A COMPARISON OF PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL PREDICTIONS AND EXPERIMENTAL-DATA FOR INHALED ETHANOL IN MALE AND FEMALE B6C3F(1) MICE, F344 RATS, AND HUMANS

Ethanol is added to unleaded gasoline as an oxygenate to decrease carb on monoxide automobile emissions. This introduces inhalation as a new possible route of environmental exposure to humans. Knowledge of the p harmacokinetics of inhaled ethanol is critical for adequately assessin g the dosimetry of this chemical in humans. The purpose of this study was to characterize the pharmacokinetics of inhaled ethanol in male an d female B6C3F(1) 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 et hanol concentrations (BEC) were reached within 30 min in rats and with in 5 min in mice. Maximum BEC ranged from 71 mu M in rats to 105 mu M in mice. Exposure to 200 ppm ethanol for 30 min resulted in peak BEC o f approximately 25 mu M in mice and approximately 15 mu M in rats. Pea k BEC of about 10 mu M were measured following exposure to 50 ppm in f emale rats and male and female mice, while blood ethanol was undetecta ble in male rats. No sex-dependent differences in peak BEC at any expo sure level were observed. Species-dependent differences were found fol lowing exposure to 200 and 600 ppm. A blood flow limited PBPK model fo r ethanol inhalation was developed in mice, rats, and humans which acc ounted for a fractional absorption of ethanol. Compartments for the mo del included the pulmonary blood and air, brain, liver, fat, and rapid ly perfused and slowly perfused tissues. The PBPK model accurately sim ulated BEC in rats and mice at all exposure levels, as well as BEC rep orted in human males in previously published studies. Simulated peak B EC in human males following exposure to 50 and 600 ppm ranged from 7 t o 23 mu M and 86 and 293 mu M, 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. (C) 1997 Academic Press.