Citation:

Kapraun, D., T. Zurlinden, M. Verner, C. Chiang, M. Dzierlenga, L. Carlson, P. Schlosser, AND G. Lehmann. A Generic Pharmacokinetic Model for Quantifying Mother-to-Offspring Transfer of Lipophilic Persistent Environmental Chemicals. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 189(2):155-174, (2022). https://doi.org/10.1093/toxsci/kfac084

Impact/Purpose:

We sought to create a multi-species pharmacokinetic (PK) model that quantifies mother-to-offspring transfer of lipophilic persistent environmental chemicals (LPECs) during pregnancy and lactation and facilitates internal dosimetry calculations for mothers and offspring. This model will be used to perform the hazard identification and dose-response analysis components of the Integrated Risk Information System (IRIS) assessment for polychlorinated biphenyls (PCBs).

Description:

Lipophilic persistent environmental chemicals (LPECs) can accumulate in a woman’s body and transfer to her developing child across the placenta and via breast milk. To assess health risks associated with developmental exposures to LPECs, we developed a pharmacokinetic (PK) model that quantifies mother-to-offspring transfer of LPECs during pregnancy and lactation and facilitates internal dosimetry calculations for offspring. We parameterized the model for mice, rats, and humans using time-varying functions for body mass and milk consumption rates. The only required substance-specific parameter is the elimination half-life of the LPEC in the animal species of interest. We used the model to estimate wholebody concentrations in mothers and offspring following maternal exposures to hexachlorobenzene (HCB) and 2,20 ,4,40 ,5,50 - hexachlorobiphenyl (PCB 153) and compared these with measured concentrations from animal studies. We also compared estimated concentrations for humans to those generated using a previously published human LPEC PK model. Finally, we compared human equivalent doses (HEDs) calculated using our model and an allometric scaling method. Estimated and observed whole-body concentrations of HCB and PCB 153 in offspring followed similar trends and differed by less than 60%. Simulations of human exposure yielded concentration estimates comparable to those generated using the previously published model, with concentrations in offspring differing by less than 12%. HEDs calculated using our PK model were about 2 orders of magnitude lower than those generated using allometric scaling. Our PK model can be used to calculate internal dose metrics for offspring and corresponding HEDs and thus informs assessment of developmental toxicity risks associated with LPECs. 

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