Associations of perfluorooctanoic acid with menopause and chronic kidney disease Open Access

Abstract

In this dissertation I investigated the associations of perflurooctanoic acid (PFOA) with menopause and chronic kidney disease (CKD) in a mid-Ohio Valley community cohort (N=32,254), subjected to a wide range of PFOA exposures via drinking water since 1951. Persistent in the environment and the human body, PFOA is found at low concentrations in the serum of nearly all U.S. residents. Earlier menopause and CKD have been positively associated with increased serum PFOA in previous cross-sectional studies.

Using Cox proportional hazards models, I conducted longitudinal analyses of menopause among women, aged 40 years or greater, (N=8,759) and of chronic kidney disease (CKD) among adults, aged 20 years or greater (N=32,254). In prior work, year-specific serum PFOA concentrations (1951-2011) in this population were retrospectively modeled, independently of measured PFOA. Estimated glomerular filtration rate (eGFR; a marker of kidney function) and serum PFOA level were measured in blood samples collected at enrollment (2005/2006). Individual self-reported histories of menopause and CKD were collected in 2008-2011, and self-reported CKD was validated via medical records or the US Renal Data System registry. I retrospectively investigated associations of menopause and of CKD with modeled PFOA exposure, either using year-specific estimates or estimated cumulative PFOA exposure. For both outcomes, I prospectively analyzed cohort members who had not yet experienced the outcome at enrollment. Using cross-sectional analyses to assess possible reverse causation, I evaluated the associations of measured and modeled serum PFOA with menopause among women aged 30-65, and with eGFR among adults. I also assessed the impact of the number of years since menopause on measured serum PFOA concentrations.

In longitudinal analyses, neither menopause nor CKD were associated with exposure to cumulative or year-specific PFOA estimates. Measured serum PFOA was positively associated with both menopause and eGFR (trend tests p=0.0005 and p=0.013, respectively), while modeled serum PFOA was not. Measured serum PFOA concentrations appeared to increase for the first seven years after menopause (trend test, p<0.0001). These results suggest that earlier menopause and CKD are not caused by PFOA exposure, and that positive findings in previous cross-sectional studies may have been the result of reverse causation.

Table of Contents

Chapter 1: Introduction_____________________________________1
Perfluorooctanoic acid (PFOA or C8)__________________________________1

The mid-Ohio Valley cohort and the strength of its data__________________ 2

Prior findings in the literature: Menopause and CKD_____________________ 5

Study design of papers 1 and 2_____________________________________ 7

Reverse causation and serum biomarkers of chemical exposure ____________ 10

Study design of paper 3___________________________________________ 13

References_____________________________________________________15

Chapter 2: Perfluorooctanoic acid exposure and natural menopause:
a longitudinal study in a community cohort_____________________25

Abstract_______________________________________________________26

Introduction____________________________________________________27

Methods_______________________________________________________29

Cohort recruitment & survey_______________________________________ 29
Serum PFOA concentrations: measured and modeled____________________ 31
Data analysis___________________________________________________ 32

Results________________________________________________________36

Cohort characteristics & hysterectomy survival analysis results____________ 36

Menopause survival analysis results_________________________________ 36

Discussion_____________________________________________________38

Conclusion_____________________________________________________41

References_____________________________________________________42

Tables and Figures _______________________________________________ 50

Appendix Tables and Figures _______________________________________ 57

Chapter 3: Perfluorooctanoic acid and chronic kidney disease:
longitudinalanalysis of a Mid-Ohio Valley community______________61

Abstract________________________________________________________62

Introduction_____________________________________________________63

Methods________________________________________________________66

Study cohort & survey data_________________________________________ 66
Case definition and cohort construction________________________________ 67

Modeled PFOA exposure____________________________________________ 69
Data analyses____________________________________________________ 70

Results_________________________________________________________72

Cohort characteristics______________________________________________ 72

Survival analysis: Cumulative PFOA exposure___________________________ 72
Survival analysis: Serum PFOA estimates______________________________ 73

Discussion______________________________________________________73

Conclusion______________________________________________________76

References______________________________________________________77

Tables and Figures ________________________________________________ 84

Appendix Tables __________________________________________________ 89

Chapter 4: A study of reverse causation: Examining the associations of
perfluorooctanoic acid serum levels with two outcomes_____________91

Abstract_________________________________________________________92

Introduction______________________________________________________94

Methods_________________________________________________________98

Data: Surveys, PFOA and eGFR_______________________________________ 99
Analyses: eGFR and PFOA in adults____________________________________ 100
Analyses: Menopause and PFOA_______________________________________ 101

Results___________________________________________________________103

eGFR analyses_____________________________________________________ 103
Menopause analyses________________________________________________ 104

Discussion________________________________________________________105

Conclusions_______________________________________________________109

References________________________________________________________112

Tables and Figures __________________________________________________ 119

Chapter 5: Summary and Conclusion_____________________________129

References________________________________________________________133

About this Dissertation

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School	Laney Graduate School
Department	Environmental Health Sciences
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Environmental Sciences Health Sciences, Epidemiology
Keyword	perfluorooctanoic acid chronic kidney disease reverse causality modeled exposure longitudinal cohort age at menopause reverse causation
Committee Chair / Thesis Advisor	Steenland, Kyle, Emory University
Committee Members	Winquist, Andrea, Emory University Darrow, Lyndsey, Emory University Klein, Mitchel, Emory University

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