Phthalate metabolites in urine from China, and implications for human exposures

Phthalates are esters of phthalic acid and are mainly used as plasticizers (added to plastics to increase their flexibility, transparency, durability, and longevity). Humans are exposed to phthalates through several routes. Urinary phthalate metabolites can be used as biomarkers of human exposures to phthalates. In this study, 14 phthalate metabolites were analyzed in 183 urine samples collected in 2010 from Shanghai, Guangzhou, and Qiqihaer, China. Phthalate metabolites were found in all urine samples and their total concentrations ranged from 18.6 to 3160 ng/mL (median: 331 ng/mL). Mono-n-butyl phthalate (mBP) and mono-2-isobutyl phthalate (miBP) were the major metabolites found in urine, and their respective median concentrations were 61.2 and 51.7 ng/mL; concentrations of miBP were higher than the concentrations reported for other countries, to date. Based on the urinary concentrations of phthalate metabolites, we estimated the daily intake rates in the Chinese population. The estimated daily intakes of dibutyl phthalate (DBP), diethyl phthalate (DEP), and di-(2-ethylhexyl) phthalate (DEHP) in China were 12.2, 3.8, and ~5 μg/kg bw/day, respectively. Thirty nine percent of the samples exceeded the tolerable daily intake of 10 μg/kg bw/day, proposed for DBP, by the European Food Safety Authority, but none of the estimated daily intake values exceeded the reference dose recommended by the U.S. Environmental Protection Agency.     

Exposure assessment issues in epidemiology studies of phthalates

PurposeThe purpose of this paper is to review exposure assessment issues that need to be addressed in designing and interpreting epidemiology studies of phthalates, a class of chemicals commonly used in consumer and personal care products. Specific issues include population trends in exposure, temporal reliability of a urinary metabolite measurement, and how well a single urine sample may represent longer-term exposure. The focus of this review is on seven specific phthalates: diethyl phthalate (DEP); di-n-butyl phthalate (DBP); diisobutyl phthalate (DiBP); butyl benzyl phthalate (BBzP); di(2-ethylhexyl) phthalate (DEHP); diisononyl phthalate (DiNP); and diisodecyl phthalate (DiDP).MethodsComprehensive literature search using multiple search strategies.ResultsSince 2001, declines in population exposure to DEP, BBzP, DBP, and DEHP have been reported in the United States and Germany, but DEHP exposure has increased in China. Although the half-lives of various phthalate metabolites are relatively short (3 to 18 h), the intraclass correlation coefficients (ICCs) for phthalate metabolites, based on spot and first morning urine samples collected over a week to several months, range from weak to moderate, with a tendency toward higher ICCs (greater temporal stability) for metabolites of the shorter-chained (DEP, DBP, DiBP and BBzP, ICCs generally 0.3 to 0.6) compared with those of the longer-chained (DEHP, DiNP, DiDP, ICCs generally 0.1 to 0.3) phthalates. Additional research on optimal approaches to addressing the issue of urine dilution in studies of associations between biomarkers and different type of health effects is needed.ConclusionsIn conclusion, the measurement of urinary metabolite concentrations in urine could serve as a valuable approach to estimating exposure to phthalates in environmental epidemiology studies. Careful consideration of the strengths and limitations of this approach when interpreting study results is required.     

Phthalates and their metabolites in breast milk--results from the Bavarian Monitoring of Breast Milk (BAMBI)

Phthalates have long been used as plasticizers to soften plastic products and, thus, are ubiquitous in modern life. As part of the Bavarian Monitoring of Breast Milk (BAMBI), we aimed to characterize the exposure of infants to phthalates in Germany. Overall, 15 phthalates, including di-2-ethylhexyl phthalate (DEHP), di-n-butyl phthalate (DnBP), di-isobutyl phthalate (DiBP), di-isononyl phthalate (DiNP), three primary metabolites of DEHP [mono-(2-ethylhexyl) phthalate (MEHP), mono-isobutyl phthalate (MiBP), and mono-n-butyl phthalate (MnBP)], and two secondary metabolites of DEHP were analyzed in 78 breast milk samples. We found median concentrations of 3.9 ng/g for DEHP, 0.8 ng/g for DnBP, and 1.2 ng/g for DiBP, while other parent phthalates were found in only some or none of the samples at levels above the limit of quantitation. In infant formula (n=4) we observed mean values of 19.7 ng/g (DEHP), 3.8 ng/g (DnBP), and 3.6 ng/g (DiBP). For MEHP, MiBP, and MnBP, the median values in breast milk were 2.3 μg/l, 11.8 μg/l, and 2.1 μg/l, respectively. The secondary metabolites were not detected in any samples. Using median and 95th percentile values, we estimated an "average" and "high" daily intake for an exclusively breast-fed infant of 0.6 μg/kg body weight (b.w.) and 2.1 μg/kg b.w., respectively, for DEHP, 0.1 μg/kg b.w. and 0.5 μg/kg b.w. for DnBP, and 0.2 μg/kg b.w. and 0.7 μg/kg b.w. for DiBP. For DiNP, intake values were 3.2 μg/kg b.w. and 6.4 μg/kg b.w., respectively, if all values in milk were set half of the detection limit or the detection limit. The above-mentioned "average" and "high" intake values corresponded to only about 2% to 7%, respectively, of the recommended tolerable daily intake. Thus, it is not likely that an infant's exposure to phthalates from breast milk poses any significant health risk. Nevertheless, other sources of phthalates in this vulnerable phase have to be considered. Moreover, it should be noted that for infants nourished with formula, phthalate intake is of the same magnitude or slightly higher (DEHP) than for exclusively breast-fed infants.     

Phthalates in German daycare centers: Occurrence in air and dust and the excretion of their metabolites by children (LUPE 3)

Phthalates have been used for decades in large quantities, leading to the ubiquitous exposure of the population.In an investigation of 63 German daycare centers, indoor air and dust samples were analyzed for the presence of 10 phthalate diesters. Moreover, 10 primary and secondary phthalate metabolites were quantified in urine samples from 663 children attending these facilities. In addition, the urine specimens of 150 children were collected after the weekend and before they went to daycare centers.Di-isobutyl phthalate (DiBP), dibutyl phthalate (DnBP), and di-2-ethylhexyl phthalate (DEHP) were found in the indoor air, with median values of 468, 227, and 194 ng/m³, respectively. In the dust, median values of 888 mg/kg for DEHP and 302 mg/kg for di-isononyl phthalate (DiNP) were observed. DnBP and DiBP were together responsible for 55% of the total phthalate concentration in the indoor air, whereas DEHP and DiNP were responsible for 70% and 24% of the total phthalate concentration in the dust.Median concentrations in the urine specimens were 44.7 μg/l for the DiBP monoester, 32.4 μg/l for the DnBP monoester, and 16.5 μg/l and 17.9 μg/l for the two secondary DEHP metabolites. For some phthalates, we observed significant correlations between their concentrations in the indoor air and dust and their corresponding metabolites in the urine specimens using bivariate analyses. In multivariate analyses, the concentrations in dust were not associated with urinary metabolite excretion after controlling for the concentrations in the indoor air.The total daily “high” intake levels based on the 95th percentiles calculated from the biomonitoring data were 14.1 μg/kg b.w. for DiNP and 11.9 μg/kg b.w. for DEHP. Compared with tolerable daily intake (TDI) values, our “high” intake was 62% of the TDI value for DiBP, 49% for DnBP, 24% for DEHP, and 9% for DiNP. For DiBP, the total daily intake exceeded the TDI value for 2.4% of the individuals. Using a cumulative risk-assessment approach for the sum of DEHP, DnBP, and DiBP, 20% of the children had concentrations exceeding the hazard index of one. Therefore, a further reduction of the phthalate exposure of children is needed.     

Urinary phthalate metabolite and bisphenol A associations with ultrasound and delivery indices of fetal growth

Growth of the fetus is highly sensitive to environmental perturbations, and disruption can lead to problems in pregnancy as well as later in life. This study investigates the relationship between maternal exposure to common plasticizers in pregnancy and fetal growth. Participants from a longitudinal birth cohort in Boston were recruited early in gestation and followed until delivery. Urine samples were collected at up to four time points and analyzed for concentrations of phthalate metabolites and bisphenol A (BPA). Ultrasound scans were performed at four time points during pregnancy for estimation of growth parameters, and birthweight was recorded at delivery. Growth measures were standardized to a larger population. For the present analysis we examined cross-sectional and repeated measures associations between exposure biomarkers and growth estimates in 482 non-anomalous singleton pregnancies. Cross-sectional associations between urinary phthalate metabolites or BPA and growth indices were imprecise. However, in repeated measures models, we observed significant inverse associations between di-2-ethylhexyl phthalate (DEHP) metabolites and estimated or actual fetal weight. An interquartile range increase in summed DEHP metabolites was associated with a 0.13 standard deviation decrease in estimated or actual fetal weight (95% confidence interval = − 0.23, − 0.03). Associations were consistent across different growth parameters (e.g., head circumference, femur length), and by fetal sex. No consistent associations were observed for other phthalate metabolites or BPA. Maternal exposure to DEHP during pregnancy was associated with decreased fetal growth, which could have repercussive effects.     

Lactational exposure to phthalates in Southern Italy

BackgroundPhthalates, reproductive toxicants in animals, are synthetic chemicals with ubiquitous human exposures because of their extensive use, with potential detrimental health effects. Infants are considered to represent a population at increased risk, as they are exposed early in life to several different sources of exposure to phthalates.Objectives and methodsLittle information exists on phthalate exposure through breast milk from different geographic areas. By means of a LC/LC–MS/MS method we tested the presence of several different phthalate metabolites in breast milk from 62 healthy mothers living in Southern Italy.ResultsThe simple monoesters mono-isobutyl phthalate (MiBP) (median 18.8 μg/l) and mono(2-ethylhexyl) phthalate (MEHP) (median 8.4 μg/l) were present in all milk samples, whereas mono-n-butyl phthalate (MnBP) (median 1.5 μg/l) and mono-benzyl phthalate (MBzP) (median < 0.3 μg/l) were found in 64.5% and 43.5% of the samples, respectively. Among the oxidative metabolites of DEHP and DiNP only mono(2-ethyl-5-carboxypentyl) phthalate (5cx-MEPP) and monoisononyl phthalate with one hydroxyl group (OH-MiNP) were detectable in one and 13 samples (21%), respectively.ConclusionsThese findings indicate that exposure to phthalates through breast milk in Southern Italian infants is comparable to that of other countries, thus confirming that human milk may represent an additional potential source of phthalate exposure in a population at increased risk. However, different milk concentrations of MiBP may suggest a different pattern of usage of di-iso-butyl phthalate in Europe, as compared to USA, whereas for the first time, we detected an oxidative DiNP metabolite, whose significance remains unclear.     

The internal exposure of Taiwanese to phthalate--an evidence of intensive use of plastic materials

Phthalates are widely used in industry and consumer products. Di-(2-ethylhexyl) phthalate (DEHP) and di-n-butylphthalate (DBP) show the greatest potency of reproductive toxicants among phthalates. The purposes of this study are to examine the migration level of phthalate from PVC films by simulating food handling and to reveal the body burden of phthalate for Taiwanese. In order to estimate a worst-case of phthalate migration, food was covered with polyvinyl chloride (PVC) films and then microwave heated. Results show that DEHP level in food increased significantly after heating for 3 min. Under the heating condition, the calculated intake of phthalate and the percentage of the tolerable daily intake (TDI, based on body weight of 60 kg) from eating one 400-g meal were 1705.6 microg and 92.2% for DEHP. Determination of urinary metabolites from 60 subjects reveals more than 90% of samples were detectable for mono-methyl phthalate (MMP), mono-butyl phthalate (MBP) and mono-ethylhexyl phthalate (MEHP). Notably, the median value of estimated daily intake of DEHP had reached 91.6% of TDI established by the European Union Scientific Committee for Toxicity, Ecotoxicity and the Environment (CSTEE) (1998). Thirty-seven percent of the study population exceeded the TDI and 85% exceeded the reference dose (RfD) of the US EPA. We conclude that the body burden of DEHP for Taiwanese reflects the intensives use of plastic materials in the region. The regulation of PVC for food preparation is necessary.     

The influence of resource strategies on childhood phthalate exposure—The role of REACH in a zero waste society

The present study aims to investigate how resource strategies, which intend to reduce waste and increase recycling, influence on human exposure to hazardous chemicals from material recycling. In order to examine the flows of hazardous chemicals in recycled material, a mass flow analysis of plastics and paper at European level, including the flow of phthalates, i.e. di(2-ethylhexyl) phthalate (DEHP), di-n-butyl phthalate (DBP), and benzyl-butyl phthalate (BBP), has been performed. The result for the year 2012 shows that 26% of plastic wastes and 60% of paper consumed in Europe were recycled. This corresponds to the finding that approximately 4% of DEHP and BBP and 18% of DBP annual demands in Europe as raw material re-enter the product cycle with recycled plastics and paper. To examine the potential contribution of the phthalate exposure through recycled plastics and paper, a case study assessing the childhood exposures to phthalates from foods packed in recycled paper and plastics has been performed for 2-year-old children in Denmark. The result verifies that an increase in recycled paperboard and PET bottles in food packaging material causes a significant increase in childhood exposure to DBP corresponding to an additional exposure of 0.116–0.355 μg/kg bw/day; up to 18% of the total DBP exposure in Danish 2-year-olds. While most of the DEHP exposure can be explained, more than 50% of DBP and 70% of BBP exposure sources still remain to be identified. Finally, a conceptual framework for a circular economy based on sustainable and clean resource flows is proposed in order to increase material recycling without increasing adverse health effects.     

Intake of phthalates and di(2-ethylhexyl)adipate: results of the Integrated Exposure Assessment Survey based on duplicate diet samples and biomonitoring data

Phthalates are ubiquitous environmental chemicals with potential detrimental health effects. The purpose of our study was to quantify dietary intake of phthalates and of DEHA (Di-ethylhexyl adipate) using duplicate diet samples and to compare these data with the calculated data based on urinary levels of primary and secondary phthalate metabolites. 27 female and 23 male healthy subjects aged 14-60 years collected daily duplicate diet samples over 7 consecutive days. Overall, 11 phthalates were measured in the duplicates by GC/MS and LC/MS methods. Urinary levels of primary and secondary phthalate metabolites are also available. The median (95th percentile) daily intake via food was 2.4 (4.0) microg/kg b.w. (Di-2-ethylhexyl phthalate, DEHP), 0.3 (1.4) microg/kg b.w. (Di-n-butyl phthalate, DnBP), 0.6 (2.1) microg/kg b.w. (Di-isobutyl phthalate, DiBP) and 0.7 (2.2) microg/kg b.w. for DEHA. MEPH (Mono-2-ethylhexyl phthalate) was detectable only in minor concentrations in the samples, thus conversion of DEHP to MEHP and dietary intake of MEHP were negligible. When comparing back-calculated intake data of the DEHP metabolites with dietary DEHP intake from the day before significant correlations were observed for most of the metabolites. No correlation was found for DnBP and only a weak but significant correlation for DiBP. The median and 95th percentile daily dietary intake of all target analytes did not exceed the recommended tolerable daily intake. Our data indicated that food was the predominant intake source of DEHP, whilst other sources considerably contributed to the daily intake of DnBP and DiBP in an adult population.     

Changes in epidemiologic associations with different exposure metrics: A case study of phthalate exposure associations with body mass index and waist circumference

The use of human biomonitoring data to characterize exposure to environmental contaminants in epidemiology studies has expanded greatly in recent years. Substantial variability in effect measures may arise when using different exposure metrics for a given contaminant, and it is often not clear which metric is the best surrogate for the ‘causal’ or ‘true’ exposure. Here we evaluated variability and potential bias in epidemiologic associations resulting from the use of different phthalate exposure metrics in the 2009–2010 National Health and Nutrition Examination Survey (NHANES). We examined associations between urinary phthalate metabolites and the outcomes of body mass index (BMI) and waist circumference (WC). We examined each of the following NHANES-derived exposure metrics for metabolites of individual phthalates: molar excretion rate (nmol/min), molar amount (nmol), molar concentration (nmol/mL, with and without additional model adjustment for creatinine), creatinine corrected molar concentration (nmol/g creatinine), and reconstructed daily phthalate intake (nmol/kg/day). In order to investigate potential biasing effect of each metric, we first assumed that daily intake of the parent phthalate is the causal exposure. We then constructed a simulated population based on the 2009–2010 NHANES, and randomly assigned each individual a di-2-ethylhexyl phthalate (DEHP) intake dose based on a published distribution, but independent of any other factor. Accordingly, all associations between these randomly assigned intake doses and individuals' BMI and WC should be null. Next, demographic data in the NHANES were incorporated into a pharmacokinetic model to predict urinary molar excretions of five DEHP metabolites based on the randomly assigned DEHP intake. The predicted molar excretions were then used to calculate the same exposure metrics listed above. Three exposure metrics (randomly generated intake, excretion rate, urine concentration) showed no significant associations with BMI, which supports the null hypothesis stated above. In contrast, metrics adjusted for creatinine showed a significant negative correlation, and reconstructed daily intake showed a significant positive correlation, indicating the introduction of bias away from the true (i.e., null) association. Interestingly, trends in the simulation analysis were similar to those seen in the observed NHANES data. Our findings show that, at least in this example case, the choice of exposure metric can introduce significant bias of varying magnitude and direction into the calculation of epidemiologic associations.     

Development and application of simple pharmacokinetic models to study human exposure to di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP)

In a published controlled dosing experiment, a single individual consumed 5 mg each of labeled di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP) on separate occasions and tracked metabolites in his blood and urine over 48 h. Data from this study were used to structure and calibrate simple pharmacokinetic (PK) models for these two phthalates, which predict urine and blood metabolite concentrations with a given phthalate intake scenario (times and quantities). The calibrated models were applied to a second published experiment in which 5 individuals fasted over the course of a 48-h weekend (bottled water only), and their full urine voids were captured and measured for DnBP and DiBP metabolites. One goal of this model application was to confirm the validity of the calibrated models — their validity would be demonstrated if a profile of intakes could be found which adequately duplicated the metabolite concentrations measured in the urine. A second goal was to study patterns of exposure for this group. It was found that all metabolites could be duplicated very well with individual-specific “best-fit” intake scenarios, with one exception. It appears that the model predicted much lower concentrations of the metabolite, 3carboxy-mono-propylphthalate (MCPP), than were observed in all individuals. Modeled as a metabolite of DnBP, this suggests that DnBP was not the major source of MCPP in the urine. For all 5 individuals, the reconstructed dose profiles of the two phthalates were similar: about 6 small bolus doses per day and an intake of about 0.5 μg/kg-day. The intakes did not appear to be associated with diary-reported activities (personal hygiene and medication) of the participants. The modeled frequent intakes suggested one (or both) of two possibilities: ongoing exposures such as an inhalation exposure, or no exposure but rather an ongoing release of body stores of the phthalate metabolites from past exposures.     

Personal care product use and urinary levels of phthalate metabolites in Mexican women

Sources of phthalates other than Polyvinyl chloride (PVC) related products are scarcely documented in Mexico. The objective of our study was to explore the association between urinary levels of nine phthalate metabolites and the use of personal care products. Subjects included 108 women who participated as controls in an ongoing population-based case-control study of environmental factors and genetic susceptibility to breast cancer in northern Mexico. Direct interviews were performed to inquire about sociodemographic characteristics, reproductive history, use of personal care products, and diet. Phthalate metabolites measured in urine by high performance liquid chromatography-isotope dilution tandem mass spectrometry were monoethyl phthalate (MEP), monobenzyl phthalate (MBzP), mono-n-butyl phthalate (MBP), mono-isobutyl phthalate (MiBP), mono-3-carboxypropyl phthalate (MCPP) as well as mono-2-ethylhexyl phthalate (MEHP), mono-2-ethyl-5-oxohexyl phthalate (MEOHP), mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP), mono-2-ethyl-5-carboxypentyl phthalate (MECPP) that are metabolites of di-ethylhexyl phthalate (DEHP). Detectable urinary concentrations of phthalate metabolites varied from 75% (MEHP) to 100% (MEP, MBP, MEOHP, MEHHP and MECPP). Medians of urinary concentrations of some phthalate metabolites were significantly higher among users of the following personal care products compared to nonusers: body lotion (MEHHP, MECPP and sum of DEHP metabolites (ΣDEHP)), deodorant (MEHP and ΣDEHP), perfume (MiBP), anti-aging facial cream (MEP, MBP and MCPP) and bottled water (MCPP, MEHHP and MEOHP). Urinary concentrations of MEP showed a positive relationship with the number of personal care products used. Our results suggest that the use of some personal care products contributes to phthalate body burden that deserves attention due to its potential health impact.     

Phthalates dietary exposure and food sources for Belgian preschool children and adults

Numerous studies have indicated that for phthalates, the intake of contaminated foods is the most important exposure pathway for the general population. Up to now, data on dietary phthalate intake are scarce and – to the authors' knowledge – not available for the Belgian population. Therefore, the purpose of this study was: (1) to assess the long-term intake of the Belgian population for eight phthalates considering different exposure scenarios (benzylbutyl phthalate (BBP); di-n-butyl phthalate (DnBP); dicyclohexyl phthalate (DCHP); di(2-ethylhexyl) phthalate (DEHP); diethyl phthalate (DEP); diisobutyl phthalate (DiBP); dimethyl phthalate (DMP), di-n-octyl phthalate (DnOP)); (2) to evaluate the intake of BBP, DnBP, DEP and DEHP against tolerable daily intake (TDI) values; and (3) to assess the contribution of the different food groups to the phthalate intake. The intake assessment was performed using two Belgian food consumption databases, one with consumption data of preschool children (2.5 to 6.5 years old) and another of adults (≥ 15 years old), combined with a database of phthalate concentrations measured in over 550 food products sold on the Belgian market. Phthalate intake was calculated using the ‘Monte Carlo Risk Assessment’ programme (MCRA 7.0). The intake of DEHP was the highest, followed by DiBP. The intake of BBP, DnBP and DEP was far below the TDI for both children and adults. However, for DEHP, the 99th percentile of the intake distribution of preschoolers in the worst case exposure scenario was equal to 80% of the TDI, respectively. This is not negligible, since other exposure routes of DEHP exist for children as well (e.g. mouthing of toys). Bread was the most important contributor to the DEHP intake and this may deserve further exploration, since the origin of this phthalate in bread remains unclear.     

Phthalate exposure and reproductive parameters in young men from the general Swedish population

BackgroundIn animals, exposure to certain phthalates negatively affects the male reproductive function. Human results are conflicting and mostly based on subfertile males, in whom the association between exposure and reproductive function may differ from the general population.ObjectivesTo study if levels of phthalate metabolites were associated with semen quality and reproductive hormones in general Swedish men.MethodsWe recruited 314 young men delivering semen, urine and blood samples at the same visit. We analyzed reproductive hormones and several semen parameters including progressive motility and high DNA stainability (HDS)—a marker for sperm immaturity. In urine, we analyzed metabolites of phthalates, including diethylhexyl phthalate (DEHP). We studied associations between urinary levels of the metabolites and seminal as well as serum reproductive parameters, accounting for potential confounders.ResultsDEHP metabolite levels, particularly urinary mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), were negatively associated with progressive sperm motility, which was 11 (95% CI: 5.0–17) percentage points lower in the highest quartile of MECPP than in the lowest. Further, men in the highest quartile of the DEHP metabolite monoethylhexyl phthalate had 27% (95% CI: 5.5%–53%) higher HDS than men in the lowest quartile.ConclusionsDEHP metabolite levels seemed negatively associated with sperm motility and maturation.     

构建湿地去除酞酸酯的基质微生物和酶机制研究

随着塑料制品的广泛使用，酞酸酯的污染越来越引起人们的广泛关注。目前，DBP(邻苯二甲酸二丁酯)和DEHP(邻苯二甲酸二异辛酯)已成为全球最普遍的污染物之一。报告了复合垂直流构建湿地对含酞酸酯(DBP等)的污水污染的去除效果，以及湿地去除酞酸酯的基质微生物和酶方面的净化机理。具体结果如下：复合垂直流构建湿地对酞酸酯污染具有较好的净化效果，去除率高达99．9％以上；构建湿地对酞酸酯的净化主要发生在氧气含量相对较多的下行流池，上行流他的净化作用相对较差；同时分层实验还发现，构建湿地的净化作用主要集中在湿地上层基质中。通过研究，为进一步研究利用构建湿地处理酞酸酯污染提供了有益的参考。     

Positive association between concentration of phthalate metabolites in urine and microparticles in adolescents and young adults

Di-(2-ethylhexyl) phthalate (DEHP) has been used worldwide in various products for many years. In vitro studies have shown that exposure to DEHP and its metabolite mono(2-ethylhexyl) phthalate (MEHP) induces endothelial cell apoptosis. Moreover, exposure to DEHP had been linked to cardiovascular risk factors and cardiovascular diseases in epidemiological studies. Circulating microparticles have been known to be indicators of vascular injury. However, whether DEHP or its metabolites are independently associated with microparticles in humans remains unknown. From 2006 to 2008, we recruited 793 subjects (12–30 years) from a population-based sample to participate in this cardiovascular disease prevention examination. Each participant was subjected to interviews and biological sample collection to determine the relationship between concentrations of DEHP metabolites MEHP, mono(ethyl-5-hydroxyhexyl) phthalate, and mono(2-ethly-5-oxoheyl) phthalate in urine and concentrations of endothelial microparticles (CD62E and CD31 +/CD42a −), platelet microparticles (CD62P and CD31 +/CD42a +), and CD14 in serum. Multiple linear regression analysis revealed that an ln-unit increase in MEHP concentration in urine was positively associated with an increase in serum microparticle counts/μL of 0.132 (± 0.016) in CD31 +/CD42a − (endothelial apoptosis marker), 0.117 (± 0.023) in CD31 +/CD42a + (platelet apoptosis marker), and 0.026 (± 0.007) in CD14 (monocyte, macrophage, and neutrophil activation marker). There was no association between DEHP metabolite concentration and CD62E or CD62P. In conclusion, a higher MEHP concentration in urine was associated with an increase in endothelial and platelet microparticles in this cohort of adolescents and young adults. Further studies are warranted to clarify the causal relationship between exposure to DEHP and atherosclerosis.     

Transfer of eight phthalates through the milk chain — A case study

This survey determined the levels of eight phthalates – i.e. dimethyl phthalate (DMP), diethyl phthalate (DEP), diisobutyl phthalate (DiBP), di-n-butyl phthalate (DnBP), benzylbutyl phthalate (BzBP), di(2-ethylhexyl) phthalate (DEHP), dicyclohexyl phthalate (DCHP) and di-n-octyl phthalate (DnOP) – in several Belgian milk and dairy products. Samples were obtained from various farms, a dairy factory and from different shops in order to investigate phthalate contamination “from farm to fork”. At several stages in the milk chain, product contamination with phthalates – mostly DiBP, DnBP, BzBP and DEHP – was observed. At farm level, the mechanical milking process and the intake of phthalate containing feed by the cattle were found to be possible contamination sources. At industry and retail level, contact materials including packaging materials were additional contamination sources for phthalates in milk and dairy products.     

Increased levels of phthalates in very low birth weight infants with septicemia and bronchopulmonary dysplasia

Very low birth weight infants (VLBW; birth weight < 1500 g) are exposed to potentially harmful phthalates from medical devices during their hospital stay. We measured urinary phthalate concentrations among hospitalized VLBW infants participating in a nutritional study. Possible associations between different phthalates and birth weight (BW), septicemia and bronchopulmonary dysplasia (BPD) were evaluated. Forty-six VLBW infants were enrolled in this randomized controlled nutritional study. The intervention group (n = 24) received increased quantities of energy, protein, fat, essential fatty acids and vitamin A, as compared to the control group (n = 22). The concentrations of 12 urinary phthalate metabolites were measured, using high-performance liquid chromatography coupled to tandem mass spectrometry, at 3 time points during the first 5 weeks of life. During this study, the levels of di (2-ethylhexyl) phthalate (DEHP) metabolites decreased, whereas an increasing trend was seen regarding metabolites of di-iso-nonyl phthalate (DiNP). Significantly higher levels of phthalate metabolites were seen in infants with lower BW and those diagnosed with late onset septicemia or BPD. A significant positive correlation between the duration of respiratory support and DEHP metabolites was observed (p ≤ 0.01) at 2.9 weeks of age. Birth weight was negatively associated with urinary phthalate metabolite concentrations. Infants with lower BW and those diagnosed with septicemia or BPD experienced prolonged exposure from medical equipment containing phthalates, with subsequent higher levels of phthalate metabolites detected. Clinical Trial Registration no.: NCT01103219.     

Predictors and long-term reproducibility of urinary phthalate metabolites in middle-aged men and women living in urban Shanghai

Phthalate esters are man-made chemicals commonly used as plasticizers and solvents, and humans may be exposed through ingestion, inhalation, and dermal absorption. Little is known about predictors of phthalate exposure, particularly in Asian countries. Because phthalates are rapidly metabolized and excreted from the body following exposure, it is important to evaluate whether phthalate metabolites measured at a single point in time can reliably rank exposures to phthalates over a period of time. We examined the concentrations and predictors of phthalate metabolite concentrations among 50 middle-aged women and 50 men from two Shanghai cohorts, enrolled in 1997–2000 and 2002–2006, respectively. We assessed the reproducibility of urinary concentrations of phthalate metabolites in three spot samples per participant taken several years apart (mean interval between first and third sample was 7.5 years [women] or 2.9 years [men]), using Spearman's rank correlation coefficients and intra-class correlation coefficients. We detected ten phthalate metabolites in at least 50% of individuals for two or more samples. Participant sex, age, menopausal status, education, income, body mass index, consumption of bottled water, recent intake of medication, and time of day of collection of the urine sample were associated with concentrations of certain phthalate metabolites. The reproducibility of an individual's urinary concentration of phthalate metabolites across several years was low, with all intra-class correlation coefficients and most Spearman rank correlation coefficients ≤ 0.3. Only mono(2-ethylhexyl) phthalate, a metabolite of di(2-ethylhexyl) phthalate, had a Spearman rank correlation coefficient ≥ 0.4 among men, suggesting moderate reproducibility. These findings suggest that a single spot urine sample is not sufficient to rank exposures to phthalates over several years in an adult urban Chinese population.     

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

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.