Citation:

Schlosser, P., D. Kapraun, T. Zurlinden, AND M. Verner. Cross-Generational Accumulation of Persistent Compounds. Society for Risk Analysis Annual Meeting, NA, NA (Virtual), December 05 - 09, 2021.

Impact/Purpose:

Describe results of pharmacokinetic modeling of PFDA in humans for developmental exposure, which have general implications for long-term bio-persistent compounds in general.

Description:

Rationale: Some chemicals such as highly chlorinated polychlorinated biphenyls (PCB) and long-chain perfluoroalkyl substances (PFAS) have elimination half-lives of multiple years, meaning that accumulation occurs over a significant portion of a person’s lifetime. Of particular concern is gestational and lactational transfer of these compounds which may lead to high exposures to fetuses and children. A simple pharmacokinetic analysis could assume that concentrations in a woman of childbearing age are at steady-state, but it is not clear that this assumption is correct for long-half-life compounds. One can also ask if the in-utero and lactational exposure of a female child might significantly add to her body-burden when she reaches adulthood and has children. Approach: A pharmacokinetic model was adapted from Verner et al. (2016) (https://doi.org/10.1021/acs.est.5b04399) to evaluate the dosimetry of perfluoroalkyl substances (PFAS) in laboratory animals and humans while accounting for growth of the individual and her offspring, distribution to the fetus, and lactational transfer to her child. For perfluorodecanoic acid (PFDA) the half-life in women was estimated to be 7.7 years when menstruating and 11 years otherwise. Using a corresponding age-dependent clearance and assuming a constant mg/kg/d dose of PFDA and a standard growth curve, PFDA dosimetry was integrated over a woman’s lifetime to conception at age 24.25 y, childbirth at age 25, breast-feeding of her daughter to age 1, and growth of the daughter to the age at which her mother conceived, 24.25. Results and Discussion: Model simulation results indicate that a woman born with zero body burden and exposed at a constant dose to age 24.25 only reaches about 70% of steady-state concentration by that age (given the higher clearance due to menstrual blood loss after menarche). Her simulated daughter is then born with a much higher concentration of PFDA than the mother, and if exclusively breast-fed for 1 year is predicted to receive a large bolus such that she exceeds steady-state levels for 1-2 years. If the daughter is assumed to be subsequently exposed at the same dose as the mother, her body burden is predicted to be approximately 20% higher than the mother’s at age 24.25, indicating modest cross-generational accumulation. Management/Policy Implications: Initial simulation results for a woman exposed at a constant dose indicate that assuming steady-state concentration when she conceives a child may over-predict her body burden. However, accounting for cross-generational accumulation showed that this assumption yields less than 10% over-prediction for a compound with a half-life of 8-10 years. While there are significant health benefits to breast-feeding that likely offset the concern for exposure to bioaccumulative compounds, the predicted spike in concentration for a breast-fed child is concerning. Since the concentration in a young adult woman depends on her exposure from childhood, the effect of this lifetime exposure, as well as lactational transfer to a child, should be included when estimating safe exposure levels.

Record Details: