Human Age- and Sex-Dependent Differences in PFAS Elimination -- SRA 2025 presentation
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Rationale
Per- and polyfluoroalkyl substances (PFAS) are a broad group of synthetic chemicals with wide use and human exposure. Many PFAS are only slowly eliminated by humans and other animals, leading to significant bioaccumulation with long-term exposure. More specifically, the rate of elimination, or clearance (CL), determines the blood concentration that will be reached for a given exposure. PFAS exposure has been associated with adverse health effects in humans, including in developing fetuses and young children. Therefore, human CL of PFAS, and how it may depend on age and sex, needs to be quantified to predict the relationship between exposure and possible adverse effects. We evaluated the degree of age- and sex-dependence in the CL for three slowly-cleared PFAS, PFHxS, PFNA and PFDA, which may inform CL dependencies for other PFAS.
Approach
Data that can be used to quantify human CL and other pharmacokinetic (PK) parameters of PFAS were identified through systematic review and targeted searches. Controlled human PK studies of PFAS which would best inform CL are extremely rare, likely due to the ethical concerns with such studies. However, measurements of human PFAS serum concentrations in US males and females from incidental exposures are available from the National Health and Nutrition Examination Survey (NHANES), though with the substantial limitation that those data are cross-sectional spot-samples. These data show clear sex- and age-dependent differences for some PFAS. The relative PFAS concentration in (non-pregnant/breastfeeding) females vs age-matched males was therefore used as an estimate of the inverse of the relative CL; i.e. concentration(males)/concentration(females) was assumed to equal CL(females)/CL(males). The absolute CL in reference populations of men (and women expected to have similar CL as men) was estimated from other available data. Biological mechanisms that could explain the observed data were also evaluated. Results of the absolute and relative CL analyses were then combined to estimate total CL as a function of age and sex for each PFAS.
Results and Discussion
The NHANES data indicate that women of reproductive age (approximately 12-50 y) have significantly higher CL than their male counterparts for PFHxS and PFNA, but not PFDA. For PFHxS, the CL in reproductive age females was estimated to be 75% greater than same-aged males, with an absolute CL difference of 0.031 mL/kg-d. For PFNA a CL difference of 0.021 mL/kg-d was estimated. But for PFDA the concentration difference between females and males varied in a manner not consistent with reproductive age and the average CL difference was only estimated to be 0.013 mL/kg-d. Menstrual fluid loss has been proposed as a mechanism for higher PFAS CL in women but data comparing PFAS concentrations in menstrual fluid to blood plasma were not found. Since plasma protein binding is > 99% for all three PFAS and plasma is a significant portion of menstrual fluid, the increase in CL predicted by this mechanism is the same for all three. Hence, there is uncertainty regarding the mechanism and absolute CL difference between women of reproductive age and others.
Management/Policy Implications (e.g., Why does it matter?)
PFAS may be excreted in menstrual fluid but the observed plasma concentration differences between men and women cannot be predicted assuming the same exposure levels and a single rate of menstrual CL. Until predictive mechanistic data are available, empirical, PFAS-specific data (e.g., NHANES)