Development and evaluation of a pregnancy Physiologically Based Toxicokinetic (pPBTK) model for high-throughput application

Abstract : In utero exposures to chemicals have been associated with adverse effects that can be observed over the whole lifetime. These exposures are commonly assessed with cord sampling at delivery or maternal sampling over the pregnancy. Pregnancy physiologically-based toxicokinetic (pPBTK) models are adequate tools for estimating the internal exposure of the fetus throughout pregnancy. We reviewed the placental transfers of chemicals described in published pPBTK models and compared the impact of the model structure on the fetal dosimetry. We also proposed a placental transfer structure accounting for both histiotrophic (trophoblastic plugs block the spiral arteries in the 1st trimester) and hemotrophic (spiral arteries inflow the intervillous space with maternal blood in the 2nd and 3rd trimesters) nutrition phases. It comprises two diffusional constants separating maternal placenta, intervillous space and fetal placenta. Under a single dose exposure, four patterns of fetal dosimetry were observed and related to assumptions about the number of diffusion constants between maternal and fetal blood. The placental transfer model was integrated in a pPBTK model that is an extension of the generic PBTK model included in the httk R package. Two types of parameterization were tested for the placental diffusional constant between intervillous space and fetal placental compartment, either with a semi-empirical equation or with a passive diffusion clearance scaling method based on in vitro apparent permeabilities. The model predictions were evaluated with published data. It shows a good predictive capacity as predictions of maternal and cord serum concentrations felt into the 10-fold range of observed concentrations. The type of placental diffusion constant parameterization does not influence the classification of fetal to maternal exposure ratios. Our pPBTK model coupled with in silico tools or in vitro data for parametrization can be used to assess the in utero exposures for a wide range of chemicals throughout pregnancy.