous papers. In this paper, the data were used to demonstrate that highly lipophilic toxicants, such as PAHs, were diffusion-limited during clearance from the respiratory tract. Organic toxicants are usually regarded as perfusion-limited during clearance from the lungs. Within minutes after inhalation, the perfusion-limited substance is though to be cleared from all regions of the respiratory tract to the circulating blood. However, the length of time required for appearance of highly lipophilic PAHs in blood exiting the lungs following transient exposures of the alveolar region suggested that alveolar clearance of highly lipophilic PAHs was diffusion-limited. But even though this transport was diffusion-limited, clearance of the highly lipophilic PAH benzo(a)pyrene (BaP) from the thin alveolar epithelium of the dog took only minutes, whereas clearance through the thicker epithelium of the conducting airways took hours. This phenomenon of slow airway clearance results from slower diffusion of highly lipophilic substances through the thicker air/blood barrier of the conducting airways compared to the thinner alveolar epithelium. A direct result of slowed clearance is a high concentration of BaP in the bronchial walls and an increased opportunity for metabolism to reactive forms. For this reason, the bronchial epithelium may become a preferential target of inhaled highly lipophilic toxicants. While the elevated dose during diffusion-limited clearance involves only a few cell layers, the importance of this microdosimetry in contributing to local toxicity should not be overlooked. The findings suggest that bronchial cancer following inhalation exposures is more likely to be induced by highly lipophilic carcinogens such as PAHs than by less lipophilic carcinogens.