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 di sposition of 2-methoxyacetic acid (2-MAA: the proximate toxicant deriv ed from oxidation of the ethylene glycol ether, 2-methoxyethanol) was developed in pregnant rodents. This model was validated with pharmacok inetic (PK) data from dams and embryos during major organogenesis. A p hysiological model of human pregnancy was then combined with the PBPK model and linked to an empirical 2-MAA PK model with 2 maternal compar tments and a single or multiple conceptus compartment, depending on th e developmental stage. This approach is intended to allow more realist ic human pregnancy risk assessments by refining the reference dose cal culations via uncertainty factors. It will be possible to eliminate an uncertainty factor of 10 for interspecies extrapolations in the 2-met hoxyethanol risk assessment if the PBPK model described here is used.