Physiologically based pharmacokinetic models applicable to organogenesis: extrapolation between species and potential use in prenatal toxicity risk assessments.
A physiologically based pharmacokinetic (PBPK) model describing the disposition of 2-methoxyacetic acid (2-MAA; the proximate toxicant derived from oxidation of the ethylene glycol ether, 2-methoxyethanol) was developed in pregnant rodents. This model was validated with pharmacokinetic (PK) data from dams and embryos during major organogenesis. A physiological model of human pregnancy was then combined with the PBPK model and linked to an empirical 2-MAA PK model with 2 maternal compartments and a single or multiple conceptus compartment, depending on the developmental stage. This approach is intended to allow more realistic human pregnancy risk assessments by refining the reference dose calculations via uncertainty factors. It will be possible to eliminate an uncertainty factor of 10 for interspecies extrapolations in the 2-methoxyethanol risk assessment if the PBPK model described here is used.
Welsch
F
F
Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709, USA.
Blumenthal
G M
GM
Conolly
R B
RB
D000085:Acetates / Q000493:pharmacokinetics* / Q000633:toxicity; D000818:Animals; D005026:Ethylene Glycols / Q000633:toxicity*; D005260:Female; D005333:Fetus / Q000187:drug effects*; D006801:Humans; D008954:Models, Biological; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000378:metabolism*; D018570:Risk Assessment
D000085:Acetates; D005026:Ethylene Glycols; C005219:methyl cellosolve; C013598:methoxyacetic acid