Considerable exposure to the endocrine disrupting chemicals phthalates and bisphenol-A in intensive care unit (ICU) patients
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
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2023, Environmental Toxicology and PharmacologyCitation Excerpt :The authors also observed a significant difference between concentrations of BPA for infants based on gestational age (younger infants: 242 μg/l; older infants: 29 μg/l; Kruskal–Wallis p value= 0.06). Three studies reported a positive correlation between the increase in BPA and the higher number of samples collected per patient (Calafat et al., 2009; Huygh et al., 2015; Duty et al., 2013). Duty et al. (2013) observed a positive correlation between the increase in the number of invasive medical devices used and the increase in BPA levels in the patient’s urine; however, it was not statistically significant for the groups “low-intensity medical device use” and “high-intensity medical device use” (13.2 µg/l and 18.5 µg/l, respectively, p = 0.13).