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

Author:
Kieskamp, Kyra Kimberly, Worley, Rachel Rogers, McLanahan, Eva D., Verner, Marc-André
Source:
Environment international 2018 v.111 pp. 260-267
ISSN:
0160-4120
Subject:
Monte Carlo method, adults, animal models, breast feeding, children, dosimetry, environmental protection, fetus, half life, humans, lactation, lowest observed effect level, maternal exposure, mice, perfluorooctanoic acid, pharmacokinetics, pregnancy, pups, risk, toxic substances
Abstract:
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.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, 1mg/kg/day). Further, we investigated the impact of breastfeeding duration and PFOA half-life on the estimated HEDs.First, a pharmacokinetic model of pregnancy and lactation in mice was used to estimate plasma PFOA levels in pups following a maternal exposure to 1mg 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.Estimated PFOA maternal HED50s ranged from 3.0×10⁻⁴ to 1.1×10⁻³mg/kg/day and HED01s ranged from 4.7×10⁻⁵ to 2.1×10⁻⁴mg/kg/day. All calculated HEDs were lower than the HED based on adult dosimetry derived by the Environmental Protection Agency (EPA) (5.3×10⁻³mg/kg/day).Our results suggest that fetal/child dosimetry should be considered when deriving health-based toxicity values for potential developmental toxicants.
Agid:
6156816