Incorporation of fetal and child PFOA dosimetry in the derivation of health-based toxicity values

Background: Multiple agencies have developed health-based toxicity values for exposure to perfluorooctanoic acid (PFOA). Although PFOA exposure occurs in utero and through breastfeeding, current health-based toxicity values have not been derived using fetal or child dosimetry. Therefore, current values may underestimate the potential risks to fetuses and nursing infants. Objective: Using fetal and child dosimetry, we aimed to calculate PFOA maternal human equivalent doses (HEDs), corresponding to a developmental mouse study lowest observed adverse effect level (LOAEL, 1 mg/kg/day). Further, we investigated the impact of breastfeeding duration and PFOA half-life on the estimated HEDs. Methods: First, a pharmacokinetic model of pregnancy and lactation in mice was used to estimate plasma PFOA levels in pups following a maternal exposure to 1 mg PFOA/kg/day for gestational days 1-17. Four plasma PFOA concentration metrics were estimated in pups: i) average prenatal; ii) average postnatal; iii) average overall (prenatal and postnatal); and iv) maximum. Then, Monte Carlo simulations were performed using a pharmacokinetic model of pregnancy and lactation in humans to generate distributions of maternal HEDs that would result in fetal/child plasma levels equivalent to those estimated in pups using the mouse model. Median (HED50) and 1st percentile (HED01) of calculated HEDs were calculated. Results: Estimated PFOA maternal HED(50)s ranged from 3.0x 10(-4) to 1.1 x10(-3) mg/kg/day and HED(01)s ranged from 4.7 x10(-5) to 2.1 x10(-4) mg/kg/day. All calculated HEDs were lower than the HED based on adult dosimetry derived by the Environmental Protection Agency (EPA) (5.3 x10(-3) mg/kg/day). Conclusion: Our results suggest that fetal/ hild dosimetry should be considered when deriving health-based toxicity values for potential developmental toxicants.