Elsevier

Environment International

Volume 82, September 2015, Pages 61-68
Environment International

Full length article
Can the observed association between serum perfluoroalkyl substances and delayed menarche be explained on the basis of puberty-related changes in physiology and pharmacokinetics?,☆☆

https://doi.org/10.1016/j.envint.2015.05.006Get rights and content

Highlights

  • Ability to simulate longitudinal trends in blood biomarkers in early life

  • Kinetic variation contributed to the association between PFAS and age at menarche.

  • MC-PBPK modeling can enhance interpretation of epidemiological associations.

Abstract

Background

An association between serum levels of two perfluoroalkyl substances (PFAS) and delayed age at menarche was reported in a cross-sectional study of adolescents. Because perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) have half-lives of years, growth dilution and the development of a new route of excretion (menstruation) could account for some or all of the reported association.

Objectives

To assess how much of the epidemiologic association between PFAS and delayed menarche can be explained by the correlation of growth and maturation with PFAS body burden.

Methods

We developed a Monte Carlo (MC) physiologically-based pharmacokinetic (PBPK) model of PFAS to simulate plasma PFAS levels in a hypothetical female population aged 2 to 20 years old. Realistic distributions of physiological parameters as well as timing of growth spurts and menarche were incorporated in the model. The association between PFAS level and delayed menarche in the simulated data was compared with the reported association.

Results

The prevalence of menarche, distributions of age-dependent physiological parameters, and quartiles of serum PFAS concentrations in the simulated subjects were comparable to those reported in the epidemiologic study. The delay of menarche in days per natural log increase in PFAS concentrations in the simulated data were about one third as large as the observed values.

Conclusion

The reported relationship between PFAS and age at menarche appears to be at least partly explained by pharmacokinetics rather than a toxic effect of these substances.

Introduction

Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are perfluoroalkyl substances (PFAS) that have been used in a wide variety of industrial processes and manufacturing of consumer products such as textiles, paper, packaging, and coating additives for the past six decades (Lopez-Espinosa et al., 2011, Lindstrom et al., 2011). These longer-chain PFAS are resistant to degradation and have been shown to be present in wildlife and human worldwide. The potential sources of exposure to PFAS include ingestion of water and food or migration from food packaging and cookware, use of commercial products, or inhalation of outdoor and indoor air and household dust (Lau et al., 2007). Among these exposure pathways, overall dietary exposure is likely to be the dominant intake pathway in the general population (Noorlander et al., 2011, Washburn et al., 2005).

Contamination of drinking water with PFOA in the Mid-Ohio Valley recently triggered a comprehensive series of studies on potential health effects of exposure to PFAS. Compared with the general U.S. population in 2005–2006, in the Mid-Ohio Valley residents the median serum concentration of PFOA was 28.2 ng/ml (cf. 4.2 ng/ml) and of PFOS was 20.2 ng/ml (cf. 17.5 ng/ml) (Frisbee et al., 2009, Keto et al., 2011). An association between higher serum concentrations of PFAS and delayed menarche in girls living in this region was reported (Lopez-Espinosa et al., 2011). The serum concentrations of PFAS in the Mid-Ohio Valley residents were 100–1000 fold lower than those associated with any toxicological effects in animals (Butenhoff et al., 2004, Cui et al., 2009, White et al., 2007).

The physiological changes during puberty may have a considerable influence on plasma PFAS concentrations, especially in girls. With the long half-lives of PFOA (2.3 years) and PFOS (5.4 years), the growth spurt should cause “growth dilution”. This growth spurt is a period of rapid growth in height and weight during puberty, which begins on average at 10 years for girls. The growth dilution is an abrupt drop in PFAS concentrations due to a rapid increase in body volume during growth spurt. And the growth spurt is typically followed by the onset of menses, where loss through menstruation becomes a new route of PFAS excretion. In this case, earlier menarche would cause lower PFAS levels. Girls with later onset of growth spurt and later menarche would have higher PFAS levels.

The primary aim of this study was to assess how much of the observed association between PFAS and delayed menarche might be caused by the pharmacokinetic correlates of puberty. We don't have access to the raw data. Toward this end, we developed a Monte Carlo physiologically-based pharmacokinetic (MC-PBPK) model of PFAS that spanned adolescence. The MC-PK approach has recently provided insights into the nature of other epidemiologic associations (Verner et al., 2013, Loccisano et al., 2012). Using similar tools, we evaluated the association between PFAS and age at menarche in simulated data and compared these simulated outcomes with the epidemiologic results (Lopez-Espinosa et al., 2011).

Section snippets

Model structure

A published PBPK model for PFAS in adult humans (Loccisano et al., 2011) was modified to describe females aged 0–20 years. This model included compartments for plasma, the liver, fat, gut, rest of body, the kidneys, filtrate, and storage (Fig. 1). Tissue volumes and tissue blood flow rates were estimated based on an individual's body size measurements including body weight (BW), body height (BH), body surface area (BSA) and body mass index (BMI). The particular measurement(s) used to estimate

PFAS PBPK model

The plasma PFOA concentrations in the simulated Mid-Ohio population decreased with increasing age, and the simulated PFOS concentrations increased from age 2 to 9 years old then decreased to the adult level (Fig. 3A and B). These simulations were in good agreement with reported data (Mondal et al., 2012).

The model of growth

The age-specific distributions of BH, BW, and BMI for females of the general U.S. population (NHANES 2003–2004) and the simulated population were comparable (Fig. 4A). Age at menarche was also

Discussion

Our simulation indicates that maturation causes lower plasma PFAS concentrations because of growth dilution and menstruation. These factors accounted for about a third of the association of higher PFAS with later age at menarche observed in the Lopez-Espinosa et al. study (2011). We note that none of the parameters in the model changed with PFAS exposure; in particular, as growth and maturation occurred in the simulation, no parameter changed that would correspond to toxicity. Also, except for

Conclusion

Our results indicate that individual variations in PFAS kinetics associated with rapid growth around the onset of menstruation may contribute to the reported relationship between serum PFAS levels and age at menarche. We have demonstrated the feasibility of a MC-PBPK modeling approach to assess how much of the apparent epidemiological association during puberty can be explained by pharmacokinetic variability. With modification, the MC-PBPK model we developed can be used to assess the effect of

Acknowledgments

We would like to thank Dr. Mark Russell at DuPont and Drs. Haluk Ozkaynak, Cecilia Tan, Kristin Isaacs, Paul Schlosser, and Cory Strope at the US Environmental Protection Agency for their helpful discussion on exposure description. We would like to thank Cody Peeples at the Hamner Institutes for Health Sciences for reviewing model code and equations. This study was supported by the E.I. du Pont de Nemours and Company, 3M, the American Chemistry Council Long Range Research Initiative (ACC-LRI),

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  • Cited by (0)

    Support: 3M, E.I. du Pont de Nemours and Company, and ACC-LRI.

    ☆☆

    Presented in part at the 2014 SOT Annual Conference, Phoenix, AZ.

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