Respiratory epithelial penetration and clearance of particle-borne benzo[a]pyrene.
Exposure to diesel exhaust is a suspected risk factor for human lung cancer. The carbonaceous core of the soot particles found in diesel exhaust and the condensed organic compounds adsorbed (or bound) onto the surface of the particles are both possible contributors to this suspected risk. The extent and rate at which organic procarcinogens desorb from soot particles in the lungs after environmental and workplace exposures and the degree of metabolic activation in the lungs are also not known. We explored the relationship between a model polynuclear aromatic hydrocarbon (PAH)* and a typical carrier particle by measuring the rate of release, extent of release, and metabolic fate of benzo[a]pyrene (BaP) bound onto the carbonaceous core of diesel soot after bolus aerosol exposures of the dog's peripheral lung and trachea. Exogenous BaP was bound onto preextracted diesel soot at a surface concentration corresponding to 25% of a monomolecular layer. After deposition in the alveolar region, a fraction of BaP was rapidly desorbed from the soot and quickly absorbed into the circulating blood. Release rates then decreased drastically. When the BaP coating reached approximately 16% of a monolayer, it was not bioavailable and remained on the particles after 5.6 months in the lung. The bioavailability of BaP on particles retained in lymph nodes was markedly higher, however: after 5.6 months the surface coating of BaP was reduced to 10% of a monolayer. Fractions of BaP that remained bound to the soot surface during this 5.6 months had a low reactivity-nearly 30% of the radioactive compounds extracted from recovered soot particles were still BaP, the parent compound. In contrast, the rapidly released fraction of BaP, which was quickly absorbed through the alveolar epithelium after inhalation, appeared mostly unmetabolized in the circulation, along with low concentrations of phase I and phase II BaP metabolites. Within approximately 1 hour, however, this rapidly absorbed fraction of BaP was metabolized, most likely in the liver, with the metabolite spectrum being dominated by conjugated phase II metabolites. The fraction of BaP desorbed from particles deposited on the epithelium of the conducting airways was absorbed by the epithelium but slowly penetrated the capillary bed. The absorbed BaP was rapidly metabolized in the airway epithelium, as indicated by the influx of tritiated water (3H2O) from the lungs into the circulation. The results suggest that the dosimetry of inhaled, highly lipophilic BaP during typical exposures is bimodal. The larger fraction of bioavailable BaP deposited in the alveolar region was absorbed mostly unaltered into the blood through the alveolar type I cells and was metabolized systemically. A smaller fraction of bioavailable BaP was deposited on the airway mucosa and rapidly metabolized, most likely in the airway epithelium. The substrate levels of BaP in the epithelium of the conducting airways exceeded the systemic levels by up to two orders of magnitude. This dramatic site-of-entry to systemic duality in the dosimetry of inhaled BaP is likely to be similar in most mammalian species and should be considered in risk assessment models for PAHs in humans.
Gerde
P
P
Karolinska Institute, Institute of Environmental Medicine, Stockholm, Sweden.
Muggenburg
B A
BA
Lundborg
M
M
Tesfaigzi
Y
Y
Dahl
A R
AR
D000818:Animals; D001564:Benzo(a)pyrene / Q000493:pharmacokinetics* / Q000633:toxicity; D001682:Biological Availability; D002244:Carbon / Q000737:chemistry*; D002273:Carcinogens / Q000493:pharmacokinetics* / Q000633:toxicity; D004285:Dogs; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D019570:Inhalation Exposure; D008657:Metabolic Clearance Rate; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000378:metabolism; D014018:Tissue Distribution; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism; D001335:Vehicle Emissions / Q000032:analysis*
D002273:Carcinogens; D001335:Vehicle Emissions; D001564:Benzo(a)pyrene; D002244:Carbon