title: Associations of Perfluoroalkyl Substances (PFAS) with Lower Birth Weight: An Evaluation of Potential Confounding by Glomerular Filtration Rate Using a Physiologically Based Pharmacokinetic Model (PBPK).
abstract: BACKGROUND
  Prenatal exposure to perfluoroalkyl substances (PFAS) has been associated with lower birth weight in epidemiologic studies. This association could be attributable to glomerular filtration rate (GFR), which is related to PFAS concentration and birth weight.
  
  
  OBJECTIVE
  We used a physiologically based pharmacokinetic (PBPK) model of pregnancy to assess how much of the PFAS-birth weight association observed in epidemiologic studies might be attributable to GFR.
  
  
  METHODS
  We modified a PBPK model to reflect the association of GFR with birth weight (estimated from three studies of GFR and birth weight) and used it to simulate PFAS concentrations in maternal and cord plasma. The model was run 250,000 times, with variation in parameters, to simulate a population. Simulated data were analyzed to evaluate the association between PFAS levels and birth weight due to GFR. We compared simulated estimates with those from a meta-analysis of epidemiologic data.
  
  
  RESULTS
  The reduction in birth weight for each 1-ng/mL increase in simulated cord plasma for perfluorooctane sulfonate (PFOS) was 2.72 g (95% CI: -3.40, -2.04), and for perfluorooctanoic acid (PFOA) was 7.13 g (95% CI: -8.46, -5.80); results based on maternal plasma at term were similar. Results were sensitive to variations in PFAS level distributions and the strength of the GFR-birth weight association. In comparison, our meta-analysis of epidemiologic studies suggested that each 1-ng/mL increase in prenatal PFOS and PFOA levels was associated with 5.00 g (95% CI: -21.66, -7.78) and 14.72 g (95% CI: -8.92, -1.09) reductions in birth weight, respectively.
  
  
  CONCLUSIONS
  Results of our simulations suggest that a substantial proportion of the association between prenatal PFAS and birth weight may be attributable to confounding by GFR and that confounding by GFR may be more important in studies with sample collection later in pregnancy.
authors.affiliation: Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Verner
authors.forename: Anne E
authors.initials: AE
authors.lastname: Loccisano
authors.forename: Nils-Halvdan
authors.initials: NH
authors.lastname: Morken
authors.forename: Miyoung
authors.initials: M
authors.lastname: Yoon
authors.forename: Huali
authors.initials: H
authors.lastname: Wu
authors.forename: Robin
authors.initials: R
authors.lastname: McDougall
authors.forename: Mildred
authors.initials: M
authors.lastname: Maisonet
authors.forename: Michele
authors.initials: M
authors.lastname: Marcus
authors.forename: Reiko
authors.initials: R
authors.lastname: Kishi
authors.forename: Chihiro
authors.initials: C
authors.lastname: Miyashita
authors.forename: Mei-Huei
authors.initials: MH
authors.lastname: Chen
authors.forename: Wu-Shiun
authors.initials: WS
authors.lastname: Hsieh
authors.forename: Melvin E
authors.initials: ME
authors.lastname: Andersen
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Clewell
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Longnecker
mesh_terms: D000328:Adult; D017738:Alkanesulfonic Acids / Q000493:pharmacokinetics* / Q000633:toxicity; D001724:Birth Weight / Q000187:drug effects*; D002210:Caprylates / Q000493:pharmacokinetics* / Q000633:toxicity; D003198:Computer Simulation; D015986:Confounding Factors, Epidemiologic; D004785:Environmental Pollutants / Q000493:pharmacokinetics* / Q000633:toxicity; D005260:Female; D005466:Fluorocarbons / Q000493:pharmacokinetics* / Q000633:toxicity; D005919:Glomerular Filtration Rate; D006801:Humans; D018811:Maternal Exposure; D008954:Models, Biological; D009010:Monte Carlo Method; D011247:Pregnancy
chemical_list: D017738:Alkanesulfonic Acids; D002210:Caprylates; D004785:Environmental Pollutants; D005466:Fluorocarbons; C023036:perfluorooctanoic acid; C076994:perfluorooctane sulfonic acid