title: Quantitative bias analysis of a reported association between perfluoroalkyl substances (PFAS) and endometriosis: The influence of oral contraceptive use.
abstract: An association between serum levels of perfluoroalkyl substances (PFAS) and endometriosis has recently been reported in an epidemiologic study. Oral contraceptive use to treat dysmenorrhea (pelvic pain associated with endometriosis) could potentially influence this association by reducing menstrual fluid loss, a route of excretion for PFAS. In this study, we aimed to evaluate the influence of differential oral contraceptive use on the association between PFAS and endometriosis. We used a published life-stage physiologically based pharmacokinetic (PBPK) model to simulate plasma levels of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) from birth to age at study participation (range 18-44years). In the simulated population, PFAS level distributions matched those for controls in the epidemiologic study. Prevalence and geometric mean duration (standard deviation [SD]) of oral contraceptive use in the simulated women were based on data from the National Health and Nutrition Examination Survey; among the women with endometriosis the values were, respectively, 29% and 6.8 (3.1) years; among those without endometriosis these values were 18% and 5.3 (2.8) years. In simulations, menstrual fluid loss (ml/cycle) in women taking oral contraceptives was assumed to be 56% of loss in non-users. We evaluated the association between simulated plasma PFAS concentration and endometriosis in the simulated population using logistic regression. Based on the simulations, the association between PFAS levels and endometriosis attributable to differential contraceptive use had an odds ratio (95% CI) of 1.05 (1.02, 1.07) for a logeunit increase in PFOA and 1.03 (1.02, 1.05) for PFOS. In comparison, the epidemiologic study reported odds ratios of 1.62 (0.99, 2.66) for PFOA and 1.25 (0.87, 1.80) for PFOS. Our results suggest that the influence of oral contraceptive use on the association between PFAS levels and endometriosis is relatively small.
authors.affiliation: Department of Occupational and Environmental Health, Université de Montréal, 2375 chemin de la Cote-Sainte-Catherine, Montreal, QC H3T 1A8, Canada; Universite de Montreal Public Health Research Institute (IRSPUM), Université de Montréal, 7101, Parc Ave., Montreal, QC H3N 1X7, Canada. Electronic address: gerard.ngueta.jumeni@umontreal.ca.
authors.forename: Gerard
authors.initials: G
authors.lastname: Ngueta
authors.affiliation: Ramboll Environ, 6 Davis Dr, Research Triangle Park, NC 27709, USA. Electronic address: mlongnecker@ramboll.com.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Longnecker
authors.affiliation: ScitoVation, 6 Davis Dr, Research Triangle Park, NC 27709, USA. Electronic address: myoon@scitovation.com.
authors.forename: Miyoung
authors.initials: M
authors.lastname: Yoon
authors.affiliation: ScitoVation, 6 Davis Dr, Research Triangle Park, NC 27709, USA. Electronic address: cruark@scitovation.com.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Ruark
authors.affiliation: Ramboll Environ, 6 Davis Dr, Research Triangle Park, NC 27709, USA; ScitoVation, 6 Davis Dr, Research Triangle Park, NC 27709, USA. Electronic address: hclewell@scitovation.com.
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Clewell
authors.affiliation: Ramboll Environ, 6 Davis Dr, Research Triangle Park, NC 27709, USA; ScitoVation, 6 Davis Dr, Research Triangle Park, NC 27709, USA. Electronic address: mandersen@scitovation.com.
authors.forename: Melvin E
authors.initials: ME
authors.lastname: Andersen
authors.affiliation: Department of Occupational and Environmental Health, Université de Montréal, 2375 chemin de la Cote-Sainte-Catherine, Montreal, QC H3T 1A8, Canada; Universite de Montreal Public Health Research Institute (IRSPUM), Université de Montréal, 7101, Parc Ave., Montreal, QC H3N 1X7, Canada. Electronic address: marc-andre.verner.1@umontreal.ca.
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Verner
mesh_terms: D000328:Adult; D017738:Alkanesulfonic Acids / Q000097:blood*; D015982:Bias; D002210:Caprylates / Q000097:blood*; D003276:Contraceptives, Oral / Q000627:therapeutic use*; D004715:Endometriosis / Q000097:blood / Q000188:drug therapy / Q000453:epidemiology; D004784:Environmental Monitoring; D004785:Environmental Pollutants / Q000097:blood*; D005260:Female; D005466:Fluorocarbons / Q000097:blood*; D006801:Humans; D009749:Nutrition Surveys; D055815:Young Adult
chemical_list: D017738:Alkanesulfonic Acids; D002210:Caprylates; D003276:Contraceptives, Oral; D004785:Environmental Pollutants; D005466:Fluorocarbons; C023036:perfluorooctanoic acid; C076994:perfluorooctane sulfonic acid
keywords: Biomarkers; Endometriosis; Environmental epidemiology; Oral contraceptive use; Perfluoroalkyl substances (PFAS); Physiologically based pharmacokinetic (PBPK) modeling; Quantitative bias assessment