Particle-Associated Hydrocarbons and Lung Cancer: the Correlation Between Cellular Dosimetry and Tumor Distribution

Abstract

The well-known correlation between patterns of particle deposition in the human bronchial tree and the apparent sites of origin of primary bronchial tumors is paradoxical because clearance of inhaled particles from the bronchi is comparatively rapid, leading to a short exposure time. However, there may be a dosimetric link between the deposition of highly lipophilic carcinogens such as polycyclic aromatic hydrocarbons (PAHs) reversibly adsorbed on inhaled particles, and the distinctive distribution of preneoplastic and neoplastic lesions in the lungs. We have demonstrated that once desorbed from the particles, highly lipophilic PAHs are diffusion-limited during clearance through the airway epithelium to the capillary blood. In the Beagle dog, clearance of benzo(a)pyrene (BaP) to the blood takes only minutes in the alveoli, while in the thicker epithelium of the bronchi, clearance may take hours. The slowed clearance results in a high concentration of the PAHs in the bronchial epithelium and an increased opportunity for metabolism to reactive forms. In contrast, less lipophilic substances are perfusion-limited during clearance and are likely to clear within minutes from all regions of the lungs to the circulating blood. The greater likelihood of highly lipophilic toxicants to induce first-pass toxicity during diffusion-limited clearance links the seemingly independent parameters of lipophilicity and particle-association and gives a plausible explanation for the relationship between particle deposition patterns and the distribution of tumors in the bronchial tree. This new information on microdosimetry of PAHs in the lungs should improve risk assessments of exposure to inhaled particle-associated hydrocarbons.