Ewing Per, Blomgren Bo, Ryrfeldt Ake, Gerde Per
National Institute of Environmental Medicine, Division of Physiology, Karolinska Institutet, Stockholm, Sweden.
Toxicol Sci. 2006 Jun;91(2):332-40. doi: 10.1093/toxsci/kfj104. Epub 2006 Jan 16.
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 microm 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 1 min. For 77 min after the exposure, single-pass perfusate was collected from the lungs. Lungs were then removed and, with the perfusate, analyzed 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.
致癌性多环芳烃（PAHs）主要在进入人体的部位发挥作用。吸入含PAH的气溶胶（如烟草烟雾）后引发肺癌就是一个可能的例子。这种部位偏好的一种推测机制是，高度亲脂性的PAHs通过传导气道较厚的上皮缓慢通过，同时伴有气道上皮中的大量局部代谢。然而，气道上皮很可能在令人惊讶的低暴露水平下就被PAHs饱和。本研究的目的是量化大鼠离体灌注肺（IPL）中吸入苯并(a)芘（BaP）的饱和水平。将BaP以三种不同水平涂覆在直径为3.5微米的二氧化硅载体颗粒上。然后使用DustGun气溶胶发生器在不到1分钟的时间内将分别含有2.2、36和8400纳克BaP的载体颗粒输送到IPL中。暴露后77分钟，从肺中收集单程灌注液。然后取出肺，并与灌注液一起分析BaP和代谢产物。结果表明，肺中吸入BaP的吸收和代谢高度依赖剂量。在低暴露水平下，BaP在黏膜中的吸收与气/血屏障中的浓度成正比，并伴随着大量的局部代谢。在较高暴露水平下，上皮溶解和代谢BaP的能力变得饱和，吸收速率保持恒定，直到结晶BaP溶解，并且该过程中黏膜中产生的BaP代谢产物的比例要小得多。这种现象可能解释了在实验室动物中用含有致癌PAHs的吸入剂诱发肺癌时众所周知的困难，在这种情况下，使用的寿命暴露与人类可能经历的相似，但剂量率要高得多。
