Evaluation of the potential impact of pharmacokinetic differences on tissue dosimetry in offspring during pregnancy and lactation.

In recent years efforts have increased to develop a framework for assessing differences, both pharmacokinetic and pharmacodynamic, between children and adults for purposes of assessing risk of adverse effects following chemical exposure. The specific goal of this study was to demonstrate an approach for using PBPK modeling to compare maternal and fetal/neonatal blood and tissue dose metrics during pregnancy and lactation. Six chemical classes were targeted to provide a variety of physicochemical properties (volatility, lipophilicity, water solubility), and surrogate chemicals were selected to represent each class (isopropanol, vinyl chloride, methylene chloride, perchloroethylene, nicotine, and TCDD), based on the availability of pharmacokinetic information. These chemicals were also selected to provide different pharmacokinetic characteristics, including metabolic production of stable or reactive intermediates in the liver and competing pathways for metabolism. Changes in dosimetry during pregnancy predicted by the modeling were mainly attributable to the development of enzymatic pathways in the fetus or to changes in tissue composition in the mother and fetus during pregnancy. In general, blood concentrations were lower in the neonate during the lactation period than in the fetus during gestation. This postnatal decrease varied from only a slight change (for TCDD) to approximately four orders of magnitude (for vinyl chloride). As compared to maternal exposure, fetal/neonatal exposures ranged from approximately twice as great (for TCDD) to several orders of magnitude lower (for isopropanol). The results of this study are in general agreement with the analyses of data on pharmaceutical chemicals, which have suggested that the largest difference in pharmacokinetics observed between children and adults is for the perinatal period. The most important factor appears to be the potential for decreased clearance of toxic chemicals in the perinatal period due to immature metabolic enzyme systems, although this same factor can also reduce the risk from reactive metabolites during the same period.