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Table 1.  Characteristics of the Study Population, According to Tertiles of Urinary BPA Levels
Characteristics of the Study Population, According to Tertiles of Urinary BPA Levels
Table 2.  Association of Urinary BPA Levels With All-Cause Mortality and With Cause-Specific Mortality
Association of Urinary BPA Levels With All-Cause Mortality and With Cause-Specific Mortality
Table 3.  Stratified Analyses for the Association of Urinary BPA Levels With All-Cause Mortalitya
Stratified Analyses for the Association of Urinary BPA Levels With All-Cause Mortalitya
1.
Rochester  JR.  Bisphenol A and human health: a review of the literature.   Reprod Toxicol. 2013;42:132-155. doi:10.1016/j.reprotox.2013.08.008 PubMedGoogle ScholarCrossref
2.
Michałowicz  J.  Bisphenol A—sources, toxicity and biotransformation.   Environ Toxicol Pharmacol. 2014;37(2):738-758. doi:10.1016/j.etap.2014.02.003 PubMedGoogle ScholarCrossref
3.
Carwile  JL, Ye  X, Zhou  X, Calafat  AM, Michels  KB.  Canned soup consumption and urinary bisphenol A: a randomized crossover trial.   JAMA. 2011;306(20):2218-2220. doi:10.1001/jama.2011.1721 PubMedGoogle ScholarCrossref
4.
Ehrlich  S, Calafat  AM, Humblet  O, Smith  T, Hauser  R.  Handling of thermal receipts as a source of exposure to bisphenol A.   JAMA. 2014;311(8):859-860. doi:10.1001/jama.2013.283735 PubMedGoogle ScholarCrossref
5.
Dekant  W, Völkel  W.  Human exposure to bisphenol A by biomonitoring: methods, results and assessment of environmental exposures.   Toxicol Appl Pharmacol. 2008;228(1):114-134. doi:10.1016/j.taap.2007.12.008 PubMedGoogle ScholarCrossref
6.
Calafat  AM, Ye  X, Wong  LY, Reidy  JA, Needham  LL.  Exposure of the U.S. population to bisphenol A and 4-tertiary-octylphenol: 2003-2004.   Environ Health Perspect. 2008;116(1):39-44. doi:10.1289/ehp.10753 PubMedGoogle ScholarCrossref
7.
Lehmler  HJ, Liu  B, Gadogbe  M, Bao  W.  Exposure to bisphenol A, bisphenol F, and bisphenol S in U.S. adults and children: the National Health and Nutrition Examination Survey 2013-2014.   ACS Omega. 2018;3(6):6523-6532. doi:10.1021/acsomega.8b00824 PubMedGoogle ScholarCrossref
8.
Gore  AC.  Endocrine-disrupting chemicals.   JAMA Intern Med. 2016;176(11):1705-1706. doi:10.1001/jamainternmed.2016.5766 PubMedGoogle ScholarCrossref
9.
Vandenberg  LN, Hunt  PA, Gore  AC.  Endocrine disruptors and the future of toxicology testing—lessons from CLARITY-BPA.   Nat Rev Endocrinol. 2019;15(6):366-374. doi:10.1038/s41574-019-0173-y PubMedGoogle ScholarCrossref
10.
Gore  AC, Chappell  VA, Fenton  SE,  et al.  EDC-2: the Endocrine Society’s second scientific statement on endocrine-disrupting chemicals.   Endocr Rev. 2015;36(6):E1-E150. doi:10.1210/er.2015-1010 PubMedGoogle ScholarCrossref
11.
Heindel  JJ, Blumberg  B, Cave  M,  et al.  Metabolism disrupting chemicals and metabolic disorders.   Reprod Toxicol. 2017;68:3-33. doi:10.1016/j.reprotox.2016.10.001 PubMedGoogle ScholarCrossref
12.
Yan  S, Chen  Y, Dong  M, Song  W, Belcher  SM, Wang  HS.  Bisphenol A and 17β-estradiol promote arrhythmia in the female heart via alteration of calcium handling.   PLoS One. 2011;6(9):e25455. doi:10.1371/journal.pone.0025455 PubMedGoogle Scholar
13.
Pant  J, Ranjan  P, Deshpande  SB.  Bisphenol A decreases atrial contractility involving NO-dependent G-cyclase signaling pathway.   J Appl Toxicol. 2011;31(7):698-702. doi:10.1002/jat.1647 PubMedGoogle ScholarCrossref
14.
Patel  BB, Raad  M, Sebag  IA, Chalifour  LE.  Lifelong exposure to bisphenol a alters cardiac structure/function, protein expression, and DNA methylation in adult mice.   Toxicol Sci. 2013;133(1):174-185. doi:10.1093/toxsci/kft026 PubMedGoogle ScholarCrossref
15.
Kim  MJ, Moon  MK, Kang  GH,  et al.  Chronic exposure to bisphenol A can accelerate atherosclerosis in high-fat-fed apolipoprotein E knockout mice.   Cardiovasc Toxicol. 2014;14(2):120-128. doi:10.1007/s12012-013-9235-x PubMedGoogle ScholarCrossref
16.
Sui  Y, Park  SH, Helsley  RN,  et al.  Bisphenol A increases atherosclerosis in pregnane X receptor-humanized ApoE deficient mice.   J Am Heart Assoc. 2014;3(2):e000492. doi:10.1161/JAHA.113.000492 PubMedGoogle Scholar
17.
Patel  BB, Kasneci  A, Bolt  AM,  et al.  Chronic exposure to bisphenol A reduces successful cardiac remodeling after an experimental myocardial infarction in male C57bl/6n mice.   Toxicol Sci. 2015;146(1):101-115. doi:10.1093/toxsci/kfv073 PubMedGoogle ScholarCrossref
18.
Carwile  JL, Michels  KB.  Urinary bisphenol A and obesity: NHANES 2003-2006.   Environ Res. 2011;111(6):825-830. doi:10.1016/j.envres.2011.05.014 PubMedGoogle ScholarCrossref
19.
Trasande  L, Attina  TM, Blustein  J.  Association between urinary bisphenol A concentration and obesity prevalence in children and adolescents.   JAMA. 2012;308(11):1113-1121. doi:10.1001/2012.jama.11461 PubMedGoogle ScholarCrossref
20.
Liu  B, Lehmler  HJ, Sun  Y,  et al.  Bisphenol A substitutes and obesity in US adults: analysis of a population-based, cross-sectional study.   Lancet Planet Health. 2017;1(3):e114-e122. doi:10.1016/S2542-5196(17)30049-9 PubMedGoogle ScholarCrossref
21.
Do  MT, Chang  VC, Mendez  MA, de Groh  M.  Urinary bisphenol A and obesity in adults: results from the Canadian Health Measures Survey  [in French].  Health Promot Chronic Dis Prev Can. 2017;37(12):403-412. doi:10.24095/hpcdp.37.12.02 PubMedGoogle ScholarCrossref
22.
Lang  IA, Galloway  TS, Scarlett  A,  et al.  Association of urinary bisphenol A concentration with medical disorders and laboratory abnormalities in adults.   JAMA. 2008;300(11):1303-1310. doi:10.1001/jama.300.11.1303 PubMedGoogle ScholarCrossref
23.
Ning  G, Bi  Y, Wang  T,  et al.  Relationship of urinary bisphenol A concentration to risk for prevalent type 2 diabetes in Chinese adults: a cross-sectional analysis.   Ann Intern Med. 2011;155(6):368-374. doi:10.7326/0003-4819-155-6-201109200-00005 PubMedGoogle ScholarCrossref
24.
Sun  Q, Cornelis  MC, Townsend  MK,  et al.  Association of urinary concentrations of bisphenol A and phthalate metabolites with risk of type 2 diabetes: a prospective investigation in the Nurses’ Health Study (NHS) and NHSII cohorts.   Environ Health Perspect. 2014;122(6):616-623. doi:10.1289/ehp.1307201 PubMedGoogle ScholarCrossref
25.
Bae  S, Kim  JH, Lim  YH, Park  HY, Hong  YC.  Associations of bisphenol A exposure with heart rate variability and blood pressure.   Hypertension. 2012;60(3):786-793. doi:10.1161/HYPERTENSIONAHA.112.197715 PubMedGoogle ScholarCrossref
26.
Melzer  D, Osborne  NJ, Henley  WE,  et al.  Urinary bisphenol A concentration and risk of future coronary artery disease in apparently healthy men and women.   Circulation. 2012;125(12):1482-1490. doi:10.1161/CIRCULATIONAHA.111.069153 PubMedGoogle ScholarCrossref
27.
Centers for Disease Control and Prevention, National Center for Health Statistics. The Linkage of National Center for Health Statistics Survey Data to the National Death Index — 2015 Linked Mortality File (LMF): Methodology Overview and Analytic Considerations. Updated April 11, 2019. Accessed August 13, 2019. https://www.cdc.gov/nchs/data/datalinkage/LMF2015_Methodology_Analytic_Considerations.pdf
28.
Brämer  GR.  International statistical classification of diseases and related health problems: tenth revision.   World Health Stat Q. 1988;41(1):32-36.PubMedGoogle Scholar
29.
Heron  M.  Deaths: leading causes for 2015.   Natl Vital Stat Rep. 2017;66(5):1-76.PubMedGoogle Scholar
30.
García  MC, Bastian  B, Rossen  LM,  et al.  Potentially preventable deaths among the five leading causes of death—United States, 2010 and 2014.   MMWR Morb Mortal Wkly Rep. 2016;65(45):1245-1255. doi:10.15585/mmwr.mm6545a1 PubMedGoogle ScholarCrossref
31.
Moy  E, Garcia  MC, Bastian  B,  et al.  Leading causes of death in nonmetropolitan and metropolitan areas—United States, 1999-2014.   MMWR Surveill Summ. 2017;66(1):1-8. doi:10.15585/mmwr.ss6601a1 PubMedGoogle ScholarCrossref
32.
Guenther  PM, Casavale  KO, Reedy  J,  et al.  Update of the Healthy Eating Index: HEI-2010.   J Acad Nutr Diet. 2013;113(4):569-580. doi:10.1016/j.jand.2012.12.016 PubMedGoogle ScholarCrossref
33.
Johnson  CL, Paulose-Ram  R, Ogden  CL,  et al.  National Health and Nutrition Examination Survey: analytic guidelines, 1999-2010.   Vital Health Stat 2. 2013;(161):1-24.PubMedGoogle Scholar
34.
Barr  DB, Wilder  LC, Caudill  SP, Gonzalez  AJ, Needham  LL, Pirkle  JL.  Urinary creatinine concentrations in the U.S. population: implications for urinary biologic monitoring measurements.   Environ Health Perspect. 2005;113(2):192-200. doi:10.1289/ehp.7337 PubMedGoogle ScholarCrossref
35.
VanderWeele  TJ, Ding  P.  Sensitivity analysis in observational research: introducing the E-value.   Ann Intern Med. 2017;167(4):268-274. doi:10.7326/M16-2607 PubMedGoogle ScholarCrossref
36.
Haneuse  S, VanderWeele  TJ, Arterburn  D.  Using the E-value to assess the potential effect of unmeasured confounding in observational studies.   JAMA. 2019;321(6):602-603. doi:10.1001/jama.2018.21554 PubMedGoogle ScholarCrossref
37.
Rancière  F, Lyons  JG, Loh  VH,  et al.  Bisphenol A and the risk of cardiometabolic disorders: a systematic review with meta-analysis of the epidemiological evidence.   Environ Health. 2015;14:46. doi:10.1186/s12940-015-0036-5 PubMedGoogle ScholarCrossref
38.
Han  C, Hong  YC.  Bisphenol A, hypertension, and cardiovascular diseases: epidemiological, laboratory, and clinical trial evidence.   Curr Hypertens Rep. 2016;18(2):11. doi:10.1007/s11906-015-0617-2 PubMedGoogle ScholarCrossref
39.
Gao  X, Wang  HS.  Impact of bisphenol A on the cardiovascular system—epidemiological and experimental evidence and molecular mechanisms.   Int J Environ Res Public Health. 2014;11(8):8399-8413. doi:10.3390/ijerph110808399 PubMedGoogle ScholarCrossref
40.
Lin  CY, Shen  FY, Lian  GW,  et al.  Association between levels of serum bisphenol A, a potentially harmful chemical in plastic containers, and carotid artery intima-media thickness in adolescents and young adults.   Atherosclerosis. 2015;241(2):657-663. doi:10.1016/j.atherosclerosis.2015.06.038 PubMedGoogle ScholarCrossref
41.
Lind  PM, Lind  L.  Circulating levels of bisphenol A and phthalates are related to carotid atherosclerosis in the elderly.   Atherosclerosis. 2011;218(1):207-213. doi:10.1016/j.atherosclerosis.2011.05.001 PubMedGoogle ScholarCrossref
42.
Melzer  D, Gates  P, Osborne  NJ,  et al.  Urinary bisphenol a concentration and angiography-defined coronary artery stenosis.   PLoS One. 2012;7(8):e43378. Published correction appears in PLoS One. 2012;7(11). doi:10.1371/journal.pone.0043378 PubMedGoogle Scholar
43.
Ye  X, Wong  LY, Kramer  J, Zhou  X, Jia  T, Calafat  AM.  Urinary concentrations of bisphenol A and three other bisphenols in convenience samples of U.S. adults during 2000-2014.   Environ Sci Technol. 2015;49(19):11834-11839. doi:10.1021/acs.est.5b02135 PubMedGoogle ScholarCrossref
44.
LaKind  JS, Naiman  DQ.  Temporal trends in bisphenol A exposure in the United States from 2003-2012 and factors associated with BPA exposure: spot samples and urine dilution complicate data interpretation.   Environ Res. 2015;142:84-95. doi:10.1016/j.envres.2015.06.013 PubMedGoogle ScholarCrossref
45.
Rochester  JR, Bolden  AL.  Bisphenol S and F: a systematic review and comparison of the hormonal activity of bisphenol A substitutes.   Environ Health Perspect. 2015;123(7):643-650. doi:10.1289/ehp.1408989 PubMedGoogle ScholarCrossref
46.
Trasande  L.  Exploring regrettable substitution: replacements for bisphenol A.   Lancet Planet Health. 2017;1(3):e88-e89. doi:10.1016/S2542-5196(17)30046-3 PubMedGoogle ScholarCrossref
47.
Liu  B, Lehmler  HJ, Sun  Y,  et al.  Association of bisphenol A and its substitutes, bisphenol F and bisphenol S, with obesity in United States children and adolescents.   Diabetes Metab J. 2019;43(1):59-75. doi:10.4093/dmj.2018.0045 PubMedGoogle ScholarCrossref
48.
Jacobson  MH, Woodward  M, Bao  W, Liu  B, Trasande  L.  Urinary bisphenols and obesity prevalence among US children and adolescents.   J Endocr Soc. 2019;3(9):1715-1726. doi:10.1210/js.2019-00201 PubMedGoogle ScholarCrossref
49.
Ye  X, Wong  LY, Bishop  AM, Calafat  AM.  Variability of urinary concentrations of bisphenol A in spot samples, first morning voids, and 24-hour collections.   Environ Health Perspect. 2011;119(7):983-988. doi:10.1289/ehp.1002701 PubMedGoogle ScholarCrossref
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    2 Comments for this article
    EXPAND ALL
    What is cause; what is effect?
    Duncan Turnbull, DPhil | Retired
    Study results say: "Participants with higher urinary BPA levels were at higher risk of death during the follow-up."
    Results also say: "Participants with higher urinary BPA levels were more likely to be younger, male, and non-Hispanic Black and have lower educational level, lower family income, lower physical activity, higher total energy intake, poorer dietary quality, and higher BMI."
    Quite a few of those latter characteristics well known to be associated with higher risk of death?
    What is the cause and what is the effect? Take your pick.
    CONFLICT OF INTEREST: None Reported
    Deep Rooted Evil.
    Arvind Joshi, MBBS, MD; FCGP FAMS FICP. | Founder Convener and President Our Own Discussion Group, Mumbai; Consultant Physician at Ruchi Diagnostic Center and Ruchi Clinical Laboratory Kharghar, Maharashtra State, India
    Bisphenol A is used so widely and for so long, it has already contaminated the environment, on the land as well as water bodies including oceans.
    The task at hand is two-fold: to reduce or preferably eliminate use of Bisphenol A; to decontaminate the environment.
    Reduce and eliminate use of Bisphenol A may seem difficult, but is possible. Of course care must be taken that whatever material is used to replace Bisphenol A does not turn out to be as much or more troublesome as Bisphenol A itself.
    Eliminating Bisphenol A from environment may be daunting or even impossible task.
    One of the ways may be to find out microbes which may be able to degrade environmental Bisphenol A to harmless or even useful or beneficial substances. Very easy to say, much difficult to find even in theory, far more difficult to execute on the stupendous magnitude!
    Arvind Joshi;
    MBBS, MD; FCGP, FAMS, FICP;
    Founder Convener and President: Our Own Discussion Group;
    Mumbai
    Consaltant Physician at Ruchi Diagnostic Center and Ruchi Clinical Laboratory Sunshine CHS 
    Maharashtra State, India
    CONFLICT OF INTEREST: None Reported
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    Original Investigation
    Environmental Health
    August 17, 2020

    Association Between Bisphenol A Exposure and Risk of All-Cause and Cause-Specific Mortality in US Adults

    Author Affiliations
    • 1Department of Epidemiology, College of Public Health, University of Iowa, Iowa City
    • 2Department of Nutrition and Food Hygiene, School of Public Health, Medical College, Wuhan University of Science and Technology Wuhan, Hubei, China
    • 3State Hygienic Laboratory, University of Iowa, Iowa City
    • 4Department of Pediatrics, New York University School of Medicine, New York
    • 5Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City
    JAMA Netw Open. 2020;3(8):e2011620. doi:10.1001/jamanetworkopen.2020.11620
    Key Points español 中文 (chinese)

    Question  Is exposure to bisphenol A, a ubiquitous chemical of concern, associated with long-term risk of mortality?

    Findings  In a cohort study of 3883 adults in the United States, participants with higher urinary bisphenol A levels were at higher risk for death during approximately 10 years of observation. The adjusted hazard ratio comparing the highest vs lowest tertile of urinary bisphenol A levels was 49% higher for all-cause mortality and was 46% higher, albeit not statistically significant, for cardiovascular disease mortality.

    Meaning  The findings in this study suggest that a higher level of bisphenol A exposure is associated with an increased risk of long-term all-cause mortality.

    Abstract

    Importance  Bisphenol A (BPA) is a major public health concern because of its high-volume industrial production, ubiquitous exposure to humans, and potential toxic effects on multiple organs and systems in humans. However, prospective studies regarding the association of BPA exposure with long-term health outcomes are sparse.

    Objective  To examine the association of BPA exposure with all-cause mortality and cause-specific mortality among adults in the United States.

    Design, Setting, and Participants  This nationally representative cohort study included 3883 adults aged 20 years or older who participated in the US National Health and Nutrition Examination Survey 2003-2008 and provided urine samples for BPA level measurements. Participants were linked to mortality data from survey date through December 31, 2015. Data analyses were conducted in July 2019.

    Exposures  Urinary BPA levels were quantified using online solid-phase extraction coupled to high-performance liquid chromatography–isotope dilution tandem mass spectrometry.

    Main Outcomes and Measures  Mortality from all causes, cardiovascular disease, and cancer.

    Results  This cohort study included 3883 adults aged 20 years or older (weighted mean [SE] age, 43.6 [0.3] years; 2032 women [weighted, 51.4%]). During 36 514 person-years of follow-up (median, 9.6 years; maximum, 13.1 years), 344 deaths occurred, including 71 deaths from cardiovascular disease and 75 deaths from cancer. Participants with higher urinary BPA levels were at higher risk for death. After adjustment for age, sex, race/ethnicity, socioeconomic status, dietary and lifestyle factors, body mass index, and urinary creatinine levels, the hazard ratio comparing the highest vs lowest tertile of urinary BPA levels was 1.49 (95% CI, 1.01-2.19) for all-cause mortality, 1.46 (95% CI, 0.67-3.15) for cardiovascular disease mortality, and 0.98 (95% CI, 0.40-2.39) for cancer mortality.

    Conclusions and Relevance  In this nationally representative cohort of US adults, higher BPA exposure was significantly associated with an increased risk of all-cause mortality. Further studies are needed to replicate these findings in other populations and determine the underlying mechanisms.

    Introduction

    Widespread exposure to bisphenol A (BPA) has emerged as a major public health concern.1,2 Bisphenol A is a high-volume industrial chemical produced primarily for the manufacturing of polycarbonate plastics and epoxy resins. Polycarbonate plastics based on BPA are used in many consumer products, such as plastic bottles, sports equipment, compact discs, some medical devices, and dental sealants and composites. Epoxy resins that contain BPA are used to line water pipes, coat the inside of food and beverage cans, and make thermal paper such as that used in sales receipts.3,4 As a result, BPA exposure to humans is ubiquitous from a variety of sources ranging from consumer products, food, and water to dust.5 National biomonitoring data in the United States show that BPA is detectable in more than 90% of urine samples in the general population.6,7 Currently in the United States, 12 states and Washington, DC have restrictions in place against BPA. In Europe, the European Chemical Agency has added BPA to the Candidate List of substances of very high concern.

    Evidence from animal studies has shown that BPA has endocrine-disrupting effects.8,9 Exposure to BPA can disrupt endocrine function and metabolism, inducing the development of obesity and metabolic disorders.10,11 Exposure to BPA can also induce cardiac arrhythmias, accelerate atherosclerosis, decrease atrial contraction rate and force, and lead to cardiac remodeling in animal models.12-17 Moreover, previous epidemiologic studies have shown that BPA exposure is associated with an increased risk of obesity,18-21 diabetes,22-24 hypertension,25 and cardiovascular disease (CVD).22,26 However, most of the previous epidemiologic studies are cross-sectional, and prospective cohort studies examining the association of BPA exposure with long-term health outcomes are sparse. Although growing evidence suggests that BPA has potentially toxic effects on a variety of organs and systems in humans, the association between BPA exposure and risk of mortality remains unknown. In the present study, we used data from a nationally representative cohort to examine the association of BPA exposure with all-cause and cause-specific mortality in US adults.

    Methods
    Study Population

    The National Health and Nutrition Examination Survey (NHANES) is a nationally representative health survey program of the civilian noninstitutionalized resident population in the United States. It is administered by the National Center for Health Statistics (NCHS) at the Centers for Disease Control and Prevention (CDC). The uniqueness of the NHANES program is that it not only collects questionnaire data through in-person interviews but also performs health examinations in the Mobile Examination Center and collects specimens for laboratory tests. The NHANES protocol has been approved by the NCHS Ethics Review Board. Written informed consent was obtained in NHANES from all participants. All participants received a cash payment for their time and effort and were compensated for transportation and baby or elder care during their participation.

    For the present analysis, we included adults aged 20 years or older who participated in NHANES during the period from 2003 to 2008 and had available data on BPA measurements. We linked all participants to mortality data through 2015, which enabled approximately 10 years of observation for mortality outcomes. Individuals with CVD or cancer at baseline were excluded. The data analysis was performed in July 2019. The present study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies.

    Assessment of BPA Exposure

    Spot urine samples are collected in the NHANES program from participants aged 6 years or older. The BPA levels in urine samples were measured in one-third of randomly selected NHANES participants using online solid-phase extraction coupled to high-performance liquid chromatography–isotope dilution tandem mass spectrometry at the Division of Laboratory Sciences, National Center for Environmental Health, CDC. The lower limit of detection (LLOD) for BPA was 0.36 μg/L for the 2003 to 2004 samples and 0.40 μg/L for the 2005 to 2008 samples. For BPA levels below the LLOD (<7% of the samples provided by this study population), the NHANES staff assigned a value of the LLOD divided by the square root of 2. A detailed description of the methods of BPA measurement in NHANES was published previously.6

    Ascertainment of Mortality Outcomes

    We used the NHANES Public-Use Linked Mortality File through December 31, 2015, which was linked by the NCHS to the National Death Index with a probabilistic matching algorithm to determine mortality status.27 The National Death Index is an NCHS centralized database of all deaths in the United States. Data about the underlying cause of death were used for case definition according to the International Statistical Classification of Diseases, Tenth Revision.28 Accordingly, the NCHS classified cardiovascular mortality as death from heart disease (codes I00-I09, I11, I13, and I20-I51) or cerebrovascular disease (codes I60-I69) and cancer mortality as death from malignant neoplasms (codes C00-C97). This approach has been previously validated by the CDC and used in many CDC reports.29-31

    Assessment of Covariates

    Information on age, sex, race/ethnicity, educational level, family income, smoking status, alcohol drinking, physical activity, and dietary intake was collected using questionnaires. According to the 1997 US federal Office of Management and Budget standards, race/ethnicity was categorized into Hispanic (including Mexican and non-Mexican Hispanic), non-Hispanic White, non-Hispanic Black, and other. Family income was categorized as the ratio of family income to the federal poverty level (<1.0, 1.0-1.9, 2.0-3.9, and ≥4.0). A higher income to poverty ratio indicates a better family income status. Self-reported educational status was grouped as lower than high school, high school, and college or higher. In accordance with the NCHS classifications, individuals who smoked less than 100 cigarettes in their lifetime were defined as never smokers; those who had smoked more than 100 cigarettes but did not smoke at the time of survey were considered former smokers; and those who had smoked more than 100 cigarettes in their lifetime and smoked cigarettes at the time of survey were considered current smokers. Alcohol intake was categorized as none (0 g/d), moderate drinking (0.1 to 27.9 g/d for men and 0.1 to 13.9 g/d for women), and heavy drinking (≥28 g/d for men and ≥14 g/d for women). For physical activity, participants were asked an array of questions related to daily activities in the questionnaire, from which metabolic equivalent of task (MET) minutes per week was calculated. There have been some changes in physical activity questionnaires in NHANES since the 2007 to 2008 questionnaire. Therefore, physical activity for each participant was categorized according to standards appropriate for each cycle as follows: (1) below, less than 600 MET min/wk or 150 min/wk of moderate-intensity exercise; (2) meet, 600 to 1200 MET min/wk or 150 to 300 min/wk of moderate-intensity exercise; or (3) exceed, at least 1200 MET min/wk or 300 min/wk of moderate-intensity exercise. Dietary information was collected by 24-hour dietary recall interviews, from which total energy intake was calculated using the US Department of Agriculture Automated Multiple-Pass Method. We used the Healthy Eating Index-2010 (HEI-2010) to indicate the overall quality of diet (HEI-2010 scores range from 0 to 100, with 100 being the best-quality diet).32 Body weight and height were measured by trained health technicians following the NHANES Anthropometry Procedures Manual. Body mass index (BMI) was calculated as the weight in kilograms divided by the height in meters squared. Urinary creatinine level was measured using the Jaffé rate reaction, in which creatinine reacts with picrate in an alkaline solution to form a red creatinine-picrate complex.

    Statistical Analysis

    The NHANES program uses a complex, multistage probability sampling design to represent a national, civilian, noninstitutionalized population in the United States. Therefore, sample weights, strata, and primary sampling units were applied following the NHANES Analytic Guidelines33 to account for the unequal probability of selection, oversampling of certain subpopulations, and nonresponse adjustment.

    Mean values and proportions of baseline characteristics were compared using linear regression for continuous variables and logistic regression for categorical variables. We used Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% CIs for the associations between BPA exposure and risk of mortality. Follow-up time for each person was calculated as the difference between the NHANES examination date and the last known date alive or censored from the linked mortality file. In the fully adjusted model, we adjusted for age, sex, race/ethnicity, educational level, family income level, smoking status, alcohol intake, physical activity, total energy intake, overall diet quality indicated by HEI-2010 score, and BMI. To account for urine dilution, urinary creatinine levels were adjusted for in all the analysis models in this study, as previously recommended.34 Furthermore, we performed stratified analyses and interaction analyses to examine whether the association differed by age, sex, race/ethnicity, diet quality, physical activity, and obesity status. In addition, we conducted a sensitivity analysis using the E-value method35,36 to test whether and how our results were robust to potential unmeasured confounding. All statistical analyses were conducted using the survey modules of SAS software, version 9.4 (SAS Institute Inc). A 2-sided P < .05 was considered statistically significant.

    Results

    We included 3883 adults aged 20 years or older (weighted mean [SE] age, 43.6 [0.3] years; 2032 women [weighted, 51.4%]) in this study. During 36 514 person-years of follow-up (median follow-up, 9.6 years; maximum follow-up, 13.1 years), 344 deaths occurred, including 71 deaths from CVD and 75 deaths from cancer. Participants with higher urinary BPA levels were more likely to be younger, male, and non-Hispanic Black and have lower educational level, lower family income, lower physical activity, higher total energy intake, poorer dietary quality, and higher BMI (Table 1).

    Participants with higher urinary BPA levels were at higher risk of death during the follow-up (Table 2). After adjustment for age, sex, race/ethnicity, and urinary creatinine levels, participants with the highest tertile of urinary BPA levels had a 51% higher risk of all-cause mortality (HR, 1.51; 95% CI, 1.07-2.13) compared with those with the lowest tertile of urinary BPA levels. The association was not appreciably changed after further adjustment for other covariates. In the fully adjusted model including demographic characteristics, socioeconomic status, dietary and lifestyle factors, BMI, and urinary creatinine levels, the HR for all-cause mortality among participants with the highest tertile of urinary BPA levels compared with those with the lowest tertile was 1.49 (95% CI, 1.01-2.19). Similar results were observed for CVD mortality (HR, 1.46; 95% CI, 0.67-3.15), although this association was not statistically significant. Exposure to BPA was not associated with cancer mortality (HR, 0.98; 95% CI, 0.40-2.39). Stratified analyses showed that the observed associations of BPA exposure with mortality did not significantly differ by age, sex, race/ethnicity, diet quality, physical activity, or obesity status (Table 3; eTable in the Supplement). In the sensitivity analysis using the E-value to assess the potential of unmeasured confounding, the E-value was 2.34 for all-cause mortality for the point estimate and 1.11 for the lower confidence bound. The E-values for CVD mortality were 2.28 for the point estimate and 1.0 for the lower confidence bound; for cancer mortality, the E-value was 1.16 for the point estimate and 1.0 for the lower confidence bound.

    Discussion

    In a prospective cohort of a US nationally representative sample, we found that BPA exposure was significantly and positively associated with all-cause mortality in adults. The association remained significant after adjustment for demographic characteristics, socioeconomic status, dietary and lifestyle factors, BMI, and urinary creatinine levels. There was a statistically nonsignificant association between BPA exposure and CVD mortality and no association between BPA exposure and cancer mortality.

    To our knowledge, this is the first study examining the association of BPA exposure with risk of mortality. Our findings are in line with previous epidemiologic studies showing a significant association of BPA exposure with cardiometabolic disorders, including diabetes, hypertension, and CVD.37-39 In addition, BPA exposure is also associated with atherosclerosis,40,41 coronary artery stenosis,42 and reduction in heart rate variability in humans.25 The potential mechanisms underlying increased risk of mortality associated with BPA remain to be elucidated, which may include alteration in cardiac calcium handling, ion channel inhibition or activation, oxidative stress and inflammation, epigenetic modifications, and variations in transcriptome or proteome expression.38,39

    Our findings may have major public health implications. Exposure to BPA is ubiquitous among humans, affecting more than 90% of the general US population.6,7,43 Although BPA exposure has decreased over time in the United States,44 it was still detected in 95.7% of urine samples from participants in NHANES during the period from 2013 to 2014.7 Given the wide range of potentially toxic effects of BPA in humans, it is imperative and important to minimize human exposure to BPA. Substitution of BPA with other bisphenol analogues, such as bisphenol F and bisphenol S, is becoming popular7,45; however, the health effects of those emerging BPA substitutes remain largely unknown.20,46 Evidence from animal and epidemiologic studies, although still limited, suggest that some BPA substitutes may have toxic effects similar to BPA.45,47,48

    Strengths and Limitations

    This study has several strengths. We used nationally representative data from NHANES, which enables us to generalize our findings to a broader population. In addition, the abundant data from NHANES, including comprehensive information on demographic and socioeconomic characteristics, anthropometric measures, and diet and lifestyle factors, provide the opportunity to adjust for a variety of potential confounding factors. There are some limitations in this study. First, spot urine samples were used to measure BPA concentrations in NHANES because it is challenging and less feasible to collect 24-hour urine samples in a large sample size, nationally representative cohort. Although within-person and between-person variability exists, previous evidence shows that urinary concentrations of BPA derived from a single spot-sampling approach may adequately reflect the average exposure of a population to BPA when urine samples are collected from a sufficiently large population with random meal ingestion and bladder emptying times.49 Second, the NHANES Linked Mortality File identified causes of death through linkage to the National Death Index, which is based on death certificates. This approach has been previously validated by the CDC and used in many CDC reports29-31 and other relevant literature. However, we could not rule out the possibility of errors in the classification of the cause of death. Third, although many potential confounders were adjusted for, there might still be residual confounding by unmeasured factors. However, the sensitivity analysis using E-values showed that the association between BPA and all-cause mortality could only be negated by an unmeasured cofounder that had associations with both BPA exposure and all-cause mortality with an HR of at least 2.34. This HR was higher than the HRs of the known confounders that were measured in this study (range, 1.02-1.97). Therefore, it is unlikely that an unmeasured confounder would be more substantially associated with all-cause mortality than the known risk factors evaluated in the present study by having an HR exceeding 2.34.

    Conclusions

    Our findings from a nationally representative cohort suggested that higher BPA exposure was significantly associated with an increased risk of all-cause mortality among US adults. The observed but statistically nonsignificant association between BPA exposure and CVD mortality warrants further investigation. In addition, further studies are needed to replicate our findings in other populations and determine the underlying mechanisms.

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    Article Information

    Accepted for Publication: May 15, 2020.

    Published: August 17, 2020. doi:10.1001/jamanetworkopen.2020.11620

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Bao W et al. JAMA Network Open.

    Corresponding Author: Wei Bao, MD, PhD, Department of Epidemiology, College of Public Health, University of Iowa, 145 N Riverside Dr, Room S431 CPHB, Iowa City, IA 52242 (wei-bao@uiowa.edu).

    Author Contributions: Dr Bao had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Bao, Trasande.

    Acquisition, analysis, or interpretation of data: Bao, Liu, Rong, Dai, Lehmler.

    Drafting of the manuscript: Bao, Trasande, Lehmler.

    Critical revision of the manuscript for important intellectual content: Bao, Liu, Rong, Dai, Lehmler.

    Statistical analysis: Liu.

    Obtained funding: Bao.

    Administrative, technical, or material support: Bao, Rong, Lehmler.

    Supervision: Bao, Trasande.

    Conflict of Interest Disclosures: Dr Lehmler reported receiving grants from the National Institutes of Health during the conduct of the study. No other disclosures were reported.

    Funding/Support: This work was supported by grant P30 ES005605 from the National Institute of Environmental Health Sciences through the University of Iowa Environmental Health Sciences Research Center.

    Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Additional Contributions: We thank the participants and staff of the National Health and Nutrition Examination Survey and the National Center for Environmental Health for their valuable contributions.

    References
    1.
    Rochester  JR.  Bisphenol A and human health: a review of the literature.   Reprod Toxicol. 2013;42:132-155. doi:10.1016/j.reprotox.2013.08.008 PubMedGoogle ScholarCrossref
    2.
    Michałowicz  J.  Bisphenol A—sources, toxicity and biotransformation.   Environ Toxicol Pharmacol. 2014;37(2):738-758. doi:10.1016/j.etap.2014.02.003 PubMedGoogle ScholarCrossref
    3.
    Carwile  JL, Ye  X, Zhou  X, Calafat  AM, Michels  KB.  Canned soup consumption and urinary bisphenol A: a randomized crossover trial.   JAMA. 2011;306(20):2218-2220. doi:10.1001/jama.2011.1721 PubMedGoogle ScholarCrossref
    4.
    Ehrlich  S, Calafat  AM, Humblet  O, Smith  T, Hauser  R.  Handling of thermal receipts as a source of exposure to bisphenol A.   JAMA. 2014;311(8):859-860. doi:10.1001/jama.2013.283735 PubMedGoogle ScholarCrossref
    5.
    Dekant  W, Völkel  W.  Human exposure to bisphenol A by biomonitoring: methods, results and assessment of environmental exposures.   Toxicol Appl Pharmacol. 2008;228(1):114-134. doi:10.1016/j.taap.2007.12.008 PubMedGoogle ScholarCrossref
    6.
    Calafat  AM, Ye  X, Wong  LY, Reidy  JA, Needham  LL.  Exposure of the U.S. population to bisphenol A and 4-tertiary-octylphenol: 2003-2004.   Environ Health Perspect. 2008;116(1):39-44. doi:10.1289/ehp.10753 PubMedGoogle ScholarCrossref
    7.
    Lehmler  HJ, Liu  B, Gadogbe  M, Bao  W.  Exposure to bisphenol A, bisphenol F, and bisphenol S in U.S. adults and children: the National Health and Nutrition Examination Survey 2013-2014.   ACS Omega. 2018;3(6):6523-6532. doi:10.1021/acsomega.8b00824 PubMedGoogle ScholarCrossref
    8.
    Gore  AC.  Endocrine-disrupting chemicals.   JAMA Intern Med. 2016;176(11):1705-1706. doi:10.1001/jamainternmed.2016.5766 PubMedGoogle ScholarCrossref
    9.
    Vandenberg  LN, Hunt  PA, Gore  AC.  Endocrine disruptors and the future of toxicology testing—lessons from CLARITY-BPA.   Nat Rev Endocrinol. 2019;15(6):366-374. doi:10.1038/s41574-019-0173-y PubMedGoogle ScholarCrossref
    10.
    Gore  AC, Chappell  VA, Fenton  SE,  et al.  EDC-2: the Endocrine Society’s second scientific statement on endocrine-disrupting chemicals.   Endocr Rev. 2015;36(6):E1-E150. doi:10.1210/er.2015-1010 PubMedGoogle ScholarCrossref
    11.
    Heindel  JJ, Blumberg  B, Cave  M,  et al.  Metabolism disrupting chemicals and metabolic disorders.   Reprod Toxicol. 2017;68:3-33. doi:10.1016/j.reprotox.2016.10.001 PubMedGoogle ScholarCrossref
    12.
    Yan  S, Chen  Y, Dong  M, Song  W, Belcher  SM, Wang  HS.  Bisphenol A and 17β-estradiol promote arrhythmia in the female heart via alteration of calcium handling.   PLoS One. 2011;6(9):e25455. doi:10.1371/journal.pone.0025455 PubMedGoogle Scholar
    13.
    Pant  J, Ranjan  P, Deshpande  SB.  Bisphenol A decreases atrial contractility involving NO-dependent G-cyclase signaling pathway.   J Appl Toxicol. 2011;31(7):698-702. doi:10.1002/jat.1647 PubMedGoogle ScholarCrossref
    14.
    Patel  BB, Raad  M, Sebag  IA, Chalifour  LE.  Lifelong exposure to bisphenol a alters cardiac structure/function, protein expression, and DNA methylation in adult mice.   Toxicol Sci. 2013;133(1):174-185. doi:10.1093/toxsci/kft026 PubMedGoogle ScholarCrossref
    15.
    Kim  MJ, Moon  MK, Kang  GH,  et al.  Chronic exposure to bisphenol A can accelerate atherosclerosis in high-fat-fed apolipoprotein E knockout mice.   Cardiovasc Toxicol. 2014;14(2):120-128. doi:10.1007/s12012-013-9235-x PubMedGoogle ScholarCrossref
    16.
    Sui  Y, Park  SH, Helsley  RN,  et al.  Bisphenol A increases atherosclerosis in pregnane X receptor-humanized ApoE deficient mice.   J Am Heart Assoc. 2014;3(2):e000492. doi:10.1161/JAHA.113.000492 PubMedGoogle Scholar
    17.
    Patel  BB, Kasneci  A, Bolt  AM,  et al.  Chronic exposure to bisphenol A reduces successful cardiac remodeling after an experimental myocardial infarction in male C57bl/6n mice.   Toxicol Sci. 2015;146(1):101-115. doi:10.1093/toxsci/kfv073 PubMedGoogle ScholarCrossref
    18.
    Carwile  JL, Michels  KB.  Urinary bisphenol A and obesity: NHANES 2003-2006.   Environ Res. 2011;111(6):825-830. doi:10.1016/j.envres.2011.05.014 PubMedGoogle ScholarCrossref
    19.
    Trasande  L, Attina  TM, Blustein  J.  Association between urinary bisphenol A concentration and obesity prevalence in children and adolescents.   JAMA. 2012;308(11):1113-1121. doi:10.1001/2012.jama.11461 PubMedGoogle ScholarCrossref
    20.
    Liu  B, Lehmler  HJ, Sun  Y,  et al.  Bisphenol A substitutes and obesity in US adults: analysis of a population-based, cross-sectional study.   Lancet Planet Health. 2017;1(3):e114-e122. doi:10.1016/S2542-5196(17)30049-9 PubMedGoogle ScholarCrossref
    21.
    Do  MT, Chang  VC, Mendez  MA, de Groh  M.  Urinary bisphenol A and obesity in adults: results from the Canadian Health Measures Survey  [in French].  Health Promot Chronic Dis Prev Can. 2017;37(12):403-412. doi:10.24095/hpcdp.37.12.02 PubMedGoogle ScholarCrossref
    22.
    Lang  IA, Galloway  TS, Scarlett  A,  et al.  Association of urinary bisphenol A concentration with medical disorders and laboratory abnormalities in adults.   JAMA. 2008;300(11):1303-1310. doi:10.1001/jama.300.11.1303 PubMedGoogle ScholarCrossref
    23.
    Ning  G, Bi  Y, Wang  T,  et al.  Relationship of urinary bisphenol A concentration to risk for prevalent type 2 diabetes in Chinese adults: a cross-sectional analysis.   Ann Intern Med. 2011;155(6):368-374. doi:10.7326/0003-4819-155-6-201109200-00005 PubMedGoogle ScholarCrossref
    24.
    Sun  Q, Cornelis  MC, Townsend  MK,  et al.  Association of urinary concentrations of bisphenol A and phthalate metabolites with risk of type 2 diabetes: a prospective investigation in the Nurses’ Health Study (NHS) and NHSII cohorts.   Environ Health Perspect. 2014;122(6):616-623. doi:10.1289/ehp.1307201 PubMedGoogle ScholarCrossref
    25.
    Bae  S, Kim  JH, Lim  YH, Park  HY, Hong  YC.  Associations of bisphenol A exposure with heart rate variability and blood pressure.   Hypertension. 2012;60(3):786-793. doi:10.1161/HYPERTENSIONAHA.112.197715 PubMedGoogle ScholarCrossref
    26.
    Melzer  D, Osborne  NJ, Henley  WE,  et al.  Urinary bisphenol A concentration and risk of future coronary artery disease in apparently healthy men and women.   Circulation. 2012;125(12):1482-1490. doi:10.1161/CIRCULATIONAHA.111.069153 PubMedGoogle ScholarCrossref
    27.
    Centers for Disease Control and Prevention, National Center for Health Statistics. The Linkage of National Center for Health Statistics Survey Data to the National Death Index — 2015 Linked Mortality File (LMF): Methodology Overview and Analytic Considerations. Updated April 11, 2019. Accessed August 13, 2019. https://www.cdc.gov/nchs/data/datalinkage/LMF2015_Methodology_Analytic_Considerations.pdf
    28.
    Brämer  GR.  International statistical classification of diseases and related health problems: tenth revision.   World Health Stat Q. 1988;41(1):32-36.PubMedGoogle Scholar
    29.
    Heron  M.  Deaths: leading causes for 2015.   Natl Vital Stat Rep. 2017;66(5):1-76.PubMedGoogle Scholar
    30.
    García  MC, Bastian  B, Rossen  LM,  et al.  Potentially preventable deaths among the five leading causes of death—United States, 2010 and 2014.   MMWR Morb Mortal Wkly Rep. 2016;65(45):1245-1255. doi:10.15585/mmwr.mm6545a1 PubMedGoogle ScholarCrossref
    31.
    Moy  E, Garcia  MC, Bastian  B,  et al.  Leading causes of death in nonmetropolitan and metropolitan areas—United States, 1999-2014.   MMWR Surveill Summ. 2017;66(1):1-8. doi:10.15585/mmwr.ss6601a1 PubMedGoogle ScholarCrossref
    32.
    Guenther  PM, Casavale  KO, Reedy  J,  et al.  Update of the Healthy Eating Index: HEI-2010.   J Acad Nutr Diet. 2013;113(4):569-580. doi:10.1016/j.jand.2012.12.016 PubMedGoogle ScholarCrossref
    33.
    Johnson  CL, Paulose-Ram  R, Ogden  CL,  et al.  National Health and Nutrition Examination Survey: analytic guidelines, 1999-2010.   Vital Health Stat 2. 2013;(161):1-24.PubMedGoogle Scholar
    34.
    Barr  DB, Wilder  LC, Caudill  SP, Gonzalez  AJ, Needham  LL, Pirkle  JL.  Urinary creatinine concentrations in the U.S. population: implications for urinary biologic monitoring measurements.   Environ Health Perspect. 2005;113(2):192-200. doi:10.1289/ehp.7337 PubMedGoogle ScholarCrossref
    35.
    VanderWeele  TJ, Ding  P.  Sensitivity analysis in observational research: introducing the E-value.   Ann Intern Med. 2017;167(4):268-274. doi:10.7326/M16-2607 PubMedGoogle ScholarCrossref
    36.
    Haneuse  S, VanderWeele  TJ, Arterburn  D.  Using the E-value to assess the potential effect of unmeasured confounding in observational studies.   JAMA. 2019;321(6):602-603. doi:10.1001/jama.2018.21554 PubMedGoogle ScholarCrossref
    37.
    Rancière  F, Lyons  JG, Loh  VH,  et al.  Bisphenol A and the risk of cardiometabolic disorders: a systematic review with meta-analysis of the epidemiological evidence.   Environ Health. 2015;14:46. doi:10.1186/s12940-015-0036-5 PubMedGoogle ScholarCrossref
    38.
    Han  C, Hong  YC.  Bisphenol A, hypertension, and cardiovascular diseases: epidemiological, laboratory, and clinical trial evidence.   Curr Hypertens Rep. 2016;18(2):11. doi:10.1007/s11906-015-0617-2 PubMedGoogle ScholarCrossref
    39.
    Gao  X, Wang  HS.  Impact of bisphenol A on the cardiovascular system—epidemiological and experimental evidence and molecular mechanisms.   Int J Environ Res Public Health. 2014;11(8):8399-8413. doi:10.3390/ijerph110808399 PubMedGoogle ScholarCrossref
    40.
    Lin  CY, Shen  FY, Lian  GW,  et al.  Association between levels of serum bisphenol A, a potentially harmful chemical in plastic containers, and carotid artery intima-media thickness in adolescents and young adults.   Atherosclerosis. 2015;241(2):657-663. doi:10.1016/j.atherosclerosis.2015.06.038 PubMedGoogle ScholarCrossref
    41.
    Lind  PM, Lind  L.  Circulating levels of bisphenol A and phthalates are related to carotid atherosclerosis in the elderly.   Atherosclerosis. 2011;218(1):207-213. doi:10.1016/j.atherosclerosis.2011.05.001 PubMedGoogle ScholarCrossref
    42.
    Melzer  D, Gates  P, Osborne  NJ,  et al.  Urinary bisphenol a concentration and angiography-defined coronary artery stenosis.   PLoS One. 2012;7(8):e43378. Published correction appears in PLoS One. 2012;7(11). doi:10.1371/journal.pone.0043378 PubMedGoogle Scholar
    43.
    Ye  X, Wong  LY, Kramer  J, Zhou  X, Jia  T, Calafat  AM.  Urinary concentrations of bisphenol A and three other bisphenols in convenience samples of U.S. adults during 2000-2014.   Environ Sci Technol. 2015;49(19):11834-11839. doi:10.1021/acs.est.5b02135 PubMedGoogle ScholarCrossref
    44.
    LaKind  JS, Naiman  DQ.  Temporal trends in bisphenol A exposure in the United States from 2003-2012 and factors associated with BPA exposure: spot samples and urine dilution complicate data interpretation.   Environ Res. 2015;142:84-95. doi:10.1016/j.envres.2015.06.013 PubMedGoogle ScholarCrossref
    45.
    Rochester  JR, Bolden  AL.  Bisphenol S and F: a systematic review and comparison of the hormonal activity of bisphenol A substitutes.   Environ Health Perspect. 2015;123(7):643-650. doi:10.1289/ehp.1408989 PubMedGoogle ScholarCrossref
    46.
    Trasande  L.  Exploring regrettable substitution: replacements for bisphenol A.   Lancet Planet Health. 2017;1(3):e88-e89. doi:10.1016/S2542-5196(17)30046-3 PubMedGoogle ScholarCrossref
    47.
    Liu  B, Lehmler  HJ, Sun  Y,  et al.  Association of bisphenol A and its substitutes, bisphenol F and bisphenol S, with obesity in United States children and adolescents.   Diabetes Metab J. 2019;43(1):59-75. doi:10.4093/dmj.2018.0045 PubMedGoogle ScholarCrossref
    48.
    Jacobson  MH, Woodward  M, Bao  W, Liu  B, Trasande  L.  Urinary bisphenols and obesity prevalence among US children and adolescents.   J Endocr Soc. 2019;3(9):1715-1726. doi:10.1210/js.2019-00201 PubMedGoogle ScholarCrossref
    49.
    Ye  X, Wong  LY, Bishop  AM, Calafat  AM.  Variability of urinary concentrations of bisphenol A in spot samples, first morning voids, and 24-hour collections.   Environ Health Perspect. 2011;119(7):983-988. doi:10.1289/ehp.1002701 PubMedGoogle ScholarCrossref
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