Abstract
Background
Di(2-ethylhexyl) phthalate (DEHP) may produce toxicity, posing a risk to human health. Medical devices composed of DEHP are frequently used in catheterization, but few studies have investigated DEHP exposure during catheterization. The aim of this prospective series was to characterize the exposure pattern of DEHP during catheterization.
Methods
We enrolled 16 patients with congenital heart disease undergoing catheterization. Collection of urine was done to measure DEHP metabolites on hospitalization, before catheterization, after catheterization, and at discharge. The following DEHP metabolites were measured: mono-(2-ethylhexyl) phthalate (MEHP), mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and the ratio of MEHP to overall metabolites (MEHP%) was determined. DEHP exposure from polyvinyl chloride (PVC)-containing catheter and infusion systems were recorded in detail. Differences in DEHP levels before and after catheterization were analyzed.
Results
Urinary levels of MEHP, MEHHP, and MEOHP significantly decreased from before catheterization to after catheterization (all p < 0.01), but did not change significantly from initial hospitalization to before catheterization. Urinary MEHP% significantly decreased from initial hospitalization to before catheterization (p < 0.001), then increased after catheterization (p < 0.001), and decreased gradually at discharge (p = 0.03). Urinary MEHP% after catheterization and at discharge was significantly positively related to the duration of using PVC-containing catheter systems. There was a significant positive correlation between urinary MEHP% and the duration of using PVC-containing infusion system before catheterization, and a borderline significant correlation at both post-catheterization time slots.
Conclusions
Our results demonstrated that urinary MEHP% may be a potential biomarker of DEHP contamination from the use of PVC-containing catheters or infusion systems.
Keywords: Catheterization, Di(2-ethylhexyl) phthalate, Metabolites, Polyvinyl chloride
INTRODUCTION
Di(2-ethylhexyl) phthalate (DEHP) is widely used in polyvinyl chloride (PVC) disposable medical devices, including intravenous (IV) tubing and PVC tubing.1 DEHP can increase the flexibility of a PVC plastic tube. DEHP is not strongly bound to the plastic tube, so it can easily migrate from the tubing system and enter the body during direct contact with blood or lipophilic substances.1 Concerns have been raised about potential DEHP toxicity. Previous studies have reported the reproductive-related toxicity and cardiotoxic effects of DEHP and its metabolites.2-4 Other potential adverse effects include an increased incidence of asthma and allergies,5-7 liver toxicity,8 acute irritant symptoms,8 abnormal neurodevelopment,9,10 and high blood pressure.11,12
Patients undergoing medical interventions such as intravenous therapy, hemodialysis, extracorporeal membrane oxygenation (ECMO), cardiopulmonary bypass, and catheterization can be exposed to DEHP released from PVC. Few previous studies have examined health outcomes related to phthalate exposure during interventions. A high DEHP level has been reported in patients undergoing hemodialysis.13,14 Von Rettberg et al. reported that using DEHP-containing PVC infusion systems contributed to the development of cholestasis.15 However, no significant adverse effects on physical growth and pubertal maturity were reported in adolescents exposed to significant quantities of DEHP as neonates on ECMO.16 Takahashi et al. showed that using tubing free of DEHP significantly reduced the release of this agent during cardiopulmonary bypass, which may minimize exposure to DEHP.17
In the human body, DEHP rapidly hydrolyzes into monoesters, mono-(2-ethylhexyl) phthalate (MEHP), and subsequently oxidized into mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP).2,10,17,18 These two oxidative metabolites of DEHP are better biomarkers of long-term exposure to DEHP compared to MEHP in urine or blood. A novel phenotypic marker, the relative percentage of MEHP, has been explored as a surrogate for the function of cytochrome P450 phase I enzymes during catheterization and intravenous infusion. A susceptibility biomarker of DEHP in the human body is needed to assess exposure and health outcomes.
Few studies have reported human biomonitoring data of DEHP exposure during catheterization. Therefore, the aim of this prospective series was to characterize the exposure pattern of DEHP released from PVC medical devices during catheterization.
METHODS
Study subjects
A total of 16 patients [male (M)/ female (F) 12/4; mean age, 15.7 ± 10.4 years] with congenital heart disease who underwent catheterization were enrolled at the Department of Pediatrics, Kaohsiung Veterans General Hospital, Taiwan. Medical records were reviewed for age, sex, diagnosis, and catheterization type. The patient’s diagnoses were as follows: atrial septal defect (n = 7), patent ductus arteriosus (n = 2), coarctation (n = 2), valvar pulmonary stenosis (n = 2), ventricular septal defect (n = 1), tetralogy of Fallot (n = 1), and valvar aortic stenosis (n = 1). The types of cardiac catheterization were transcatheter closure (n = 8), balloon dilation (n = 6), and hemodynamic study (n = 2). We prospectively recorded the following data: use of plastic food containers before fasting, kinds of catheters, intravenous drip amount, and duration of PVC-containing infusion during hospitalization as well as PVC-containing catheters during the catheterization. Urine samples were collected to measure DEHP exposure.
Urine sample collection
According to kinetic information of DEHP,18 the excreted times of the maximum (half-live) concentrations of MEHP, MEHHP, and MEOHP are 2 (5), 4 (10), and 4 (10) hours in urine after oral DEHP exposure. Urine samples were collected on hospitalization, pre-catheterization (fasting for 6 hours before catheterization), post-catheterization (after catheterization before meals), and at discharge (Figure 1). There were no IV infusions between hospitalization and pre-catheterization. The washout period was defined as the fasting period between hospitalization and pre-catheterization. Spot urine samples were collected in 250-ml glass vessels at each sampling time, and then transferred into 12-ml amber glass bottles for the analyses of DEHP metabolite concentrations. To prevent possible contamination of the urine samples, the glass bottles were washed in methanol, hexane and acetone, and then sealed with aluminum foil. All urine samples were collected at the same time and stored at -80 °C until they were analyzed.
Figure 1.
The sampling strategy of phthalate exposure during catheterization.
Urinary DEHP metabolite analysis
The analytical method for determining the urinary concentrations of DEHP metabolites has been published elsewhere.19 MEHP, MEHHP, and MEOHP were measured using high-performance liquid chromatography, and quantitation was performed using tandem mass spectrometry with electro-spray ionization. Briefly, 1 ml of urine sample was used, mixed with 250 μL ammonium acetate and then spiked with a mixture of isotope phthalate monoester standards and 5 μL β-glucuronidase enzyme. The sample solution was then purified using a solid-phase extraction cartridge (ABS Elut Nexus, Agilent). Aliquots of 1 mL of formic acid and H2O were individually added to remove hydrophilic compounds, and then 2 ml each of acetonitrile and ethyl acetate were eluted in turn to collect phthalate metabolites. One quality control (QC) and one blank sample were included in each batch of samples analyzed. The QC sample was spiked in pooled urine with a mixture of phthalate monoester standards (50 ng/ml). The calibration ranges of urinary phthalate monoesters were 1-1000 ng/ml. The correlation coefficient (R2) and relative standard deviation (of the calibration curve) should be higher than 0.995 and lower than 15%, respectively. The phthalate monoester level in the blank sample should be lower than twice the method detection limit in each batch. Creatinine was used to correct the dilution of the urine. The limits of detection for the three urinary monoesters were 0.06 ng/ml (MEHP), 0.10 ng/ml (MEOHP), and 0.13 ng/ml (MEHHP). Concentrations < limit of detection (LOD) were set to one-half the LOD for calculations.
Ethics statement
The study protocol was approved by the Institutional Review Board of Kaohsiung Veterans General Hospital, Taiwan (VGHKS98-CT2-23). Written informed consent was obtained from the patients or their guardians.
Statistical analysis
Continuous variables are expressed as means with standard deviation (range) or geometric means with selected percentiles. Categorical variables are presented as numbers and percentages. Paired-samples test (or Wilcoxon signed-rank test) was used to compare urinary DEHP metabolites among the four sampling times. Both Pearson and Spearman correlation analyses were carried out to explore the duration of using PVC-containing catheter systems and PVC-containing infusion systems for the changes in urinary DEHP metabolites. MEHP% (MEHP level / MEHP + MEHHP + MEOHP levels) was defined as the phenotypic marker of the proportion of DEHP metabolism and excretion of MEHP in urine, indicating effective metabolization to the oxidative metabolites after exposure to DEHP during the catheterization or IV infusion. MEHP% values were calculated based on creatinine-adjusted values. p < 0.05 was considered statistically significant.
RESULTS
A total of 16 patients (M/F 12/4; mean age, 15.7 ± 10.4 years) with congenital heart disease were enrolled. The average duration of using PVC-containing catheter systems was employed for 2.56 hours. The urine sampling times were at an average of 20.1, 24.1 and 78.8 hours after hospitalization. The average duration of using PVC-containing infusion systems was 38.7 hours. The amount of PVC-containing infusion was 1100 ± 686.6 ml. Fourteen of the subjects used plastic containers before fasting (Table 1).
Table 1. Demographic data and individual parameters of patients.
| Patients (n = 16) | |
| Age (years) | 15.7 ± 10.4 (5.3-37.3)* |
| Height (cm) | 141 ± 22.8 (111-178)* |
| Weight (kg) | 37.6 ± 21.5 (16.6-82.0)* |
| BMI | 19.0 ± 5.0 (13.2-29.4)* |
| Sex, n (%) | |
| Male | 12 (75)# |
| Female | 4 (25)# |
| Urine sampling time after hospitalization (hr) | |
| Pre-cardiac catheterization | 20.1 ± 1.48 (17.3-24.3)* |
| Post-cardiac catheterization | 24.1 ± 5.53 (19.3-31.6)* |
| Hospital discharge | 78.8 ± 31.6 (41.5-141)* |
| Duration of PVC-containing catheter system (hr) | 2.56 ± 0.78 (1.25-3.92)* |
| Duration of PVC-containing infusion system (hr) | 38.7 ± 18.5 (13.0-75.0)* |
| Amount of PVC-containing infusion (ml) | 1100 ± 686.6 (500-2500)* |
| Using plastic food container before fasting, n (%) | |
| Yes | 14 (87.5)# |
| No | 2 (12.5)# |
BMI, body mass index; PVC, polyvinyl chloride.
* Values are expressed as mean ± standard deviation (range). # Values are expressed as number (%).
Table 2 shows the distribution of urinary phthalate metabolites (μg/g creatinine) (MEHP, MEHHP, MEOHP, and MEHP%) on hospitalization, pre-catheterization, post-catheterization, and at discharge. Urinary levels of MEHP, MEHHP, and MEOHP significantly decreased from pre-catheterization to post-catheterization (all p < 0.01), but did not change significantly from initial hospitalization to pre-catheterization. From post-catheterization to discharge, MEHP level did not change significantly, but MEHHP and MEOHP levels increased significantly (both p < 0.05). Urinary MEHP% significantly decreased from initial hospitalization to pre-catheterization (p < 0.001), then increased at post-catheterization (p < 0.001), and decreased gradually at discharge (p = 0.03). Figure 2 shows the serial changes in MEHP level, MEHP%, MEHHP level, and MEOHP level from hospitalization to discharge.
Table 2. Distribution of creatinine-adjusted phthalate metabolites in urine (μg/g creatinine).
| Phthalate metabolites | No. | Geometric mean | Selected Percentiles | p value | |||
| 10th | 50th | 90th | Max | ||||
| Hospitalization | |||||||
| MEHP | 16 | 8.00 | 2.50 | 10.0 | 22.9 | 25.9 | - |
| MEHHP | 16 | 24.6 | 7.40 | 28.8 | 80.2 | 102 | - |
| MEOHP | 16 | 24.2 | 6.00 | 27.2 | 87.2 | 100 | - |
| MEHP% | 16 | 14.5 | 9.35 | 14.6 | 22.2 | 24.3 | - |
| Pre-cardiac catheterization | |||||||
| MEHP | 16 | 6.90 | 2.00 | 7.4 | 21.4 | 27.1 | 0.275* |
| MEHHP | 16 | 30.9 | 8.00 | 35.7 | 87.1 | 96.8 | 0.091* |
| MEOHP | 16 | 30.5 | 8.90 | 33.3 | 93.5 | 105 | 0.107* |
| MEHP% | 16 | 10.6 | 6.94 | 11.1 | 14.6 | 18.4 | < 0.001* |
| Post-cardiac catheterization | |||||||
| MEHP | 16 | 6.60 | 2.10 | 7.70 | 18.3 | 19.9 | 0.007# |
| MEHHP | 16 | 18.3 | 3.60 | 18.3 | 67.4 | 105 | < 0.001# |
| MEOHP | 16 | 19.4 | 4.10 | 18.4 | 79.9 | 129 | < 0.001# |
| MEHP% | 16 | 15.4 | 8.45 | 16.4 | 22.1 | 24.1 | < 0.001# |
| Hospital discharge | |||||||
| MEHP | 16 | 7.66 | 3.18 | 6.60 | 26.8 | 28.9 | 0.222† |
| MEHHP | 16 | 23.4 | 7.31 | 25.3 | 61.6 | 63.1 | 0.029† |
| MEOHP | 16 | 26.9 | 8.06 | 27.4 | 75.3 | 89.0 | 0.026† |
| MEHP% | 16 | 13.6 | 7.04 | 13.3 | 23.6 | 25.3 | 0.030† |
DEHP, di(2-ethylhexyl) phthalate; MEHP, mono-(2-ethylhexyl) phthalate; MEHHP, mono-(2-ethyl-5-oxohexyl) phthalate; MEOHP, mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP).
* Wilcoxon singed-ranks test was performed between hospitalization and pre-cardiac catheterization. # Wilcoxon singed-ranks test was performed between pre-cardiac catheterization and post-cardiac catheterization. † Wilcoxon singed-ranks test was performed between post-cardiac catheterization and hospital discharge.
Figure 2.
Comparisons of urinary creatinine-adjusted phthalate metabolites [MEHP (A), MEHP% (B), MEHHP (C) and MEOHP (D)] among different sampling times (1 = Hospitalization, 2 = Pre-cardiac catheterization, 3 = Post-cardiac catheterization, and 4 = Hospital discharge). The black dot represents an outlier of concentration distributions of urinary phthalate metabolites. DEHP, di(2-ethylhexyl) phthalate; MEHP, mono-(2-ethylhexyl) phthalate; MEHHP, mono-(2-ethyl-5-oxohexyl) phthalate; MEOHP, mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP).
Table 3 shows the Spearman correlation coefficients between levels of urinary DEHP metabolites and duration of using PVC-containing catheter systems (or PVC-containing infusion system) in all subjects. After catheterization, the duration of using PVC-containing catheter systems was significantly positively correlated with MEHP% (r = 0.694, p = 0.003) except for MEHP, MEHHP, and MEOHP levels. At discharge, the duration of using PVC-containing catheter system was positively correlated with MEHHP level (r = 0.573, p = 0.020), MEOHP level (r = 0.569, p = 0.015), and MEHP% (r = 0.750, p = 0.001). Before catheterization, the duration of using PVC-containing infusion systems was positively correlated with MEHP% (r = 0.656, p = 0.015) except for MEHP, MEHHP, and MEOHP levels. After catheterization, the duration of using PVC-containing infusion system was related to MEHP% with borderline significance (r = 0.487, p = 0.065) except for MEHP, MEHHP, and MEOHP levels. At discharge, the duration of using PVC-containing infusion systems was not correlated with MEHP level, MEHP%, MEHHP level, and MEOHP level. Pearson correlation analysis showed similar significant findings to Spearman correlation analysis (Table 3).
Table 3. Spearman correlation coefficients between levels of urinary metabolites and the duration of using PVC-containing catheterization system and PVC-containing infusion system in all subjects (μg/g creatinine).
| The duration of using PVC-containing catheter system | The duration of using PVC-containing infusion system | |||||||
| Pearson correlation | Spearman correlation | Pearson correlation | Spearman correlation | |||||
| r | p value | r | p value | r | p value | r | p value | |
| Hospitalization | ||||||||
| MEHP | - | - | - | - | 0.282 | 0.351 | 0.223 | 0.411 |
| MEHHP | - | - | - | - | 0.202 | 0.454 | 0.072 | 0.792 |
| MEOHP | - | - | - | - | 0.234 | 0.383 | 0.130 | 0.632 |
| MEHP% | - | - | - | - | 0.287 | 0.342 | 0.199 | 0.455 |
| Pre-cardiac catheterization | ||||||||
| MEHP | - | - | - | - | -0.193 | 0.528 | -0.225 | 0.472 |
| MEHHP | - | - | - | - | 0.059 | 0.828 | 0.072 | 0.791 |
| MEOHP | - | - | - | - | 0.050 | 0.854 | 0.015 | 0.791 |
| MEHP% | - | - | - | - | 0.656 | 0.015 | 0.471 | 0.065 |
| Post-cardiac catheterization | ||||||||
| MEHP | 0.265 | 0.382 | 0.214 | 0.443 | 0.166 | 0.588 | 0.080 | 0.818 |
| MEHHP | 0.413 | 0.112 | 0.281 | 0.292 | 0.149 | 0.582 | 0.185 | 0.492 |
| MEOHP | 0.437 | 0.091 | 0.214 | 0.122 | 0.166 | 0.538 | 0.219 | 0.415 |
| MEHP% | 0.694 | 0.003 | 0.796 | 0.010 | 0.487 | 0.098 | 0.361 | 0.169 |
| Hospital discharge | ||||||||
| MEHP | 0.481 | 0.059 | 0.522 | 0.066 | -0.141 | 0.645 | -0.122 | 0.795 |
| MEHHP | 0.573 | 0.020 | 0.452 | 0.035 | 0.084 | 0.757 | 0.035 | 0.804 |
| MEOHP | 0.569 | 0.015 | 0.418 | 0.020 | 0.246 | 0.359 | 0.134 | 0.621 |
| MEHP% | 0.750 | 0.001 | 0.861 | 0.005 | 0.260 | 0.391 | 0.138 | 0.611 |
DEHP, di(2-ethylhexyl) phthalate; MEHP, mono-(2-ethylhexyl) phthalate; MEHHP, mono-(2-ethyl-5-oxohexyl) phthalate; MEOHP, mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP); PVC, polyvinyl chloride.
DISCUSSION
Our results demonstrated that urinary MEHP% significantly decreased from initial hospitalization to before catheterization, then increased after catheterization and decreased gradually at discharge. DEHP is released from the highly flexible types of PVC medical devices (e.g. IV bags and catheters) mostly during internal contact with the fluids of the human body.20 DEHP and its metabolites have short half-lives within 10 hours and are rapidly excreted in the urine.18 A kinetic study by Koch et al. reported that the excreted times of the maximum (half-live) concentrations of MEHP, MEHHP, and MEOHP were 2 (5), 4 (10), and 4 (10) hours in urine after oral DEHP exposure.18 For longer-chained phthalates (such as DEHP and di-isononyl phthalate), oxidized secondary metabolites are the primary metabolites excreted in human urine, with longer biological half-lives between 3 to 18 hours.1,2,18 The different half-lives of MEHP, MEHHP and MEOHP may partially explain the insignificant correlation of the three metabolites with the duration of using PVC-containing catheters. The significant correlation between MEHP% and use of PCV-containing catheters suggests that %MEHP could be a novel phenotypic marker of DEHP exposure during catheterization. IV infusion was not performed between hospitalization and before catheterization in this study. The reason for the higher %MEHP on initial hospitalization may be due to environmental or dietary exposure to DEHP before admission. In this series, the washout period (at least 6 hours) during the fasting time for catheterization avoided potential contamination from dietary exposure. Subsequently, the value of urinary %MEHP after catheterization was significantly higher than that before catheterization. This suggests that %MEHP is a sensitive biomarker of DEHP exposure during catheterization. Our data suggest that DEHP may be leached from a long duration of using PVC-containing catheters and IV infusion systems and accumulate in the body. The amplitude of variation in urinary MEHP% at the four sampling times was higher than that of urinary MEHP, indicating the higher utility of urinary MEHP% to detect DEHP exposure associated with PVC-containing medical devices. To the best of our knowledge, this is the first study to identify a sensitive biomarker, MEHP%, to evaluate DEHP exposure during catheterization. Although DEHP leaching from PVC-containing catheter and infusion systems was transient, the potential toxicity of DEHP exposure and its metabolites cannot be ignored. Particularly with regards to the suspected endocrine disruption effects of DEHP, the estimated internal levels of DEHP and its metabolites in patients following catheterization might be alarming.
DEHP can soften plastics and is used in medical devices and food containers. The frequent use of DEHP leads to widespread human exposure. An animal study showed that high mono-(2-ethylhexyl) phthalate levels acutely induced vimentin localization in Sertoli cells, and increased caspase 3 activity in the testis of mice.21 Chronically high DEHP levels have also been shown to result in various biological effects, including testicular atrophy, proliferation of peroxisomes, and potential liver tumors in mice.22 Harmful effects related to DEHP exposure in children have also been reported, including reproductive-related toxicity and cardiotoxic effects of DEHP and its metabolites,2-4 increased incidence of asthma and allergies,5-7 precocious puberty,23 liver toxicity,8 acute irritant symptoms,8 abnormal neurodevelopment,9,10 and high blood pressure.11,12 Our results reveal the potential for DEHP exposure during admission for cardiac catheterization, an issue which deserves more attention. Further longitudinal studies are required to elucidate the long-term effect of DEHP exposure after catheterization.
DEHP is well-known to be harmful, so it is an important issue to eliminate DEHP exposure in medical interventions. Non-DEHP-PVC tubes have been successfully used as substitutes.24-27 Avoiding lipid content and albumin in the tubing system has been reported to decrease the leaching of DEHP.28-32 Heparin coatings in PVC tubing sets has also been shown to avoid the leaching of DEHP into the blood.32 Routine heparinization during catheterization may decrease DEHP leaching from the catheters. The substitution of other materials for PVC and heparin coating would have the additional benefit of reducing exposure to DEHP in many medical interventions.
There are some limitations in this study. First, this is an observational study with a small number of patients at a single center. Despite the small sample size in this series, previous studies have suggested that DEHP exposure biomarkers measured in urine may be reasonable indicators of certain phthalate levels in the human body.1,2,5,7,9,12-15,18-20 Second, the diurnal variation in urinary DEHP metabolites may be a limitation of this study. Third, we did not have information about exposure to DEHP from IV sets only due to a lack of a comparison group. Fourth, quantitative analysis of DEHP levels in catheterization tubing systems and IV infusion systems was not performed. Fifth, some variables such as food and environmental factors were not evaluated accurately. Not only medical devices (such as catheter tubes, intravenous tubing, and blood transfusion bags), but also ingestion of contaminated food, inhalation of hospital aerosol sprays and personal care products were also potential routes of DEHP exposure in the patients. These may have been confounding factors for the measurement of DEHP exposure. However, the washout period (at least 6 hours) during the fasting time for catheterization avoided potential contamination from dietary exposure. Sixth, no obvious clinical effects of DEHP exposure during catheterization were recorded or analyzed in this study. Further multi-center studies with a larger number of subjects are warranted.
CONCLUSIONS
The use of DEHP in flexible PVC medical applications has caused a serious backlash in recent years. Our results suggest that urinary MEHP% may be a potential biomarker of DEHP contamination from the use of PVC-containing catheters or infusion systems. Further studies are required to evaluate the effect of DEHP exposure in the human body during catheterization.
Acknowledgments
Part of this research was supported by the Kaohsiung Veterans General Hospital (KSVGH110-091, KSVGH 110-093, KSVGH111-101) and VTY Joint Re-search Program (VGHUST110-G3-3-3). The authors would also like to thank all the attendants who participated in this study.
DECLARATION OF CONFLICT OF INTEREST
We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work.
REFERENCES
- 1.Shea KM American Academy of Pediatrics Committee on Environmental Health. Pediatric exposure and potential toxicity of phthalate plasticizers. Pediatrics. 2003;111:1467–1474. doi: 10.1542/peds.111.6.1467. [DOI] [PubMed] [Google Scholar]
- 2.Kavlock R, Boekelheide K, Chapin R, et al. NTP Center for the Evaluation of Risks to Human Reproduction: phthalates expert panel report on the reproductive and developmental toxicity of di(2-ethylhexyl) phthalate. Reprod Toxicol. 2002;16:529–653. doi: 10.1016/s0890-6238(02)00032-1. [DOI] [PubMed] [Google Scholar]
- 3.Sjoberg P, Lindquist NG, Montin G, et al. Effects of repeated intravenous infusions of the plasticizer di-(2-ethylhexyl) phthalate in young male rats. Arch Toxicol. 1985;58:78–83. doi: 10.1007/BF00348313. [DOI] [PubMed] [Google Scholar]
- 4.Barry YA, Labow RS, Rock G, et al. Cardiotoxic effects of the plasticizer metabolite, mono (2-ethylhexyl) phthalate (MEHP), on human myocardium. Blood. 1988;72:1438–1439. [PubMed] [Google Scholar]
- 5.Bornehag CG, Sundell J, Weschler CJ, et al. The association between asthma and allergic symptoms in children and phthalates in house dust: a nested case-control study. Environ Health Perspect. 2004;112:1393–1397. doi: 10.1289/ehp.7187. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Li MC, Chen CH, Guo YL. Phthalate esters and childhood asthma: a systematic review and congener-specific meta-analysis. Environ Pollut. 2017;229:655–660. doi: 10.1016/j.envpol.2017.06.083. [DOI] [PubMed] [Google Scholar]
- 7.Shi W, Lin Z, Liao C, et al. Urinary phthalate metabolites in relation to childhood asthmatic and allergic symptoms in Shanghai. Environ Int. 2018;121:276–286. doi: 10.1016/j.envint.2018.08.043. [DOI] [PubMed] [Google Scholar]
- 8.Voss C, Zerban H, Bannasch P, et al. Lifelong exposure to di-(2-ethylhexyl)-phthalate induces tumors in liver and testes of Sprague-Dawley rats. Toxicology. 2005;206:359–371. doi: 10.1016/j.tox.2004.07.016. [DOI] [PubMed] [Google Scholar]
- 9.Jankowska A, Polańska K, Koch HM, et al. Phthalate exposure and neurodevelopmental outcomes in early school age children from Poland. Environ Res. 2019;179:108829. doi: 10.1016/j.envres.2019.108829. [DOI] [PubMed] [Google Scholar]
- 10.Radke EG, Braun JM, Nachman RM, et al. Phthalate exposure and neurodevelopment: a systematic review and meta-analysis of human epidemiological evidence. Environ Int. 2020;137:105408. doi: 10.1016/j.envint.2019.105408. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Trasande L, Sathyanarayana S, Spanier AJ, et al. Urinary phthalates are associated with higher blood pressure in childhood. J Pediatr. 2013;163:747–753. doi: 10.1016/j.jpeds.2013.03.072. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Yao Y, Chen DY, Yin JW, et al. Phthalate exposure linked to high blood pressure in Chinese children. Environ Int. 2020;143:105958. doi: 10.1016/j.envint.2020.105958. [DOI] [PubMed] [Google Scholar]
- 13.Pollack GM, Buchanan JF, Slaughter RL, et al. Circulating concentrations of di(2-ethylhexyl) phthalate and its de-esterified phthalic acid products following plasticizer exposure in patients receiving hemodialysis. Toxicol Appl Pharmacol. 1985;79:257–267. doi: 10.1016/0041-008x(85)90347-3. [DOI] [PubMed] [Google Scholar]
- 14.Faouzi MA, Dine T, Gressier B, et al. Exposure of hemodialysis patients to di-2-ethylhexyl phthalate. Int J Pharm. 1999;180:113–121. doi: 10.1016/s0378-5173(98)00411-6. [DOI] [PubMed] [Google Scholar]
- 15.von Rettberg H, Hannman T, Subotic U, et al. Use of di(2-ethylhexyl) phthalate-containing infusion systems increases the risk for cholestasis. Pediatrics. 2009;124:710–716. doi: 10.1542/peds.2008-1765. [DOI] [PubMed] [Google Scholar]
- 16.Rais-Bahrami K, Nunez S, Revenis ME, et al. Follow-up study of adolescents exposed to di(2-ethylhexyl) phthalate (DEHP) as neonates on extracorporeal membrane oxygenation (ECMO) support. Environ Health Perspect. 2004;112:1339–1340. doi: 10.1289/ehp.6901. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Takahashi Y, Shibata T, Sasaki Y, et al. Di(2-ethylhexyl) phthalate exposure during cardiopulmonary bypass. Asian Cardiovasc Thorac Ann. 2008;16:4–6. doi: 10.1177/021849230801600102. [DOI] [PubMed] [Google Scholar]
- 18.Koch HM, Preuss R, Angerer J. Di(2-ethylhexyl) phthalate (DEHP): human metabolism and internal exposure -- an update and latest results. Int J Androl. 2006;29:155–165. doi: 10.1111/j.1365-2605.2005.00607.x. [DOI] [PubMed] [Google Scholar]
- 19.Huang PC, Kuo PL, Guo YL, et al. Associations between urinary phthalate monoesters and thyroid hormones in pregnant women. Hum Reprod. 2007;22:2715–2722. doi: 10.1093/humrep/dem205. [DOI] [PubMed] [Google Scholar]
- 20.Chiellinia F, Ferria M, Morellia A, et al. Perspectives on alternatives to phthalate plasticized poly(vinyl chloride) in medical devices applications. Prog Polym Sci. 2013;38:1067–1088. [Google Scholar]
- 21.Dalgaard M, Nellemann C, Lam HR, et al. The acute effects of mono(2-ethylhexyl) phthalate (MEHP) on testes of prepubertal Wistar rats. Toxicol Lett. 2001;122:69–79. doi: 10.1016/s0378-4274(01)00348-4. [DOI] [PubMed] [Google Scholar]
- 22.David RM, Moore MR, Finney DC, et al. Chronic toxicity of di(2-ethylhexyl) phthalate in mice. Toxicol Sci. 2000;58:377–385. doi: 10.1093/toxsci/58.2.377. [DOI] [PubMed] [Google Scholar]
- 23.Chen CY, Chou YY, Wu YM, et al. Phthalates may promote female puberty by increasing kisspeptin activity. Hum Reprod. 2013;28:2765–2773. doi: 10.1093/humrep/det325. [DOI] [PubMed] [Google Scholar]
- 24.Flaminio LM, De Angelis L, Ferazza M, et al. Leachability of a new plasticizer tri-(2-ethylhexyl)-trimellitate from haemodialysis tubing. Int J Artif Organs. 1988;11:435–439. [PubMed] [Google Scholar]
- 25.Tickner JA, Schettler T, Guidotti T, et al. Health risks posed by use of di-2-ethylhexyl phthalate (DEHP) in PVC medical devices: a critical review. Am J Ind Med. 2001;39:100–111. doi: 10.1002/1097-0274(200101)39:1<100::aid-ajim10>3.0.co;2-q. [DOI] [PubMed] [Google Scholar]
- 26.Takahashi Y, Shibata T, Sasaki Y, et al. Impact of non-di-(2-ethylhexyl) phthalate cardiopulmonary bypass tubes on inflammatory cytokines and coagulation-fibrinolysis systems during cardiopulmonary bypass. J Artif Organs. 2009;12:226–231. doi: 10.1007/s10047-009-0477-0. [DOI] [PubMed] [Google Scholar]
- 27.Tokhadze N, Chennell P, Bernard L, et al. Impact of alternative materials to plasticized PVC infusion tubings on drug sorption and plasticizer release. Sci Rep. 2019;9:18917. doi: 10.1038/s41598-019-55113-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Loff S, Subotic U, Reinicke F, et al. Extraction of di-ethylhexyl-phthalate from perfusion lines of various material, length and brand by lipid emulsions. J Pediatr Gastroenterol Nutr. 2004;39:341–345. doi: 10.1097/00005176-200410000-00008. [DOI] [PubMed] [Google Scholar]
- 29.Bagel S, Dessaigne B, Bourdeaux D, et al. Influence of lipid type on bis (2-ethylhexyl) phthalate (DEHP) leaching from infusion line sets in parenteral nutrition. J Parenter Enteral Nutr. 2011;35:770–775. doi: 10.1177/0148607111414021. [DOI] [PubMed] [Google Scholar]
- 30.Faessler D, McCombie G, Biedermann M, et al. Leaching of plasticizers from polyvinylchloride perfusion lines by different lipid emulsions for premature infants under clinical conditions. Int J Pharm. 2017;520:119–125. doi: 10.1016/j.ijpharm.2017.01.046. [DOI] [PubMed] [Google Scholar]
- 31.Burkhart HM, Joyner N, Niles S, et al. Presence of plasticizer di-2(ethylhexyl) phthalate in primed extracorporeal circulation circuits. ASAIO J. 2007;53:365–367. doi: 10.1097/MAT.0b013e3180317395. [DOI] [PubMed] [Google Scholar]
- 32.Hildenbrand SL, Lehmann HD, Wodarz R, et al. PVC-plasticizer DEHP in medical products: do thin coatings really reduce DEHP leaching into blood? Perfusion. 2005;20:351–357. doi: 10.1191/0267659105pf836oa. [DOI] [PubMed] [Google Scholar]