Filser J G, Schmidbauer R, Rampf F, Baur C M, Pütz C, Csanády G A
GSF-Institute of Toxicology, Neuherberg, Germany.
Toxicol Appl Pharmacol. 2000 Nov 15;169(1):40-51. doi: 10.1006/taap.2000.9027.
A physiological toxicokinetic (PT) model was developed for inhaled propylene gas (PE) in mouse, rat, and human. Metabolism was simulated to occur in the liver (90%) and in the richly perfused tissue group (10%). The partition coefficients tissue:air were determined in vitro using tissues of mice, rats, and humans. Most of the tissues have partition coefficients of around 0.5. Only adipose tissue displays a 10 times higher value. The partition coefficient blood:air in human is 0.44, about half of that in rodents. PE can accumulate in the organism only barely. For male B6C3F1 mice and male Fischer 344/N rats, parameters of PE metabolism were obtained from gas uptake experiments. Maximum rates of metabolism (V(maxmo)) were 110 micromol/h/kg in mice and 50.4 micromol/h/kg in rats. V(maxmo)/2 was reached in mice at 270 ppm and in rats at 400 ppm of atmospheric PE. Pretreatment of the animals with sodium diethyldithiocarbamate resulted in an almost complete inhibition of PE metabolism in both species. Preliminary toxicokinetic data on PE metabolism in humans were obtained in one volunteer who was exposed up to 4.5 h to constant concentrations of 5 and 25 ppm PE. The PT model was used to calculate PE blood concentrations at steady state. At 25 ppm, the blood values were comparable across species, with 0.19, 0.32, and 0.34 micromol/L for mouse, rat, and human, respectively. However, the corresponding rates of PE metabolism differed dramatically, being 8.3, 2.1, and 0.29 micromol/h/kg in mouse, rat, and human. For a repeated human exposure to 25 ppm PE in air (8 h/day, 5 days/week), PE concentrations in venous blood were simulated. The prediction demonstrates that PE is eliminated so rapidly that it cannot accumulate in the organism. For low exposure concentrations, it became obvious that the rate of uptake into blood by inhalation is limited by the blood flow through the lung and the rate of metabolism is limited by the blood flow through the metabolizing organs.
建立了小鼠、大鼠和人类吸入丙烯气体（PE）的生理毒代动力学（PT）模型。模拟代谢发生在肝脏（90%）和血液灌注丰富的组织组（10%）中。使用小鼠、大鼠和人类的组织在体外测定组织：空气分配系数。大多数组织的分配系数约为0.5。只有脂肪组织的分配系数值高10倍。人类血液：空气分配系数为0.44，约为啮齿动物的一半。PE在生物体中几乎不会蓄积。对于雄性B6C3F1小鼠和雄性Fischer 344/N大鼠，PE代谢参数通过气体摄取实验获得。小鼠的最大代谢速率（V(maxmo)）为110微摩尔/小时/千克，大鼠为50.4微摩尔/小时/千克。大气中PE浓度为270 ppm时小鼠达到V(maxmo)/2，400 ppm时大鼠达到V(maxmo)/2。用二乙基二硫代氨基甲酸钠预处理动物导致两个物种的PE代谢几乎完全受到抑制。在一名志愿者中获得了人类PE代谢的初步毒代动力学数据，该志愿者暴露于5和25 ppm PE的恒定浓度下长达4.5小时。PT模型用于计算稳态下的PE血药浓度。在25 ppm时，各物种的血药浓度相当，小鼠、大鼠和人类分别为0.19、0.32和0.34微摩尔/升。然而，相应的PE代谢速率差异很大，小鼠、大鼠和人类分别为8.3、2.1和0.29微摩尔/小时/千克。对于人类重复暴露于空气中25 ppm的PE（每天8小时，每周5天），模拟了静脉血中的PE浓度。预测表明PE消除迅速，不会在生物体中蓄积。对于低暴露浓度，很明显吸入血液的摄取速率受肺血流量限制，代谢速率受代谢器官血流量限制。
