Andersen M E, Gargas M L, Ramsey J C
Toxicol Appl Pharmacol. 1984 Mar 30;73(1):176-87. doi: 10.1016/0041-008x(84)90065-6.
A method is described for evaluating systemic extraction of soluble vapors during inhalation exposures. The physiological basis of the method is the inability to achieve complete equilibrium of vapor between arterial blood and inhaled air whenever there is substantial extraction of the soluble vapor during a single pass through the systemic circulation. The technique was applied to estimate styrene extraction ratios at the end of 6-hr exposures in male rats exposed to various concentrations of inhaled styrene. From extraction ratios and several physiological constants, metabolic constants were evaluated for styrene metabolism in vivo. In naive rats, the maximum velocity of metabolism was 10.0 mg/kg/hr, and Km was of the order of 0.2 mg/liter. Pretreatment with pyrazole (320 mg/kg, 1/2 hr before exposure) essentially abolished in vivo styrene metabolism, while pretreatment with phenobarbital (80 mg/kg/day for the 4 days before styrene exposure) increased Vmax about sixfold. Prior exposure to styrene (1000 ppm for 6 hr/day on each of 4 days before experimentation) increased Vmax by a factor of 2. Significant induction of styrene metabolism in vivo was observed in 24-hr continuous exposure to 400, 600, or 1200 ppm. A curve fitting routine was employed with a physiological model of styrene inhalation kinetics to estimate the dynamics of the induction process in the 24-hr exposures. At 400 ppm, induction began after a lag of 15.5 hr, had a half-life of 3.5 hr, and reached 2.7 times the Vmax in naive rats. At 600 ppm, it began after 10.6 hr, proceeded with a half-life of 2.2 hr, and increased Vmax by 3.4 times. At 1200 ppm, induction began earlier, 4.6 hr, and reached a greater value, 4.4 times Vmax, but had a half-life similar to that at 600 ppm. No induction occurred in 48-hr exposure to 200 ppm. Induction complicates kinetic modeling of continuous inhalation with soluble, well-metabolized vapors because it is time and concentration dependent. These methods should prove useful for studying the in vivo metabolism of other soluble, well-metabolized vapors and for examining the time course of induction of the metabolizing enzymes for these chemicals.
本文描述了一种评估吸入暴露期间可溶性蒸气全身摄取情况的方法。该方法的生理学基础是，当可溶性蒸气单次通过体循环存在大量摄取时，动脉血和吸入空气之间无法实现蒸气的完全平衡。该技术用于估计暴露于不同浓度吸入苯乙烯的雄性大鼠在6小时暴露结束时的苯乙烯摄取率。根据摄取率和几个生理常数，评估了体内苯乙烯代谢的代谢常数。在未接触过的大鼠中，最大代谢速度为10.0毫克/千克/小时，米氏常数约为0.2毫克/升。用吡唑预处理（320毫克/千克，暴露前半小时）基本上消除了体内苯乙烯代谢，而用苯巴比妥预处理（在苯乙烯暴露前4天每天80毫克/千克）使最大代谢速度增加了约6倍。预先暴露于苯乙烯（实验前4天每天6小时暴露于1000 ppm）使最大代谢速度增加了2倍。在连续24小时暴露于400、600或1200 ppm时，观察到体内苯乙烯代谢有显著诱导。采用曲线拟合程序结合苯乙烯吸入动力学的生理模型来估计24小时暴露中诱导过程的动态变化。在400 ppm时，诱导在15.5小时的滞后时间后开始，半衰期为3.5小时，达到未接触过的大鼠最大代谢速度的2.7倍。在600 ppm时，它在10.6小时后开始，半衰期为2.2小时，最大代谢速度增加了3.4倍。在1200 ppm时，诱导开始得更早，为4.6小时，达到更高的值，最大代谢速度的4.4倍，但半衰期与600 ppm时相似。在48小时暴露于200 ppm时未发生诱导。诱导使连续吸入可溶性、易代谢蒸气的动力学建模变得复杂，因为它与时间和浓度有关。这些方法应证明对研究其他可溶性、易代谢蒸气的体内代谢以及检查这些化学物质代谢酶诱导的时间进程有用。
