Physiologically based pharmacokinetic model for chronic inhalation of 2-butoxyethanol

2-Butoxyethanol (2BE) is used extensively in the production of cleaning age nts and as a general solvent. It is primarily metabolized in the liver to 2 -butoxyacetic acid (2BAA), which is excreted in urine. The objective of thi s study was to develop a physiologically based pharmacokinetic (PBPK) model describing the toxicokinetic behavior of 2BE and 2BAA in different species following repeated, long-term exposures. The PBPK model was first develope d for short-term 2BE exposure to male rats. Allometric scaling was employed to estimate physiological and biochemical model parameters based on body w eight. To accommodate differences in 2BE toxicokinetics in female rats, a h igher V-max for 2BE metabolism to 2BAA, higher plasma protein binding sites for 2BAA, and lower V-max for 2BAA excretion through the kidney were incor porated into the model. For mice, a higher V-max for 2BE metabolism to 2BAA for both sexes and higher plasma protein binding sites for 2BAA for female mice were also incorporated into the model. Subsequently, the model was ex panded to simulate 2BE and 2BAA toxicokinetics far long-term, repeated expo sures by incorporating time-dependent changes in model parameters. To refle ct physiological/biochemical changes in animals during a chronic exposure, parameters for cardiac output, body composition, metabolic capacity, protei n binding, or capacity of renal excretion were adjusted over time depending on species and sex. Sensitivity analysis was performed to better understan d how sensitive model responses were to uncertainties in input parameters. The resulting PBPK model was used to simulate toxicokinetic data acquired d uring a 2-year inhalation toxicity and carcinogenicity study in male and fe male F344/N rats and B6C3F1 mice. (C) 1998 Academic Press.