Pastino G M, Asgharian B, Roberts K, Medinsky M A, Bond J A
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709, USA.
Toxicol Appl Pharmacol. 1997 Jul;145(1):147-57. doi: 10.1006/taap.1997.8161.
Ethanol is added to unleaded gasoline as an oxygenate to decrease carbon monoxide automobile emissions. This introduces inhalation as a new possible route of environmental exposure to humans. Knowledge of the pharmacokinetics of inhaled ethanol is critical for adequately assessing the dosimetry of this chemical in humans. The purpose of this study was to characterize the pharmacokinetics of inhaled ethanol in male and female B6C3F1 mice and F344 rats and to develop a physiologically based pharmacokinetic (PBPK) model for inhaled ethanol in mice, rats, and humans. During exposure to 600 ppm for 6 hr, steady-state blood ethanol concentrations (BEC) were reached within 30 min in rats and within 5 min in mice. Maximum BEC ranged from 71 microM in rats to 105 microM in mice. Exposure to 200 ppm ethanol for 30 min resulted in peak BEC of approximately 25 microM in mice and approximately 15 microM in rats. Peak BEC of about 10 microM were measured following exposure to 50 ppm in female rats and male and female mice, while blood ethanol was undetectable in male rats. No sex-dependent differences in peak BEC at any exposure level were observed. Species-dependent differences were found following exposure to 200 and 600 ppm. A blood flow limited PBPK model for ethanol inhalation was developed in mice, rats, and humans which accounted for a fractional absorption of ethanol. Compartments for the model included the pulmonary blood and air, brain, liver, fat, and rapidly perfused and slowly perfused tissues. The PBPK model accurately simulated BEC in rats and mice at all exposure levels, as well as BEC reported in human males in previously published studies. Simulated peak BEC in human males following exposure to 50 and 600 ppm ranged from 7 to 23 microM and 86 and 293 microM, respectively. These results illustrate that inhalation of ethanol at or above the concentrations expected to occur upon refueling results in minimal BEC and are unlikely to result in toxicity.
乙醇作为一种含氧化合物被添加到无铅汽油中，以减少汽车一氧化碳排放。这使得吸入成为人类环境暴露的一种新的可能途径。了解吸入乙醇的药代动力学对于充分评估该化学物质在人体内的剂量测定至关重要。本研究的目的是表征雄性和雌性B6C3F1小鼠以及F344大鼠吸入乙醇的药代动力学，并建立小鼠、大鼠和人类吸入乙醇的生理药代动力学（PBPK）模型。在暴露于600 ppm 6小时期间，大鼠在30分钟内达到稳态血乙醇浓度（BEC），小鼠在5分钟内达到。最大BEC范围从大鼠的71 microM到小鼠的105 microM。暴露于200 ppm乙醇30分钟导致小鼠的峰值BEC约为25 microM，大鼠约为15 microM。在雌性大鼠以及雄性和雌性小鼠暴露于50 ppm后，测得的峰值BEC约为10 microM，而雄性大鼠血液中未检测到乙醇。在任何暴露水平下均未观察到峰值BEC的性别依赖性差异。在暴露于200和600 ppm后发现了物种依赖性差异。在小鼠、大鼠和人类中建立了一个血流受限的乙醇吸入PBPK模型，该模型考虑了乙醇的部分吸收。该模型的隔室包括肺血液和空气、脑肝、脂肪以及快速灌注和缓慢灌注组织。PBPK模型准确模拟了所有暴露水平下大鼠和小鼠的BEC，以及先前发表的研究中人类男性报告的BEC。人类男性暴露于50和600 ppm后的模拟峰值BEC分别为7至23 microM和86至293 microM。这些结果表明，吸入等于或高于加油时预期浓度的乙醇只会导致最低的BEC，不太可能导致毒性。
