Intake Of Di(2-ethylhexyl) Phthalate Research Articles

Intake of phthalate-tainted foods and microalbuminuria in children: The 2011 Taiwan food scandal

BackgroundA major threat to public health involving phthalate-tainted foodstuffs occurred in Taiwan in 2011. Phthalates, mainly di-(2-ethylhexyl) phthalate (DEHP), were intentionally added to several categories of food commonly consumed by children. This study investigated the relationship between intake of the phthalate-tainted foods and renal function in children. MethodsChildren aged ≤10years with possible phthalate exposure were enrolled in this study between August 2012 and January 2013. Questionnaires were used to collect details of exposure to phthalate-tainted foodstuffs, and blood and urine samples were collected for clinical biochemical workup. The clinical biomarkers of renal injury, including urinary microalbumin, N-acetyl-beta-d-glucosaminidase (NAG), and β2-microglobulin were measured. Exposure was categorized based on recommended tolerable daily intake level defined by the U.S. Environmental Protection Agency (0.02mg/kg/day) and the European Food Safety Authority (0.05mg/kg/day). ResultsWe analyzed intake and renal function of 184 children whose intake of DEHP-tainted foods was known. Higher DEHP exposure to DEHP-tainted foods was significantly associated with increase of urine albumin/creatinine ratio (ACR). Children in the high-exposed group (daily DEHP intake (DDI)>0.05mg/kg/day) had 10.395 times the risk of microalbuminuria than the low-exposed group (DDI≤0.02 and >0mg/kg/day) and no-exposed group combined after adjustment (95% CI=1.096–98.580, P=0.04). ConclusionIntake of DEHP from phthalate-tainted foods may be a potential risk factor for microalbuminuria, a marker of glomerular injury in children.

Phthalates and critically ill neonates: device-related exposures and non-endocrine toxic risks.

To assess the types and magnitudes of non-endocrine toxic risks to neonates associated with medical device-related exposures to di(2-ethylhexyl)phthalate (DEHP). Dose-response thresholds for DEHP toxicities were determined from published data, as were the magnitudes of DEHP exposures resulting from neonatal contact with polyvinyl chloride (PVC) devices. Standard methods of risk assessment were used to determine safe levels of DEHP exposure in neonates, and hazard quotients were calculated for devices individually and in aggregate. Daily intake of DEHP for critically ill preterm infants can reach 16 mg/kg per day, which is on the order of 4000 and 160,000 times higher than desired to avoid reproductive and hepatic toxicities, respectively. The non-endocrine toxicities of DEHP are similar to complications experienced by preterm neonates. DEHP exposures in neonatal intensive care are much higher than estimated safe limits, and might contribute to common early and chronic complications of prematurity. Concerns about phthalates should be expanded beyond endocrine disruption.

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.

Health hazard assessment of occupationally di-(2-ethylhexyl)-phthalate-exposed workers in China

Di-(2-ethylhexyl)-phthalate (DEHP) is a potential hazard to human health. The effects of occupational high level DEHP exposure on human health were evaluated by measuring the plasma cholinesterase, residues, renal and hepatic biochemical markers. The study was conducted in three representative polyvinyl chloride manufacturing facilities from large size (S1), medium side (S2) to small size (S3). Total 456 adult males including 352 exposed workers (occupational) and 104 control workers (background) were selected. The average DEHP concentrations in respirable particulate matter were 233, 291, and 707μgm−3 for S1–S3, respectively, compared with 0.26μgm−3 in the background atmosphere (labeled by S4). The results showed significant decreases in post exposure plasma cholinesterase (PChE) levels (<30%) from the exposed workers as compared to baseline. These exposed workers had been evaluated for plasma DEHP residues. Regression analyses explored that PChE decreased significantly with increasing plasma DEHP residues. Serum aspartate aminotransferase, alanine aminotransferase, creatinine, urea, gamma glutamyltransferase, malondialdehyde, total antioxidant and C-reactive protein were significantly raised as compared to the controls. Of the 352 exposed workers, 116 (33.0%) had a daily DEHP intake 22.7μgkgbw−1d−1 , which is more than 20μgkgbw−1d−1 specified by the US Environmental Protection Agency. The study demonstrated that occupational phthalate exposure produces health hazards.

Concentration of di(2-ethylhexyl) phthalate (DEHP) in foods and its dietary exposure in China

Di(2-ethylhexyl) phthalate (DEHP) is a common plasticizer used in food contact materials that has been reported as an endocrine disruptor. In the present study, DEHP concentrations were analyzed in foods in order to determine dietary exposure among the Chinese population, including the general population (aged 2-100) and four age group, that is children aged 2-6, adolescent aged 7-12, young people aged 13-17 and adults aged 18 years old and above. 1704 food samples were collected during 2011-2012 and categorized into 12 food groups which covered major foods in China. Food consumption data were taken from China National Nutrient and Health Survey which was performed in 2002 and includes data from 68,959 subjects. Mean concentrations of DEHP were combined with individual food consumption data to estimate dietary exposure. It was found that DEHP levels in foods ranged from not detected to 3.41 mg/kg, with highest mean values in meat (0.23 mg/kg) and vegetable oils (0.21 mg/kg). Mean dietary intakes of DEHP in the general population, children, and adults were 2.34, 4.51, 2.03 μg/kg bw per day, respectively. The 97.5% intakes in these populations were 5.22, 8.43, 3.64 μg/kg bw per day, respectively. The main food sources of DEHP dietary intake were cereals (39.44%), drinking water (16.94%) and meat (15.81%) in children, and cereals (44.57%), meat (15.70%) and drinking water (12.28%) for adults. These findings suggested that dietary exposure to DEHP among Chinese population was lower than tolerable daily intake of DEHP and there are no health concerns based on generally accepted exposure limits.

Species and inter-individual differences in metabolic capacity of di(2-ethylhexyl)phthalate (DEHP) between human and mouse livers

This study was conducted to assess inter-species and inter-individual differences in the metabolism of di(2-ethylhexyl)phthalate (DEHP) in humans and mice. The activities of four DEHP-metabolizing enzymes [lipase, UDP-glucuronocyltransferase (UGT), alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH)] were measured in the livers of 38 human subjects of various ages and in eight 129/Sv male mice. Microsomal lipase activity was significantly lower in humans than in mice. The V max/K m value in humans was one-seventh of that in mice, microsomal UGT activity in humans was a sixth of that in mice, and cytosolic ALDH activity for 2-ethylhexanal in humans was one-half of that in mice. In contrast, ADH activity for 2-ethylhexanol was twofold higher in humans than in mice. The total amount of DEHP urinary metabolites and the concentration of mono(2-ethylhexyl)phthalate (MEHP) were much higher in intact mice than in the U.S. general population based on data reported elsewhere, regardless of the similar estimated DEHP intake between these mice and the human reference population. However, mono(2-ethyl-5-oxo-hexyl)phthalate (5oxo-MEHP) and mono(2-ethyl-5-carboxypentyl)phthalate (5cx-MEPP) levels were higher in the latter than in the former. Of note, inter-subject variability in the activities of all enzymes measured was 10-26-fold. The inter-individual variation in the metabolism of DEHP in humans may be greater than the difference between mice and humans (inter-species variation), and both may affects the risk assessment of DEHP.

Taiwan food scandal: The illegal use of phthalates as a clouding agent and their contribution to maternal exposure

In 2011 the Taiwan Food and Drug Administration reported that plasticizers di(2-ethylhexyl) phthalate (DEHP) and di-iso-nonyl phthalate (DiNP), endocrine disruptors, were illegally added to clouding agents used in foods and beverages. 965 products were found contaminated, of which 206 were exported to 22 countries. This study's purpose was to obtain English names for 28 contaminated products for which DEHP levels were reported, calculate estimated average daily intake (mg/kg/day) for a 50 kg woman consuming one portion, and compare to U.S. and E.U. guidelines for daily intake. We found that drinking just one bottle (500 ml) of sports drinks would result in an average DEHP intake of 0.14 mg/kg bw/day (range 0.091-0.341), which exceeds by several fold government guidelines (0.02-0.06 mg/kg bw/day). One (2 g) serving from 4/14 samples of contaminated dietary supplements exceeds the guideline of 0.02 mg/kg bw/day. In conclusion, consuming even one portion of tainted drinks and some powders would lead to daily intake of DEHP that greatly exceeds established safety guidelines, raising concerns about potential adverse effects, particularly reproductive tract development in the male fetus. Global distribution of DEHP-contaminated and other adulterated products should prompt governments to become proactive in food safety regulations and chemical testing.

Children's phthalate intakes and resultant cumulative exposures estimated from urine compared with estimates from dust ingestion, inhalation and dermal absorption in their homes and daycare centers.

Total daily intakes of diethyl phthalate (DEP), di(n-butyl) phthalate (DnBP), di(isobutyl) phthalate (DiBP), butyl benzyl phthalate (BBzP) and di(2-ethylhexyl) phthalate (DEHP) were calculated from phthalate metabolite levels measured in the urine of 431 Danish children between 3 and 6 years of age. For each child the intake attributable to exposures in the indoor environment via dust ingestion, inhalation and dermal absorption were estimated from the phthalate levels in the dust collected from the child’s home and daycare center. Based on the urine samples, DEHP had the highest total daily intake (median: 4.42 µg/d/kg-bw) and BBzP the lowest (median: 0.49 µg/d/kg-bw). For DEP, DnBP and DiBP, exposures to air and dust in the indoor environment accounted for approximately 100%, 15% and 50% of the total intake, respectively, with dermal absorption from the gas-phase being the major exposure pathway. More than 90% of the total intake of BBzP and DEHP came from sources other than indoor air and dust. Daily intake of DnBP and DiBP from all exposure pathways, based on levels of metabolites in urine samples, exceeded the Tolerable Daily Intake (TDI) for 22 and 23 children, respectively. Indoor exposures resulted in an average daily DiBP intake that exceeded the TDI for 14 children. Using the concept of relative cumulative Tolerable Daily Intake (TDIcum), which is applicable for phthalates that have established TDIs based on the same health endpoint, we examined the cumulative total exposure to DnBP, DiBP and DEHP from all pathways; it exceeded the tolerable levels for 30% of the children. From the three indoor pathways alone, several children had a cumulative intake that exceeded TDIcum. Exposures to phthalates present in the air and dust indoors meaningfully contribute to a child’s total intake of certain phthalates. Such exposures, by themselves, may lead to intakes exceeding current limit values.

Estimating the contribution of inhalation exposure to di-2-ethylhexyl phthalate (DEHP) for PVC production workers, using personal air sampling and urinary metabolite monitoring

Because of troubling reports of high urinary metabolite levels and adverse reproductive health effects in workers exposed to di(2-ethylhexyl)phthalate (DEHP) in occupational settings, concern about exposure to DEHP in occupational settings is increasing. However, the contributions of different routes of exposure to DEHP are unclear. We used personal air sampling and biomonitoring to determine the contribution of inhalation exposure to the body burden of DEHP in the workplace. Eighty-nine workers (high-exposure group: 66 raw-materials workers; low-exposure group: 23 administrative workers) were recruited from three polyvinyl chloride (PVC) factories. Urinary levels of mono(2-ethylhexyl) phthalate (MEHP), (mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) were measured in pre-shift and post-shift samples. The geometric means of airborne concentrations of DEHP were 5.3 μg/m3 (low-exposure group) and 32.7 μg/m3 (high-exposure group) (P<0.01). Correlation analysis showed a consistently significant association between airborne DEHP concentration and urinary DEHP metabolite levels in the high-exposure group. Calculating daily DEHP intake based on total urinary metabolite levels showed that the geometric means of total daily urinary metabolite levels of DEHP were 9.2 μg/kg/day (low-exposure group) and 15.5 μg/kg/day (high-exposure group) (P<0.01). A quartile analysis of all workers showed a significant trend toward an association between the individual contribution of inhalation exposure to DEHP and urinary DEHP metabolite levels, for which the mean inhalation contribution was 46.7% in the highest quartile. We conclude that inhalation-absorbed airborne DEHP significantly increased the total body burden of DEHP in these occupationally exposed workers.

Di(2-ethylhexyl)phthalate (DEHP) and di-n-butylphthalate (DBP) exposure through diet in hospital patients

Ready-to-eat packed meals intended to hospital patients were studied over a two-weeks period to measure the contents of di-(2-ethylhexyl) phthalate (DEHP) and di-n-butylphthalate (DBP) and to evaluate their daily intake by total diet. The packaging consisted of polyethylene terephthalate (PET) dishes sealed with polypropylene (PP) foil. The DEHP mean concentrations in total meals varied from 0.061±0.028 to 0.307±0.138μg/gwetweight (wet wt.); the DBP mean levels varied from 0.025±0.018 to 0.174±0.091μg/gwetwt. Highest levels of concentration for DEHP and DBP were found in bread with mean values of 0.307±0.138μg/gwetwt. and 0.174±0.091μg/gwetwt. for DEHP and DBP, respectively. The daily intake for DEHP was 3.1±0.9μg/kgbw and 1.5±0.5μg/kgbw for DBP.The mean±sd incidence of DEHP and DBP intake via hospital meals on the respective EFSA TDI was 6±2% (range 4–11%), and 15±5% (range 8–24%), respectively. Even if for hospital patients the major route of exposure may be represented by medical devices, the influence of the diet could have a significant value on TDI.

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 6.5years old) and another of adults (≥15years 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.

Children’s Exposure to Di(2-ethylhexyl)phthalate and Dibutylphthalate Plasticizers from School Meals

Packed school meals for children 3-10 years old were studied to evaluate the levels of di(2-ethylhexyl)phthalate (DEHP) and di-n-butylphthalate (DBP) and the influence of the packaging process on meal contamination, and their contribution to daily intake was estimated. The packaging consisted of polyethylene-coated aluminum (PE/Al) dishes thermally welded by a polyethyleneterephthalate-coated aluminum (PET/Al) foil. Foodstuffs before processing were analyzed, too. Total meals before packaging and after packaging were collected. It was found that 92% of foodstuffs employed in meal preparation contained DEHP, and 76% of them DBP, at detectable levels. In cooked foods before packaging the DEHP median concentration levels varied from 111.4 to 154.8 ng/g ww and those of DBP between 32.5 and 59.5 ng/g ww. In packed meals the DEHP median values ranged from 127.0 to 253.3 ng/g ww, and DBP median values varied from 44.1 to 80.5 ng/g ww. The mean increases of median concentrations of DEHP in cooked foods before and after packaging were 113 and 125% for DBP. For nursery and primary school children DEHP intake via school meals can raise on average the respective EFSA TDI by 18 and 12% and that of DBP by 50 and 30%.

Effect of di(2-ethylhexyl) phthalate (DEHP) on lipolysis and lipoprotein lipase activities in adipose tissue of rats

The di(2-ethylhexyl) phthalate (DEHP) is an ubiquitous environmental chemical with detrimental health effects. The present work was designed to asses some potential mechanisms by which DEHP causes, among others, a reduced body fat retention. Since this effect could be related to an alteration of adipocyte triacylglycerol (TG) metabolism, we evaluated the effects of dietary DEHP in adipose tissues upon (1) the number and size of fat cells; (2) the basal and stimulated lipolysis and (3) the lipoprotein lipase (LPL) activity. Groups of male Wistar rats were fed for 21 days a control diet alone (control group) or the same control diet supplemented with 2% (w/w) of DEHP (DEHP group). The LPL activity of DEHP-fed rats was increased in lumbar and epididymal adipose tissues. These rats had significantly reduced weight in epididymal and lumbar tissues, together with reduced size of epididymal adipocytes. These alterations do not seem to be associated with higher lipid mobility because neither basal lipolysis nor 'in vitro' stimulated lipolysis by noradrenaline (NA) showed to be modified by DEHP. Based on these results, we concluded that the adipose tissue size reduction induced by DEHP intake is not due to changes in lipolysis nor to a decreased LPL activity. More research is needed to achieve a comprehensive understanding of the potential mechanisms by which DEHP causes, among others, a reduced body fat retention.

Estimated daily intake of phthalates in occupationally exposed groups

Improved analytical methods for measuring urinary phthalate metabolites have resulted in biomarker-based estimates of phthalate daily intake for the general population, but not for occupationally exposed groups. In 2003-2005, we recruited 156 workers from eight industries where materials containing diethyl phthalate (DEP), dibutyl phthalate (DBP), and/or di(2-ethylhexyl) phthalate (DEHP) were used as part of the worker's regular job duties. Phthalate metabolite concentrations measured in the workers' end-shift urine samples were used in a simple pharmacokinetic model to estimate phthalate daily intake. DEHP intake estimates based on three DEHP metabolites combined were 0.6-850 μg/kg/day, with the two highest geometric mean (GM) intakes in polyvinyl chloride (PVC) film manufacturing (17 μg/kg/day) and PVC compounding (12 μg/kg/day). All industries, except phthalate manufacturing, had some workers whose DEHP exposure exceeded the U.S. reference dose (RfD) of 20 μg/kg/day. A few workers also exceeded the DEHP European tolerable daily intake (TDI) of 50 μg/kg/day. DEP intake estimates were 0.5-170 μg/kg/day, with the highest GM in phthalate manufacturing (27 μg/kg/day). DBP intake estimates were 0.1-76 μg/kg/day, with the highest GMs in rubber gasket and in phthalate manufacturing (17 μg/kg/day, each). No DEP or DBP intake estimates exceeded their respective RfDs. The DBP TDI (10 μg/kg/day) was exceeded in three rubber industries and in phthalate manufacturing. These intake estimates are subject to several uncertainties; however, an occupational contribution to phthalate daily intake is clearly indicated in some industries.

Determination of phthalates in raw bovine milk by gas chromatography/time-of-flight mass spectrometry (GC/TOF-MS) and dietary intakes

Low levels of phthalates, including di(2-ethylhexyl) phthalate (DEHP), in raw bovine milk were determined using gas chromatography/time-of-flight mass spectrometry (GC/TOF-MS). A fast and convenient process of sample treatment combined with TOF-MS analysis (medium resolution >5000), yielded good recoveries (85–125%) and low limits of detection (<0.002 mg kg−1). The most commonly used phthalate, DEHP, was found in 15 out of 30 samples monitored in this study. DEHP concentrations in raw milk ranged from not detected to 0.154 mg kg−1, and the mean concentration was 0.057 mg kg−1. The dietary intake of DEHP was about 0.004 mg kg−1 body weight day−1 if a child (24 months, 13 kg body weight) drinks 1 L day−1 of milk that contains the mean concentration of DEHP found in raw milk. The estimated dietary intake corresponded to 8% of the European Union tolerable daily intake (TDI) of 0.05 mg kg−1 body weight day−1. Dimethyl phthalate (DMP) and di-n-butyl phthalate (DBP) were found from two and 20 samples, respectively, at low levels. Diethyl phthalate (DEP), butylbenzyl phthalate (BBP), and di-n-octyl phthalate (DnOP) were not found in any of the samples.

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 μg 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.

Daily intake of di(2-ethylhexyl)phthalate (DEHP) by German children – A comparison of two estimation models based on urinary DEHP metabolite levels

Di(2-ethylhexyl)phthalate (DEHP) is a general-purpose plasticizer for polyvinyl chloride (PVC) and has become a ubiquitous environmental contaminant. It is suspected to be an endocrine disrupting/modulating substance in humans. Children are of special concern due to their developmental state. In our study we estimated the daily DEHP intake of 239 children aged 2–14 years by extrapolating from their urinary levels of the DEHP metabolites mono-(2-ethyl-5-hydroxyhexyl)phthalate (5OH-MEHP), mono-(2-ethyl-5-oxohexyl)phthalate (5oxo-MEHP) and mono-(2-ethylhexyl)phthalate (MEHP). We applied two calculation models based upon the volume and the creatinine-related urinary metabolite concentrations. Applying the volume- or the creatinine-based calculation model we determined a median daily DEHP intake of 7.8 or 4.3 μg/kg body weight (bw)/day and a 95th percentile of 25.2 or 15.2 μg/kg bw/day. Three children (1%) exceeded the value of the tolerable daily intake (TDI) of the European Food Safety Authority of 50 μg/kg bw/day, while 7.5% or 3% (depending on the calculation model) exceeded the reference dose (RfD) of 20 μg/kg bw/day of the US Environmental Protection Agency. In general, DEHP exposure was decreasing with increasing age and boys had higher exposures than girls. Our findings suggest that the majority of the children in the general population is exposed to quantities of DEHP below the TDI and the RfD. However, many children scoop out the preventive limit values to a considerable degree and in individual cases we observed substantial transgressions. Younger children seem to be more severely burdened, which may be due to a higher food consumption related to their bw, mouthing behaviour and/or playing near the ground.

Di(2‐ethylhexyl)phthalate (DEHP): human metabolism and internal exposure – an update and latest results1

Di(2-ethylhexyl)phthalate (DEHP) is a reproductive and developmental toxicant in animals and a suspected endocrine modulator in humans. There is widespread exposure to DEHP in the general population. Patients can be additionally exposed through DEHP-containing medical devices. Toxicokinetic and metabolic knowledge on DEHP in humans is vital not only for the toxicological evaluation of DEHP but also for exposure assessments based on human biomonitoring data. Secondary oxidized DEHP metabolites like mono-(2-ethyl-5-hydroxyhexyl)phthalate (5OH-MEHP), mono-(2-ethyl-5-oxohexyl)phthalate (5oxo-MEHP), mono-(2-ethyl-5-carboxypentyl)phthalate (5cx-MEPP) and mono-[2-(carboxymethyl)hexyl]phthalate (2cx-MMHP) are most valuable biomarkers of DEHP exposure. They represent the major share of DEHP metabolites excreted in urine (about 70% for these four oxidized metabolites vs. about 6% for MEHP); they are immune to external contamination and possibly the ultimate developmental toxicants. Long half-times of elimination make 5cx-MEPP and 2cx-MMHP excellent parameters to measure the time-weighted body burden to DEHP. 5OH-MEHP and 5oxo-MEHP more reflect the short-term exposure. We calculated the daily DEHP intake for the general population (n = 85) and for children (n = 254). Children were significantly higher exposed to DEHP than adults. Exposures at the 95th percentile (21 and 25 microg/kg/day, respectively) scooped out limit values like the Reference Dose (RfD, 20 microg/kg/day) and the Tolerable Daily Intake (TDI, 20-48 microg/kg/day) to a considerable degree. Up to 20-fold oversteppings for some children give cause for concern. We also detected significant DEHP exposures for voluntary platelet donors (n = 12, 38 microg/kg/apheresis, dual-needle technique). Premature neonates (n = 45) were exposed to DEHP up to 100 times above the limit values depending on the intensity of medical care (median: 42 microg/kg/day; 95th percentile: 1,780 microg/kg/day).

Evaluation of the effect of governmental control of human exposure to two phthalates in Japan using a urinary biomarker approach

In Japan, the use of certain phthalates has been regulated. We analyzed the effectiveness of these measures using an analytical biomarker approach. We measured two phthalate metabolites, mono- n-butyl phthalate (MBP) and mono-2-ethylhexyl phthalate (MEHP) in urine samples from 36 participants using enzymatic deconjugation, offline solid phase extraction, and HPLC-ESI-MS/MS. From the levels measured and individual values of creatinine excretion rate the daily intake was determined and compared to each corresponding tolerable daily intake (TDI). The levels of urinary MBP and MEHP were <1.8–280 and 0.76–25 μg/l, respectively. The ranges of the estimated daily intake of di- n-butyl phthalate (DBP) and di-2-ethylhexyl phthalate (DEHP) from 35 adult urine samples were 0.22–4.5 and 0.37–7.3 μg/kg/day, respectively. These values were lower than the corresponding TDIs. After comparing these values to previous exposure assessment data on DEHP in Japan, it could be seen that the DEHP intake dropped over the period from 1998 to 2001. Children were not covered in the present study, so the results may only be applicable to adults, not to the Japanese population at large. Even so, the small number of people in one specific geographic area cannot be considered representative of the adult Japanese population. In addition to MEHP, the secondary metabolites of DEHP, which are more suitable biomarkers should be measured in the future.

Effects of dietary di(2-ethylhexyl)phthalate, a putative endocrine disrupter, on enzyme activities involved in the metabolism of tryptophan to niacin in rats.

We have reported that the conversion ratio of tryptophan to niacin increased with increasing dietary concentration of di(2-ethylhexyl)phthalate (DEHP); the conversion ratio was about 2.0% in the control rat, which increased by about 30% in the rat fed with 3.0% DEHP diet. In this study, we investigated whether this abnormal increase in the conversion ratio by DEHP occurred through the alteration of the enzyme activities involved in the metabolism of tryptophan to niacin. Rats were fed with a diet containing 0%, 0.1%, 0.5%, or 1.0% DEHP for 21 days. The nine kinds of enzyme activities involved in the biosynthesis and catabolism in the liver and kidney were measured. Based on previous findings that the formation of quinolinic acid and its' metabolites significantly increased with DEHP administration, we proposed that the activity of 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase would be inhibited by DEHP intake. However, we found that the activities in the liver and kidney did not decrease in the rat fed with DEHP-containing diet. We discuss the discrepancy between the metabolite results and the enzyme activities.