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

• Published in: Toxicology and applied pharmacology 2000-05, Vol.165 (1), p.53-62
• Main Authors: Gargas, Michael L., Tyler, Tipton R., Sweeney, Lisa M., Corley, Richard A., Weitz, Karl K., Mast, Terryl J., Paustenbach, Dennis J., Hays, Sean M.
• Format: Article
• Language: English
• Subjects: 2-methoxyacetic acid; 2-Methoxyethanol; Acetates - pharmacokinetics; Acetates - urine; Animals; Biological and medical sciences; Chemical and industrial products toxicology. Toxic occupational diseases; Ethylene Glycols - pharmacokinetics; Ethylene Glycols - toxicity; Ethylene Glycols - urine; Female; Humans; Immunosuppressive Agents - pharmacokinetics; Immunosuppressive Agents - urine; Inhalation Exposure; Medical sciences; methyl cellosolve; Models, Biological; physiologically based pharmacokinetic (PBPK) model; Predictive Value of Tests; Pregnancy; Radiotherapy Planning, Computer-Assisted; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Solvents; Teratogens - pharmacokinetics; Teratogens - toxicity; Toxicology
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1006/taap.2000.8928

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-methoxyacetic acid (2-MAA), is the likely toxicant, and, as such, an understanding of the kinetics of 2-MAA is important when assessing the potential risks to humans associated with 2-ME. A previously described physiologically based pharmacokinetic (PBPK) model of 2-ME/2-MAA kinetics for rats exposed via oral or iv administration was extended and validated to inhalation exposures. 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 comparing 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 concentrations correspond to a known no observed effect level (NOEL) and a lowest 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 pregnancy component) was used to predict data collected by other investigators on the kinetics of 2-MAA excretion in urine following exposures to 2-ME in human volunteers. The partially validated human model (with the pregnancy component) was used to predict equivalent human exposure concentrations based on 2-MAA dose measures (maximum blood concentration, Cmax, and average daily area under the 2-MAA blood concentration curve, AUC, during pregnancy) that correspond to the concentrations measured at the rat NOEL and LOEL exposure concentrations. Using traditional PBPK scale-up techniques, it was 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 produce maternal 2-MAA blood concentrations (Cmax or average daily AUC) equivalent to those in rats exposed to the NOEL (10 ppm) or LOEL (50 ppm), respectively.