Development of a physiologically based pharmacokinetic model of 2-methoxyethanol and 2-methoxyacetic acid disposition in pregnant rats.
An accurate description of developing embryos' exposure to a xenobiotic is a desirable component of mechanism-based risk assessments for humans exposed to potential developmental toxicants during pregnancy. 2-Methoxyethanol (2-ME), a solvent used in the manufacture of semiconductors, is embryotoxic and teratogenic in all species tested including nonhuman primates. 2-Methoxyacetic acid (2-MAA) is the primary metabolite of 2-ME and the proximate embryotoxic agent. The objective of the work described here was to adapt an existing physiologically based pharmacokinetic (PBPK) model for 2-ME and 2-MAA kinetics during midorganogenesis in mice to rats on gestation days (GD) 13 and 15. Blood and tissue data were analyzed using the extrapolated PBPK model that was modified to simulate 2-ME and 2-MAA kinetics in maternal plasma and total embryo tissues in pregnant rats. The original mouse model was simplified by combining the embryos and placenta with the richly perfused tissue compartment. The model includes a description of the growth of the developing embryo and changes in the physiology of the dam during pregnancy. Biotransformation pathways of 2-ME to either ethylene glycol (EG) or to 2-MAA were described as first-order processes based on the data collected from rats by Green et al., (Occup. Hyg. 2, 67-75, 1996). Tissue partition coefficients (PCs) for 2-ME and 2-MAA were determined for a variety of maternal tissues and the embryos. Model simulations closely reflected the biological measurement of 2-ME and 2-MAA concentrations in blood and embryo tissue following gavage or iv administration of 2-ME or 2-MAA. The PBPK model for rats as described here is well suited for extrapolation to pregnant women and for assessment of 2-MAA dosimetry under various conditions of possible human exposure to 2-ME.
Hays
S M
SM
ChemRisk Service of McLaren/Hart, Inc., Cleveland, Ohio, USA.
Elswick
B A
BA
Blumenthal
G M
GM
Welsch
F
F
Conolly
R B
RB
Gargas
M L
ML
D000085:Acetates / Q000493:pharmacokinetics* / Q000633:toxicity; D000818:Animals; D001825:Body Fluid Compartments / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000378:metabolism; D005026:Ethylene Glycols / Q000493:pharmacokinetics* / Q000633:toxicity; D005260:Female; D008321:Mammary Glands, Animal / Q000187:drug effects; D051379:Mice; D008954:Models, Biological; D009929:Organ Size / Q000187:drug effects; D010920:Placenta / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000378:metabolism*; D051381:Rats; D013723:Teratogens / Q000493:pharmacokinetics* / Q000633:toxicity; D014018:Tissue Distribution
D000085:Acetates; D005026:Ethylene Glycols; D013723:Teratogens; C005219:methyl cellosolve; C013598:methoxyacetic acid