title: Quantitative bias analysis for epidemiological associations of perfluoroalkyl substance serum concentrations and early onset of menopause.
abstract: An association between increased serum concentrations of perfluoroalkyl substances (PFAS) such as perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) and early menopause has been reported (Knox et al., 2011; Taylor et al., 2014). This association may be explained by the fact that women who underwent menopause no longer excrete PFAS through menstruation. Our objective was to assess how much of the epidemiologic association between PFAS and altered timing of menopause might be explained by reverse causality. We extended a published population life-stage physiologically-based pharmacokinetic (PBPK) model of PFOS and PFOA characterized by realistic distributions of physiological parameters including age at menopause. We then conducted Monte Carlo simulations to replicate the Taylor population (Taylor et al., 2014) and the Knox population (Knox et al., 2011). The analysis of the simulated data overall showed a pattern of results that was comparable to those reported in epidemiological studies. For example, in the simulated Knox population (ages 42-51) the odds ratio (OR) for menopause in the fifth quintile of PFOA compared to those in the first quintile was 1.33 (95% CI 1.26-1.40), whereas the reported OR was 1.4 (95% CI 1.1-1.8). Using our model structure, a substantial portion of the associations reported can be explained by pharmacokinetics.
authors.affiliation: ScitoVation, LLC, RTP, NC, USA; The Hamner Institutes for Health Sciences, RTP, NC, USA; The Procter & Gamble Co., Cincinnati, OH, USA. Electronic address: ruark.cd@pg.com.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Ruark
authors.affiliation: The Hamner Institutes for Health Sciences, RTP, NC, USA. Electronic address: gsong8112@gmail.com.
authors.forename: Gina
authors.initials: G
authors.lastname: Song
authors.affiliation: ScitoVation, LLC, RTP, NC, USA; The Hamner Institutes for Health Sciences, RTP, NC, USA. Electronic address: myoon@scitovation.com.
authors.forename: Miyoung
authors.initials: M
authors.lastname: Yoon
authors.affiliation: Department of Occupational and Environmental Health, Université de Montréal, Montreal, QC, Canada. Electronic address: marc-andre.verner.1@umontreal.ca.
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Verner
authors.affiliation: ScitoVation, LLC, RTP, NC, USA; The Hamner Institutes for Health Sciences, RTP, NC, USA. Electronic address: mandersen@scitovation.com.
authors.forename: Melvin E
authors.initials: ME
authors.lastname: Andersen
authors.affiliation: ScitoVation, LLC, RTP, NC, USA; The Hamner Institutes for Health Sciences, RTP, NC, USA. Electronic address: hclewell@scitovation.com.
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Clewell
authors.affiliation: RAMBOLL ENVIRON, RTP, NC, USA. Electronic address: mlongnecker@ramboll.com.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Longnecker
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D015984:Causality; D004785:Environmental Pollutants / Q000097:blood* / Q000493:pharmacokinetics; D005260:Female; D005466:Fluorocarbons / Q000097:blood* / Q000493:pharmacokinetics; D006801:Humans; D008593:Menopause; D008594:Menopause, Premature / Q000187:drug effects*; D008875:Middle Aged; D008962:Models, Theoretical; D009010:Monte Carlo Method; D016017:Odds Ratio; D055815:Young Adult
chemical_list: D004785:Environmental Pollutants; D005466:Fluorocarbons
keywords: Female; Menopause; PBPK; PFOA; PFOS; Quantitative bias analysis