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-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, C(max), 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 (C(max) or average daily AUC) equivalent to those in rats exposed to the NOEL (10 ppm) or LOEL (50 ppm), respectively.
Gargas
M L
ML
ChemRisk, A Service of McLaren/Hart, Inc., Cleveland, Ohio, USA.
Tyler
T R
TR
Sweeney
L M
LM
Corley
R A
RA
Weitz
K K
KK
Mast
T J
TJ
Paustenbach
D J
DJ
Hays
S M
SM
D000085:Acetates / Q000493:pharmacokinetics / Q000652:urine; D000818:Animals; D005026:Ethylene Glycols / Q000493:pharmacokinetics* / Q000633:toxicity / Q000652:urine; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000652:urine; D019570:Inhalation Exposure; D008954:Models, Biological; D011237:Predictive Value of Tests; D011247:Pregnancy; D011880:Radiotherapy Planning, Computer-Assisted; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D013723:Teratogens / Q000493:pharmacokinetics* / Q000633:toxicity
D000085:Acetates; D005026:Ethylene Glycols; D007166:Immunosuppressive Agents; D013723:Teratogens; C005219:methyl cellosolve; C013598:methoxyacetic acid