Elsevier

Environment International

Volume 81, August 2015, Pages 64-72
Environment International

Considerable exposure to the endocrine disrupting chemicals phthalates and bisphenol-A in intensive care unit (ICU) patients

https://doi.org/10.1016/j.envint.2015.04.008Get rights and content

Highlights

  • Adult ICU patients are markedly exposed to the phthalate DEHP and BPA.

  • Some serum and urinary levels of DEHP metabolites are the highest reported in humans.

  • Several levels of DEHP metabolites (≥ 10–50 μM) are biologically relevant.

  • Patients necessitating specialized devices with large tubings had the highest levels.

  • Both BPA and DEHP appear to be still present in many medical devices.

Abstract

Critical care medicine has largely benefited from plastic-containing medical devices. However, bisphenol-A (BPA) and phthalates present in the plastics can leach from such devices. We hypothesized that intensive care unit (ICU) patients are exposed to BPA and phthalates through (plastic) medical devices. Serum (n = 118) and urine (n = 102) samples of adult ICU patients (n = 35) were analyzed for total BPA and phthalate metabolites (PMs). Our results showed that adult ICU patients are continuously exposed to phthalates, such as di(2-ethylhexyl)phthalate (DEHP), as well as to BPA, albeit to a lesser extent. This exposure resulted in detectable high serum and urinary levels in almost every patient and at every studied time point. Moreover, these levels were significantly higher than in controls or compared to referenced literature. The chronology of exposure was demonstrated: pre-operative urinary and serum levels of the DEHP metabolites were often below the detection limit. Plastic-containing medical devices were the main source of DEHP exposure: post-operative patients on hemofiltration, extracorporeal membrane oxygenation or both showed serum levels 100-or 1000-fold higher than the levels in the general population reported in the literature. The serum and some of the urinary levels of the DEHP metabolites are the highest ever reported in humans; some at biologically highly relevant concentrations of ≥ 10–50 μM. Despite the continuously tightening regulations, BPA and DEHP appear to be still present in (some) medical devices. Because patient safety is a concern in the ICU, further research into the (possibly toxic and clinical) effects of these chemicals released from medical devices is imperiously necessary.

Introduction

Certain environmental contaminants, including the phenolic compound bisphenol-A (BPA or 4,4′-isopropylidene-2-diphenol) and phthalates, have recently emerged as endocrine disrupting chemicals (EDCs). They have been shown to alter the biological actions of many hormones, linking them to infertility, developmental changes, cancer and changes in thyroid function (Alonso-Magdalena et al., 2006, Andra and Makris, 2012, Dirinck et al., 2011, Frye et al., 2012, Hectors et al., 2011, Lang et al., 2008, Miodovnik et al., 2011, Zhou et al., 2013). Moreover di(2-ethyl hexyl) phthalate (DEHP), its metabolites (PMs) and BPA are peroxisome proliferator-activated receptor (PPAR) agonists capable of influencing glucose homeostasis and adipogenesis (Pereira-Fernandes et al., 2013). These EDCs may also have significant effects on neurodevelopmental processes, altering behavior and disrupting neurotransmitter systems (Frye et al., 2012, Lang et al., 2008). EDCs have been detected in various human body tissues and fluids (Aris, 2014, Dirtu et al., 2013, Frederiksen et al., 2010, Malarvannan et al., 2013, Shin et al., 2004).

Polymer materials (plastic, especially polyvinylchloride (PVC)) are an integral part of modern medicine and medical devices. Various EDCs are present in these medical devices and materials as major additives, possibly exposing patients to their deleterious effects. Indeed, BPA can be added to plastics like PVC used in catheters, tubing (e.g. ventilators) and hemodialyzers (Geens et al., 2012a, Murakami et al., 2007). After oral intake, terminal elimination of BPA through urinary excretion is < 6 h after a short serum half-life of < 2 h (Volkel et al., 2002). Phthalates, esters of ortho-phthalic acid, are also commonly used as softeners in PVC and are components of consumables such as personal care products, building materials, food packaging, children's toys, in addition to medical devices (especially tubing, infusion bags, and disposable gloves) and pharmaceuticals (Calafat et al., 2005, Luo et al., 2014, Marcel, 1973, Meeker et al., 2009). They may represent 20 to 40% of the final weight of the plastic (Green et al., 2005). Since BPA (when used as stabilizer in plastics) and phthalates are not covalently bound to plastics, they can gradually leach from the product and then migrate into the environment (water, medication, blood or bodily fluids) (Casals-Casas and Desvergne, 2011, Frye et al., 2012, Latini, 2005, Meeker et al., 2009).

Phthalates, such as DEHP, are hydrolyzed and biotransformed into oxidative metabolites (PMs), which can be used to monitor exposure (Blount et al., 2000, Gimeno et al., 2014, Latini, 2005, Meeker et al., 2009, Schmid and Schlatter, 1985, Silva et al., 2006). The urinary excretion follows a multi-phase elimination model with a half-life of ± 2 h (Koch et al., 2004). Diet is considered the major exposure route in the general population (Koch et al., 2012, Koch et al., 2013, Christensen et al., 2012). Unlike persistent organic pollutants, the bioaccumulation potential of BPA and phthalates is low (Geens et al., 2012b). However, many patients may come into contact with DEHP in many circumstances i.e. after donating or receiving blood products (Koch et al., 2005a, Koch et al., 2005b, Monfort et al., 2012). Hemodialysis patients can be exposed to BPA through dialysis tubing and BPA containing polysulfones in hemodialyzers (Murakami et al., 2007, Yamasaki et al., 2001). Studies in neonatal intensive care unit (NICU) have shown that urinary levels of BPA and PMs correlate with the number of medical devices used in neonates (Calafat et al., 2004, Calafat et al., 2009, Duty et al., 2013, Green et al., 2005, Weuve et al., 2006).

Therefore, we hypothesized that 1) similar to NICU patients, adult patients admitted to the intensive care unit (ICU) are exposed to BPA and phthalates, which we assessed through not only urine, but also serum levels of BPA and PMs. These levels were compared to literature-data of the general population; and 2) the levels can be linked to the admission to the ICU and the intensity of exposure to plastic containing medical devices. In order to differentiate between exposure to EDCs from medical devices and exposure from other sources (environment or diet), we have also measured triclosan (TCS), an antimicrobial chemical present in many personal care products, but not in medical devices (Allmyr et al., 2006, Lankester et al., 2013).

Section snippets

Study population

Our trial is a prospective, single-center, observational study evaluating the levels of BPA and PMs in adult patients admitted to the ICU of the Antwerp University Hospital, Belgium. Patients were eligible if older than 18 years, admitted after referral from the emergency room or after urgent surgical intervention, and were expected to stay in the ICU for more than 48 h.

A total of 35 patients were included after informed consent and serum and spot urine samples were collected as soon as possible

General characteristics

The characteristics of the study population are provided in Table 1. The average age of the 35 patients at inclusion was 57 years (54 % were men); neither age nor gender characteristics differed between patients included in this study (recruited in 2012–2014) and the control population recruited at the Weight Management Clinic between 2009 and 2012 (data not shown). For 17 patients, both the urinary and serum samples were available from day one to three and for an additional 18 patients samples

Magnitude of exposure of ICU patients

Human exposure to BPA and PMs is more than ever of interest (Casals-Casas and Desvergne, 2011, Frye et al., 2012, Geens et al., 2012a, Itoh et al., 2012, Miodovnik et al., 2011, Silver et al., 2011, Vandenberg et al., 2012, Zhou et al., 2013). Phthalates, e.g. DEHP, and BPA can migrate from the matrix when they are in prolonged contact with lipophilic environments, food and fluids. Considering reported clinical effects, there are restrictions on the use of phthalates and BPA, including EU

Conclusions

We are the first to report that adult ICU patients are markedly exposed to phthalates and, to a lesser extent, BPA. The serum and some of the urinary levels for the PMs are the highest ever reported up to this point in humans and are proof of a continuous exposure throughout the period of biomonitoring in the ICU. Patients necessitating specialized CVVH, ECMO or both had the highest levels, sometimes with an increase of 100–1000 compared with the general adult population. There is currently no

Competing interests

None.

Author contributions

Each author has participated sufficiently in the work, the data analysis, and the preparation of the manuscript, and has reviewed and approved the manuscript as submitted to take public responsibility for it. JH, KC, PJ and WV included the patients and carried out the retrieval of the data. JH and TS performed the statistical analysis. JH, KC, PJ, WV, LVG, ED and AC participated in the design of the study. GM and AC performed the analysis of the samples. JH, AC and PJ wrote the first draft of

Data availability

The authors confirm that all data underlying the findings are fully available without restriction. All data underlying the findings described in our manuscript are fully available to all interested researchers without restriction upon submission of a research proposal to the corresponding author.

Abbreviations

    5Cx-MEPP

    mono(2-ethyl-5-carboxypentyl) phthalate

    5OH-MEHP

    mono(2-ethyl-5-hydroxyhexyl) phthalate

    5oxo-MEHP

    mono(2-ethyl-5-oxohexyl) phthalate

    BPA

    bisphenol-A

    CVVH

    continuous venovenous hemofiltration

    DEHP

    di(2-ethylhexyl) phthalate

    ECMO

    extracorporeal membrane oxygenation

    EDC

    endocrine disrupting chemical

    ICU

    intensive care unit

    LOQ

    limit of quantification

    MEHP

    mono(2-ethylhexyl) phthalate

    MiBP

    mono-iso-butyl-phthalate

    NICU

    neonatal intensive care unit

    TCS

    triclosan

Acknowledgments

We acknowledge Hilde Fleurackers and Kim De Rycke for secretarial assistance and Petra Vertongen for labeling tubes and organizational support. The investigators performed the study with assistance from the medical and nursing staff from the Department of Critical Care Medicine of the Antwerp University Hospital, the Department of Endocrinology, Diabetes and Metabolism of the Antwerp University Hospital, and the Toxicological Centre of the University of Antwerp. We are indebted to the staff

References (78)

  • E. Grasselli et al.

    Direct effects of Bisphenol A on lipid homeostasis in rat hepatoma cells

    Chemosphere

    (2013)
  • K. Inoue et al.

    Evaluation and analysis of exposure levels of di(2-ethylhexyl) phthalate from blood bags

    Clin. Chim. Acta

    (2005)
  • H.M. Koch et al.

    Di(2-ethylhexyl)phthalate (DEHP) exposure of voluntary plasma and platelet donors

    Int. J. Hyg. Environ. Health

    (2005)
  • H.M. Koch et al.

    Phthalate exposure during cold plastisol application — a human biomonitoring study

    Toxicol. Lett.

    (2012)
  • H.M. Koch et al.

    Identifying sources of phthalate exposure with human biomonitoring: results of a 48 h fasting study with urine collection and personal activity patterns

    Int. J. Hyg. Environ. Health

    (2013)
  • G. Latini

    Monitoring phthalate exposure in humans

    Clin. Chim. Acta

    (2005)
  • G. Malarvannan et al.

    Distribution of persistent organic pollutants in two different fat compartments from obese individuals

    Environ. Int.

    (2013)
  • A. Miodovnik et al.

    Endocrine disruptors and childhood social impairment

    Neurotoxicology

    (2011)
  • J. Simmchen et al.

    Progress in the removal of di-[2-ethylhexyl]-phthalate as plasticizer in blood bags

    Transfus. Med. Rev.

    (2012)
  • L.M. Tetz et al.

    Mono-2-ethylhexyl phthalate induces oxidative stress responses in human placental cells in vitro

    Toxicol. Appl. Pharmacol.

    (2013)
  • Q. Zhou et al.

    Serum bisphenol-A concentration and sex hormone levels in men

    Fertil. Steril.

    (2013)
  • P. Alonso-Magdalena et al.

    The estrogenic effect of bisphenol A disrupts pancreatic beta-cell function in vivo and induces insulin resistance

    Environ. Health Perspect.

    (2006)
  • S.S. Andra et al.

    Thyroid disrupting chemicals in plastic additives and thyroid health

    J. Environ. Sci. Health C Environ. Carcinog. Ecotoxicol. Rev.

    (2012)
  • J.B. Ban et al.

    Mono-(2-ethylhexyl) phthalate induces injury in human umbilical vein endothelial cells

    PLoS One

    (2014)
  • B.C. Blount et al.

    Levels of seven urinary phthalate metabolites in a human reference population

    Environ. Health Perspect.

    (2000)
  • A.M. Calafat et al.

    Exposure to di-(2-ethylhexyl) phthalate among premature neonates in a neonatal intensive care unit

    Pediatrics

    (2004)
  • A.M. Calafat et al.

    Urinary concentrations of bisphenol A and 4-nonylphenol in a human reference population

    Environ. Health Perspect.

    (2005)
  • A.M. Calafat et al.

    Exposure to bisphenol A and other phenols in neonatal intensive care unit premature infants

    Environ. Health Perspect.

    (2009)
  • A.M. Calafat et al.

    Misuse of blood serum to assess exposure to bisphenol A and phthalates

    Breast Cancer Res.

    (2013)
  • C. Casals-Casas et al.

    Endocrine disruptors: from endocrine to metabolic disruption

    Annu. Rev. Physiol.

    (2011)
  • E. Dirinck et al.

    Obesity and persistent organic pollutants: possible obesogenic effect of organochlorine pesticides and polychlorinated biphenyls

    Obesity

    (2011)
  • A.C. Dirtu et al.

    Simultaneous determination of bisphenol A, triclosan, and tetrabromobisphenol A in human serum using solid-phase extraction and gas chromatography–electron capture negative-ionization mass spectrometry

    Anal. Bioanal. Chem.

    (2008)
  • L.J. Dumont et al.

    Exploratory in vitro study of red blood cell storage containers formulated with an alternative plasticizer

    Transfusion

    (2012)
  • S.M. Duty et al.

    Potential sources of bisphenol A in the neonatal intensive care unit

    Pediatrics

    (2013)
  • EC-Europe (European Commission)

    Restrictions on the manufacture, placing on the market and use of certain dangerous substances, preparations and articles

  • EC-Europe (European Commission)

    Amending Directive 2002/72/EC as regards the restriction of use of Bisphenol A in plastic infant feeding bottles

  • ECFR (European Council of Foreign Relations)

    Part 1199— children's toys and child care articles containing phthalates: guidance on inaccessible component parts

  • EPA (Environmental Protection Agency)

    Phthalates action plan summary

  • H. Frederiksen et al.

    Correlations between phthalate metabolites in urine, serum, and seminal plasma from young Danish men determined by isotope dilution liquid chromatography tandem mass spectrometry

    J. Anal. Toxicol.

    (2010)
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