Toxicokinetics of inhaled propylene in mouse, rat, and human

A physiological toxicokinetic (PT) model was developed for inhaled propylen e gas (PE) in mouse, rat, and human. Metabolism was simulated to occur in t he liver (90%) and in the richly perfused tissue group (10%). The partition coefficients tissue:air were determined in vitro using tissues of mice, ra ts, and humans. Most of the tissues have partition coefficients of around 0 .5. Only adipose tissue displays a 10 times higher value. The partition coe fficient 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 Fisch er 344/N rats, parameters of PE metabolism were obtained from gas uptake ex periments. Maximum rates of metabolism (V-maxmo) were 110 mu mol/h/kg in mi ce and 50.4 mu mol/h/kg in rats. V-maxmo/2 was reached in mice at 270 ppm a nd in rats at 400 ppm of atmospheric PE. Pretreatment of the animals with s odium diethyldithiocarbamate resulted in an almost complete inhibition of P E metabolism in both species. Preliminary toxicokinetic data on PE metaboli sm 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 calcul ate PE blood concentrations at steady state. At 25 ppm, the blood values we re comparable across species, with 0.19, 0.32, and 0.34 mu mol/L for mouse, rat, and human, respectively. However, the corresponding rates of PE metab olism differed dramatically, being 8.3, 2.1, and 0.29 mu mo/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 predic tion demonstrates that PE is eliminated so rapidly that it cannot accumulat e 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 th rough the lung and the rate of metabolism is limited by the blood flow thro ugh the metabolizing organs. (C) 2000 Academic Press.