Pharmacokinetic Models for Quantifying Mother-to-Offspring Transfer of Lipophilic Chemicals-poster

Lipophilic contaminants, which can accumulate in a woman’s body fat due to environmental exposures over the course of many years preceding and during pregnancy, may be transferred to her child during gestation and, after birth, through her breast milk. Because of the bioaccumulation of such compounds in fat and their subsequent partitioning into breast milk lipids, a breastfeeding infant may have an average daily exposure per unit of body mass (mg/kg/d) that greatly exceeds that of the mother. Thus, nominal maternal exposures observed or recorded in animal studies may not be adequate surrogates for the exposures experienced by developing infants. Furthermore, exposure durations and regimens for developmental animal studies vary tremendously. Maternal organisms may be exposed before, during, or after pregnancy, or during all of these periods. In order to quantitatively analyze these issues, we developed a pharmacokinetic (PK) model for lipophilic chemicals in humans, rats, and other animal species that addresses mother-to-offspring transfer of these chemicals during the critical periods of gestation and early post-natal development. This model can be used to estimate instantaneous body burdens (in mg of chemical per kg of body mass) in the mother, fetus(es), and/or infant(s) based upon gavage or intravenous dosing (in mg of chemical per kg of body mass per day) or dosing through diet (in mg of chemical per kg of food). Using our models, we demonstrated that breastfeeding infants tend to have higher average daily exposures to 2, 2’, 4, 4’, 5, 5’-hexachlorobiphenyl (PCB 153) than their mothers. Also, by considering various dose metrics, we demonstrated a method for computing human equivalent doses for points of departure identified in developmental animal studies of PCB 153. Then, by rank-ordering these human equivalent doses, we showed how one can identify those adverse outcomes most sensitive to chemical exposure.

Impact/Purpose

The poster describes development of a computational model that can be used to estimate the dose or concentration of a lipophilic chemical in a children where the exposure is via in-utero and lactational transfer from the mother. By describing decisions and assumptions made in developing the model, an opportunity for feedback and suggestions is provided to others in the scientific community. The model will ultimately be useful in estimating maternal exposure which result in doses to the child equal to benchmark doses identified from animal toxicity studies. Results shown here simply demonstrate proof of concept.

Citation

Kapraun, D., P. Schlosser, L. Carlson, AND G. Lehmann. Pharmacokinetic Models for Quantifying Mother-to-Offspring Transfer of Lipophilic Chemicals-poster. SOT Annual Meeting, Baltimore, MD, March 10 - 14, 2019.