Local metabolism in lung airways increases the uncertainty of pyrene as a biomarker of polycyclic aromatic hydrocarbon exposure

While inhaled polycyclic aromatic hydrocarbons have long been suspected toinduce lung cancer in humans, their dosimetry has not been fullyelucidated. A key question is whether the critical exposure occurs duringabsorption in the lungs, or if toxicants in the systemic circulationcontribute significantly to lung cancer risk. In particular, data areneeded to determine how the physical properties of inhalants affect localdosimetry in the respiratory tract. Pyrene, a tobacco smoke component, wasselected for study because it has physical properties between those ofhighly lipophilic benzo[a]pyrene and water- soluble nitrosamines. Aliquotsof 5 ng of pyrene dissolved in a phospholipid/ saline suspension wereinstilled as a single-spray bolus in the posterior trachea of the dog justanterior to the carina. For 3 h after instillation, blood was repeatedlysampled from the azygous vein, which drains the mucosa around the point ofinstillation, and from both sides of the systemic circulation. At 3 hpost-instillation, tissue samples were taken. Autoradiography was used todetermine the depth distribution of pyrene in the tracheal mucosa. Theconcentration of pyrene-equivalent radioactivity in the azygous vein peaked9 min after the instillation. At approximately 30 min after instillation, arapid early clearance phase shifted into a distinctly slower secondclearance phase. Rates of rapid clearance were, however, sufficiently slowto indicate diffusion-limited absorption of pyrene in the trachea. Thisfinding was corroborated by high concentrations of pyrene in the epitheliumas determined by autoradiography. High epithelial concentration of pyrenecombined with a slow penetration into the circulating blood allowedsubstantial first-pass metabolic conversion of pyrene in the trachealmucosa. A total of 13% of the instilled pyrene was retained in the trachealmucosa 3.2 h after instillation; of this, 29% was parent compound, 52% wasorganic-extractable metabolites, 14% was water-soluble metabolites and 6%(approximately 1% of the instilled amount) was covalently bound to trachealtissues. Results support the inference that lipophilic protoxicants,because of slow, diffusion-limited absorption, are more likely thanwater-soluble protoxicants to be bioactivated in the lining epithelium and,in turn, induce first-pass toxicity at the site of entry. In addition,limitations were identified in the use of systemically distributedbiomarkers of PAHs, such as urinary hydroxypyrene levels, as indicators ofthe biologically effective dose in airway target cells.