ToxSci Advance Access published online on January 16, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfj104
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1 National Institute of Environmental Medicine, Division of Physiology, Karolinska Institutet, Stockholm, Sweden
* To whom correspondence should be addressed. The carcinogenic polycyclic aromatic hydrocarbons (PAHs) are active primarily at the site-of-entry to the body. Lung cancer following inhalation of PAH-containing aerosols such as tobacco smoke is one likely example. A suggested mechanism for this site preference is a slow passage of the highly lipophilic PAHs through the thicker epithelia of the conducting airways, accompanied by substantial local metabolism in airway epithelium. However, it is likely that the airway epithelium will become saturated with PAHs at surprisingly low exposure levels. The purpose of this research was to quantify the level of saturation for inhaled benzo(a)pyrene (BaP) in the isolated, perfused lung (IPL) of the rat. BaP was coated onto carrier particles of silica 3.5 µm diameter at three different levels. The DustGun aerosol generator was then used to deliver respectively 2.2, 36, and 8400 ng of BaP to the IPL with the carrier particles in less than one min. For 77 min after the exposure, single-pass perfusate was collected from the lungs. Lungs were then removed and with the perfusate analysed for BaP and metabolites. Results show that the absorption and metabolism of inhaled BaP in the lungs was highly dose dependent. At low exposure levels absorption of BaP in the mucosa was proportional to the concentration in the air-blood barrier and proceeded with substantial local metabolism. At higher exposure levels the capacity of the epithelium to dissolve and metabolize BaP became saturated and the absorption rate remained constant until crystalline BaP had dissolved, and the process proceeded with much smaller fractions of BaP metabolites produced in the mucosa. This phenomenon may explain the well-known difficulties of inducing lung cancer in laboratory animals with inhalants containing carcinogenic PAHs, where similar lifespan exposures are used as humans may experience but with much higher dose rates.
Received October 28, 2005
Accepted January 9, 2006
Biotransformation and Toxicokinetics
Increasing Exposure Levels Cause an Abrupt Change in the Absorption and Metabolism of Acutely Inhaled Benzo(a)pyrene in the Isolated, Ventilated, and Perfused Lung of the Rat
Per Ewing 1,
Bo Blomgren 2,
Åke Ryrfeldt 1,
and
Per Gerde 1 *
2 Astra Zeneca Ltd, Safety Assessment, Södertälje, Sweden; Uppsala University, Department of Women's & Children's Health, Uppsala, Sweden
Per Gerde, E-mail: Per.Gerde{at}ki.se
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