PNNL

Abstract

Physiologically based pharmacokinetic (PBPK) models should be designed to account for naturally-occurring changes in blood components and estimate accurately how these changes affect partitioning of chemicals into tissues. This work focused on understanding the effect of blood lipid changes on the partitioning of chlorpyrifos (CPF) into plasma during pregnancy and what impact these changes have on dosimetry in both the pregnant mother and her developing fetus. We show that CPF partitions more into the plasma during gestation. This increase in partitioning correlates closely with changes in the overall lipid levels that naturally occur throughout gestation in both rats and humans. Results of in vitro partitioning studies showed that CPF is sequestered more in the low density fraction of the blood during the late stages of gestation in the rat and returns to non-pregnant patterns in the dam after birth. Also, the overall lipid profile in plasma changed by dosing rats with corn-oil, a lipid rich vehicle, which leads to a moderate change in CPF partitioning into the plasma. In addition to quantifying the partitioning changes, we modified an existing PBPK/PD model of chlorpyrifos (Timchalk et al., Tox. Sci., 2000) to accommodate tissue:blood partitioning changes during pregnancy. After applying the major physiological and biochemical changes that are expected in late pregnancy and including a slight increase in tissue: blood partitioning, the model likewise predicts increased blood CPF concentrations in late gestation rats vs. non-pregnant rats at the same dose of CPF. The rodent model was extrapolated to humans to evaluate the impact of changing lipids in the pharmacokinetic profile of chlorpyrifos in the blood of pregnant women. For the same level of environmental exposure, the model predicts the blood chlorpyrifos AUC in pregnant women will be approximately 30% higher than in a non-pregnant adult human. The low pg/g plasma CPF levels found in women at childbirth (Whyatt et al., 2003; Whyatt et al. 2004; Whyatt et al. 2005) were estimated to correspond to environmental exposures of 0.012 to 0.15 µg/kg body weight per day. Understanding the lipid concentrations and profiles over the course of different life stages will be necessary to fully understand and predict the pharmacokinetics profile of CPF and other lipophilic chemicals in the blood and tissues, as shown in this study with mothers and fetuses.