Carcinogenesis, Vol 19, 493-500, Copyright © 1998 by Oxford University Press
P Gerde, BA Muggenburg, GG Scott, JL Lewis, KH Pyon and AR Dahl
While inhaled polycyclic aromatic hydrocarbons have long been suspected to
induce lung cancer in humans, their dosimetry has not been fully
elucidated. A key question is whether the critical exposure occurs during
absorption in the lungs, or if toxicants in the systemic circulation
contribute significantly to lung cancer risk. In particular, data are
needed to determine how the physical properties of inhalants affect local
dosimetry in the respiratory tract. Pyrene, a tobacco smoke component, was
selected for study because it has physical properties between those of
highly lipophilic benzo[a]pyrene and water- soluble nitrosamines. Aliquots
of 5 ng of pyrene dissolved in a phospholipid/ saline suspension were
instilled as a single-spray bolus in the posterior trachea of the dog just
anterior to the carina. For 3 h after instillation, blood was repeatedly
sampled from the azygous vein, which drains the mucosa around the point of
instillation, and from both sides of the systemic circulation. At 3 h
post-instillation, tissue samples were taken. Autoradiography was used to
determine the depth distribution of pyrene in the tracheal mucosa. The
concentration of pyrene-equivalent radioactivity in the azygous vein peaked
9 min after the instillation. At approximately 30 min after instillation, a
rapid early clearance phase shifted into a distinctly slower second
clearance phase. Rates of rapid clearance were, however, sufficiently slow
to indicate diffusion-limited absorption of pyrene in the trachea. This
finding was corroborated by high concentrations of pyrene in the epithelium
as determined by autoradiography. High epithelial concentration of pyrene
combined with a slow penetration into the circulating blood allowed
substantial first-pass metabolic conversion of pyrene in the tracheal
mucosa. A total of 13% of the instilled pyrene was retained in the tracheal
mucosa 3.2 h after instillation; of this, 29% was parent compound, 52% was
organic-extractable metabolites, 14% was water-soluble metabolites and 6%
(approximately 1% of the instilled amount) was covalently bound to tracheal
tissues. Results support the inference that lipophilic protoxicants,
because of slow, diffusion-limited absorption, are more likely than
water-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 distributed
biomarkers of PAHs, such as urinary hydroxypyrene levels, as indicators of
the biologically effective dose in airway target cells.
ARTICLES
Local metabolism in lung airways increases the uncertainty of pyrene as a biomarker of polycyclic aromatic hydrocarbon exposure
Lovelace Respiratory Research Institute, Albuquerque, NM 87185, USA.
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