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Development of PBPK models for PFOA and PFOS for human pregnancy and lactation life stages.

ABSTRACT: Perfluoroalkyl acid carboxylates and sulfonates (PFAA) have many consumer and industrial applications. Developmental toxicity studies in animals have raised concern about potential reproductive/developmental effects of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS); however, in humans conflicting results have been reported for associations between maternal PFAA levels and these outcomes. Risk assessments and interpretation of available human data during gestation and lactation are hindered due to lack of a framework for understanding and estimating maternal, fetal, and neonatal pharmacokinetics (PK). Physiologically based pharmacokinetic (PBPK) models were developed for PFOA and PFOS for the gestation and lactation life stages in humans to understand how the physiological changes associated with development affect pharmacokinetics of these compounds in the mother, fetus, and infant. These models were derived from PBPK models for PFOA/PFOS that were previously developed for adult humans and rats during gestation and lactation and from existing human pregnancy and lactation models developed for other chemicals. The models simulated PFOA and PFOS concentrations in fetal, infant, and maternal plasma and milk, were compared to available data in humans, and also were used to estimate maternal exposure. The models reported here identified several research needs, which include (1) the identification of transporters involved in renal resorption to explain the multiyear half-lives of these compounds in humans, (2) factors affecting clearance of PFOA/PFOS during gestation and lactation, and (3) data to estimate clearance of PFOA/PFOS in infants. These models may help address concerns regarding possible adverse health effects due to PFOA/PFOS exposure in the fetus and infant and may be useful in comparing pharmacokinetics across life stages.

SUBMITTER: Loccisano AE

PROVIDER: S-EPMC3502013 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Development of PBPK models for PFOA and PFOS for human pregnancy and lactation life stages.

Loccisano Anne E AE Longnecker Matthew P MP Campbell Jerry L JL Andersen Melvin E ME Clewell Harvey J HJ

Journal of toxicology and environmental health. Part A 20130101 1

Perfluoroalkyl acid carboxylates and sulfonates (PFAA) have many consumer and industrial applications. Developmental toxicity studies in animals have raised concern about potential reproductive/developmental effects of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS); however, in humans conflicting results have been reported for associations between maternal PFAA levels and these outcomes. Risk assessments and interpretation of available human data during gestation and lactatio ...[more]

PMID: 23151209

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Project description:Globally, biomonitoring data demonstrate virtually all humans carry residues of multiple per- and polyfluoroalkyl substances (PFAS). Despite pervasive co-exposure, limited mixtures-based in vivo PFAS toxicity research has been conducted. Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) are commonly detected PFAS in human and environmental samples and both produce adverse effects in laboratory animal studies, including maternal and offspring effects when orally administered during pregnancy and lactation. To evaluate the effects of combined exposure to PFOA and PFOS, we orally exposed pregnant Sprague-Dawley rats from gestation day 8 (GD8) to postnatal day 2 (PND2) to PFOA (10-250 mg/kg/d) or PFOS (0.1-5 mg/kg/d) individually to characterize effects and dose response curve parameters, followed by a variable-ratio mixture experiment with a constant dose of PFOS (2 mg/kg/d) mixed with increasing doses of PFOA (3-80 mg/kg/d). The mixture study design was intended to: 1) shift the PFOA dose response curves for endpoints shared with PFOS, 2) allow comparison of dose addition (DA) and response addition (RA) model predictions, 3) conduct relative potency factor (RPF) analysis for multiple endpoints, and 4) avoid overt maternal toxicity. Maternal serum and liver concentrations of PFOA and PFOS were consistent between the individual chemical and mixture experiments. Combined exposure with PFOS significantly shifted the PFOA dose response curves towards effects at lower doses compared to PFOA-only exposure for multiple endpoints and these effects were well predicted by dose addition. For endpoints amenable to mixture model analyses, DA produced equivalent or better estimates of observed data than RA. All endpoints evaluated were accurately predicted by RPF and DA approaches except for maternal gestational weight gain, which produced less-than-additive results in the mixture. Data support the hypothesis of cumulative effects on shared endpoints from PFOA and PFOS co-exposure and dose additive approaches for predictive estimates of mixture effects.

Dataset Information

Development of PBPK models for PFOA and PFOS for human pregnancy and lactation life stages.

Publications

Development of PBPK models for PFOA and PFOS for human pregnancy and lactation life stages.

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