Publications : 2016

Ruark CD, Song G, Yoon M, Verner MA, Andersen ME, Clewell HJ, Longnecker MP. Quantitative bias analysis for epidemiological associations of perfluoroalkyl substance serum concentrations and early onset of menopause [abstract 0216]. Presented at the Society of Toxicology Annual Meeting, New Orleans, LA, March 2016.


A cross‐sectional epidemiologic study reported an association between increased serum concentrations of perfluoroalkyl substances (PFAS) such as perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) and early menopause (Taylor et al 2014). This association may be explained by the fact that women who underwent menopause no longer excrete PFAS through menstruation. The objective of this study was to use physiologically‐based pharmacokinetic (PBPK) modeling to assess how much of the epidemiologic association between PFAS and altered timing of menopause might be explained by reverse causality. We developed a population life‐stage PBPK model of PFOS and PFOA characterized by realistic distributions of physiological parameters including age at menopause. We then conducted a Monte Carlo simulation of a cross‐sectional National Health and Nutrition Examination Survey (NHANES) population to match the epidemiological population reported by Taylor et al. The population characteristics, including age, body mass index, age at menopause and serum PFAS concentrations were similar between the simulated and reported data. We compared the simulated hazard ratio estimates to the reported associations. In the simulated data, the hazard ratios for PFOS serum concentration tertile 2 and 3 were 1.36 (95% Confidence Interval, 1.31‐ 1.41) and 1.91 (1.85‐1.98) while the reported associations were 1.23 (1.04‐1.44) and 1.16 (0.91‐1.48). Simulated hazard ratios for PFOA serum concentration in tertile 2 and 3 were 1.24 (1.20‐1.29) and 1.31 (1.27‐1.36) while the reported associations were 1.22 (0.92‐1.62) and 1.36 (1.05‐1.75). Under our current model structure, pharmacokinetics can fully explain the reported associations between PFAS serum concentrations and early onset of menopause. In the future, we will simulate another epidemiologic study of this association (Knox et al 2011).