Gerde P, Muggenburg B A, Henderson R F
Inhalation Toxicology Research Institute, Albuquerque, New Mexico 87185.
Toxicol Appl Pharmacol. 1993 Aug;121(2):328-34. doi: 10.1006/taap.1993.1161.
The disposition of polycyclic aromatic hydrocarbons (PAHs) in the respiratory tract of the Beagle dog was measured and presented in two previous papers. In this paper, the data were used to demonstrate that highly lipophilic toxicants, such as PAHs, were diffusion-limited during clearance from the respiratory tract. Organic toxicants are usually regarded as perfusion-limited during clearance from the lungs. Within minutes after inhalation, the perfusion-limited substance is though to be cleared from all regions of the respiratory tract to the circulating blood. However, the length of time required for appearance of highly lipophilic PAHs in blood exiting the lungs following transient exposures of the alveolar region suggested that alveolar clearance of highly lipophilic PAHs was diffusion-limited. But even though this transport was diffusion-limited, clearance of the highly lipophilic PAH benzo(a)pyrene (BaP) from the thin alveolar epithelium of the dog took only minutes, whereas clearance through the thicker epithelium of the conducting airways took hours. This phenomenon of slow airway clearance results from slower diffusion of highly lipophilic substances through the thicker air/blood barrier of the conducting airways compared to the thinner alveolar epithelium. A direct result of slowed clearance is a high concentration of BaP in the bronchial walls and an increased opportunity for metabolism to reactive forms. For this reason, the bronchial epithelium may become a preferential target of inhaled highly lipophilic toxicants. While the elevated dose during diffusion-limited clearance involves only a few cell layers, the importance of this microdosimetry in contributing to local toxicity should not be overlooked. The findings suggest that bronchial cancer following inhalation exposures is more likely to be induced by highly lipophilic carcinogens such as PAHs than by less lipophilic carcinogens.
在前两篇论文中，已测量并展示了比格犬呼吸道中多环芳烃（PAHs）的分布情况。在本文中，这些数据被用于证明高亲脂性毒物，如多环芳烃，在从呼吸道清除过程中受扩散限制。有机毒物从肺部清除时通常被认为受灌注限制。吸入后几分钟内，受灌注限制的物质被认为会从呼吸道的所有区域清除到循环血液中。然而，在肺泡区域短暂暴露后，血液中出现高亲脂性多环芳烃所需的时间表明，高亲脂性多环芳烃的肺泡清除受扩散限制。但是，即使这种转运受扩散限制，高亲脂性多环芳烃苯并(a)芘（BaP）从犬类薄的肺泡上皮清除仅需几分钟，而通过传导气道较厚上皮的清除则需要数小时。这种气道清除缓慢的现象是由于与较薄的肺泡上皮相比，高亲脂性物质在传导气道较厚的气/血屏障中扩散较慢。清除缓慢的直接结果是支气管壁中BaP浓度升高，以及代谢为活性形式的机会增加。因此，支气管上皮可能成为吸入高亲脂性毒物的优先靶标。虽然在扩散限制清除过程中剂量升高仅涉及少数细胞层，但这种微剂量测定对局部毒性的影响的重要性不应被忽视。研究结果表明，吸入暴露后引发的支气管癌更有可能是由高亲脂性致癌物如多环芳烃引起的，而不是由亲脂性较低的致癌物引起。
