A toxicokinetic study of inhaled ethylene glycol monomethyl ether (2-ME) and validation of a physiologically based pharmacokinetic model for the pregnant rat and human

Exposures to sufficiently high doses of ethylene glycol monomethyl ether (2 -methoxyethanol, 2-ME) have been found to produce developmental effects in rodents and nonhuman primates. The acetic acid metabolite of 2-ME, 2-methox yacetic acid (2-MAA), is the likely toxicant, and, as such, an understandin g of the kinetics of 2-MAA is important when assessing the potential risks to humans associated with 2-ME. A previously described physiologically base d pharmacokinetic (PBPK) model of 2-ME/2-MAA kinetics for rats exposed via oral or iv administration was extended and validated to inhalation exposure s. Pregnant Sprague-Dawley rats were exposed for 5 days (gestation days 11- 15), 6 h/day, to 2-ME vapor at 10 and 50 ppm. Validation consisted of compa ring model output to maternal blood and fetal 2-ME and 2-MAA concentrations during and following 5 days of exposure (gestation days 11-15). These conc entrations correspond to a known no observed effect level (NOEL) and a lowe st observed effect level (LOEL) for developmental effects in rats. The rat PBPK model for 2-ME/2-MAA was scaled to humans and the model (without the p regnancy component) was used to predict data collected by other investigato rs on the kinetics of 2-MAA excretion in urine following exposures to 2-ME in human volunteers. The partially validated human model (with the pregnanc y component) was used to predict equivalent human exposure concentrations b ased on 2-MAA dose measures (maximum blood concentration, C-max, and averag e daily area under the 2-MAA blood concentration curve, AUG, during pregnan cy) that correspond to the concentrations measured at the rat NOEL and LOEL exposure concentrations. Using traditional PBPK scale-up techniques, it wa s calculated that pregnant women exposed for 8 h/day, 5 days/week, for the duration of pregnancy would need to be exposed to 12 or 60 ppm 2-ME to prod uce maternal 2-MAA blood concentrations (C-max or average daily AUG) equiva lent to those in rats exposed to the NOEL (10 ppm) or LOEL (50 ppm), respec tively. (C) 2000 Academic Press.