DEHP metabolites in urine of children and DEHP in house dust

Urine samples from the 2001/2002 pilot study for the German Environmental Survey on children (GerES IV) were analysed for concentrations of the primary DEHP metabolite MEHP (mono(2-ethylhexyl)phthalate) and two secondary DEHP metabolites SOH-MEHP (2-ethyl-5-hydroxy-hexylphthalate) and 5oxo-MEHP (2-ethyl-5-oxo-hexylphthalate). Urine samples had been taken from 254 children aged 3 to 14. In addition, DEHP was analysed in house dust samples. These samples had been collected with vacuum cleaners in the homes of the children. The geometric mean (GM) was 7.9 microg/l for MEHP in urine, and the GMs for the secondary metabolites 5OH-MEHP and 5oxo-MEHP were 52.1 microg/l and 39.9 microg/l. 5OH-MEHP and 5oxo-MEHP concentrations were highly correlated (r = 0.98). The correlations of 5OH-MEHP and 5oxo-MEHP with MEHP were also high (r = 0.72 and r = 0.70). The concentrations of 5OH-MEHP and 5oxo-MEHP were 8.0-fold and 6.2-fold higher than the concentrations of MEHP. The ratios 5OH-MEHP/Soxo-MEHP and 5oxo-MEHP/MEHP decreased with increasing age. Boys showed higher concentrations than girls for all three metabolites of DEHP in urine. Children aged 13-14 had the lowest mean concentrations of the secondary metabolites in urine. The house dust analyses revealed DEHP contamination of all samples. The GM was 508 mg/kg dust. No correlation could be observed between the levels of any of the urinary DEHP metabolites and those of DEHP in house dust.     

Internal exposure of nursery-school children and their parents and teachers to di(2-ethylhexyl)phthalate (DEHP)

Di(2-ethylhexyl)phthalate (DEHP) is the main plasticizer for polyvinyl chloride (PVC) products. It has become widely spread in our environment and among people. DEHP is suspected to be responsible for endocrine-disruptor-like effects in mankind. Children are probably most susceptible to these endocrine effects. In this study we determined the internal exposure of nursery school children (aged 2-6 years) to DEHP and compared it to their parents' and teachers' exposure. The DEHP-metabolites mono(2-ethyl-5-hydroxyhexyl)phthalate (5OH-MEHP), mono(2-ethyl-5-oxo-hexyl)phthalate (5oxo-MEHP) and mono(2-ethylhexyl)phthalate (MEHP) were determined in first morning urine. The sum of the three DEHP metabolites in children's and in adults' urine was 90.0 and 59.1 micrograms/l respectively (median values; p = 0.074). Concentrations of the secondary metabolites 5OH-MEHP (median: 49.6 vs. 32.1 micrograms/l; p = 0.038) and 5oxo-MEHP (median: 33.8 vs. 19.6 micrograms/l; p = 0.015) were significantly higher in children than in adults. MEHP concentrations were low both in adults and children (median: 6.6 micrograms/l vs. 9.0 micrograms/l). Creatinine adjusted values should more accurately reflect the dose taken up with respect to body weight when comparing children with adults. Total creatinine adjusted DEHP metabolites in urine were significantly higher in children than in adults (median values: 98.8 vs. 50.9 micrograms/g creatinine; p < 0.0001). This also applied to the concentrations of both secondary metabolites 5OH-MEHP (55.8 vs. 28.1 micrograms/g creatinine; p < 0.0001) and 5oxo-MEHP (38.3 vs. 17.2 micrograms/g creatinine; p < 0.0001). Creatinine corrected concentrations for the monoester MEHP in children and adults were very similar (8.7 vs. 8.6 micrograms/g creatinine; p = 0.908). Based on the sum of the three determined metabolites we estimated the DEHP dose (in microgram/kg body-weight) taken up by children to be about twice as high as the dose taken up by adults. Routes of the ubiquitous exposure to DEHP remain indistinct. In children's urine the mean relative ratios of MEHP to 5OH-MEHP to 5oxo-MEHP were 1 to 7.1 to 4.9, in adults they were 1 to 3.4 to 2.1. This might indicate an enhanced oxidative metabolism in children. To date no information on the biological activity and toxicity of oxidative metabolites of DEHP is available. Since these are the major metabolites of DEHP toxicological data on these metabolites is urgently needed.     

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

Each year thousands of healthy volunteers undergo apheresis procedures to donate blood components and safe lives. However, many disposables used in apheresis contain di(2-ethylhexyl)phthalate (DEHP). This way, donors are exposed to DEHP, which is a reproductive and developmental toxicant in animals and a suspected endocrine modulator in humans. We quantified the DEHP exposure of six plasma donors, six discontinuous-flow platelet donors and six continuous-flow platelet donors by determining three specific metabolites in urine (5OH-MEHP: mono(2-ethyl-5-hydroxyhexyl)phthalate; 5oxo-MEHP: mono(2-ethyl-5-oxo-hexyl)phthalate and MEHP: mono(2-ethylhexyl)phthalate). We found maximum concentrations in urine samples after the discontinuous-flow plateletpheresis procedure with 826 microg/l for 5OH-MEHP, 774 microg/l for 5oxo-MEHP and 266 microg/l for MEHP (mean of the six volunteers). Metabolite excretions were found to be significantly (p<0.0001) higher for both plateletpheresis techniques compared to plasmapheresis and controls. Continuous-flow plateletpheresis led to significantly higher (p<0.0001) excretions than discontinuous-flow plateletpheresis. Mean absolute DEHP exposures were 1.2 mg for discontinuous- and 2.1 mg for continuous-flow plateletpheresis. Exposure for plasmapheresis (0.37 mg) was in the range of the controls (0.41 mg). Mean DEHP doses for both plateletpheresis techniques (18.1 and 32.3 microg/kg/day) were close to or exceeded the reference dose (RfD) of the US EPA and tolerable daily intake (TDI) value of the EU on the day of the apheresis. Therefore, margins of safety might be insufficient to protect especially young men and women in their reproductive age from effects on reproductivity. At present, discontinuous-flow devices should be preferred to avert conceivable health risks from plateletpheresis donors. Strategies to avoid DEHP exposure of donors during apheresis need to be developed.     

An estimation of the daily intake of di(2-ethylhexyl)phthalate (DEHP) and other phthalates in the general population.

We analyzed 85 urine samples of the general German population for human specific metabolites of phthalates. By that we avoided contamination with the parent phthalates being omnipresent in the environment and for the first time could deduce each individual's internal exposure to phthalates without contamination. Determined were the secondary metabolites mono(2-ethyl-5-hydroxyhexyl)phthalate (5OH-MEHP) and mono(2-ethyl-5-oxo-hexyl)phthalate (5oxo-MEHP) of di(2-ethylhexyl)phthalate (DEHP) and the primary monoester metabolites of DEHP, di-noctylphthalate (DnOP), di-n-butylphthalate (DnBP), butylbenzylphthalate (BBzP) and diethylphthalate (DEP). Based on these internal exposure values we calculated the daily intake of the parent phthalates using urinary metabolite excretion factors. For DEHP we determined a median intake of 13.8 micrograms/kg body weight/day and an intake at the 95th percentile of 52.1 micrograms/kg body weight/day. The tolerable daily intake (TDI) value settled by the EU Scientific Committee for Toxicity, Ecotoxicity and the Environment (CSTEE) is 37 micrograms/kg body weight/day. Twelve percent of the subjects (10 out of 85 samples) within our collective of the general population are exceeding this value. Thirty-one percent of the subjects (26 out of 85 samples) had values higher than the reference dose (RfD) of 20 micrograms/kg body weight/day of the U.S. Environmental Protection Agency (EPA). For DnBP, BBzP, DEP and DnOP intake values at the 95th percentile were 16.2, 2.5, 22.1 and 0.42 micrograms/kg body weight/day respectively. Our results unequivocally prove that the general German population is exposed to DEHP to a much higher extent than previously believed. This is of greatest importance for public health since DEHP is not only the most important phthalate with respect to its production, use, occurrence and omnipresence but also the phthalate with the greatest endocrine disrupting potency. DEHP is strongly suspected to be a developmental and reproductive toxicant. We are not aware of any other environmental contaminant for which the TDI and RfD are exceeded to such an extent within the general population. The transgressions of the TDI and RfD for DEHP are accompanied by considerable ubiquitous exposures to DnBP and BbzP, two phthalates under scrutiny for similar toxicological mechanisms.     

Occurrence and daily variation of phthalate metabolites in the urine of an adult population

Phthalates like di-(2-ethylhexyl) phthalate (DEHP) are commonly used as plasticizers and their metabolites are suspect of especially reproductive toxicity. The aim of our study was to assess phthalate exposure in adults by measuring urinary phthalate metabolite levels and to explore individual temporal variability. Urine samples were collected by 27 women and 23 men aged 14-60 years during 8 consecutive days. We quantified four monoesters, four oxidative DEHP metabolites, and two secondary metabolites of di-isononyl phthalate (DiNP) by a LC/LC-MS/MS method. If we analyzed all 399 available samples independent of classification, the highest median values of primary metabolites in this study were found for mono-n-butyl phthalate (MnBP: 49.6 microg/l), followed by mono-isobutyl phthalate (MiBP: 44.9 microg/l), mono-benzyl phthalate (MBzP: 7.2 microg/l), and mono-2-ethylhexyl phthalate (MEHP: 4.9 microg/l). The median concentrations of the oxidized metabolites of DEHP were 8.3 microg/l for mono-(2-carboxymethylhexyl) phthalate (2cx-MMHP), 19.2 microg/l for mono-(2-ethyl-5-hydroxyhexyl) phthalate (5OH-MEHP), 14.7 microg/l for mono-(2-ethyl-5-oxohexyl) phthalate (5oxo-MEHP), and 26.2 microg/l for mono-(2-ethyl-5-carboxypentyl) phthalate (5cx-MEPP). The concentrations of the two DiNP secondary metabolites mono (oxoisononyl) phthalate (oxo-MiNP) and mono(hydroxyisononyl) phthalate (OH-MiNP) ranged from 相似文献   

Trends of the internal phthalate exposure of young adults in Germany--follow-up of a retrospective human biomonitoring study

The exposure of the general population to phthalates is of increasing public health concern. Variations in the internal exposure of the population are likely, because the amounts, distribution and application characters of the phthalate use change over time. Estimating the chronological sequences of the phthalate exposure, we performed a retrospective human biomonitoring study by investigating the metabolites of the five most prominent phthalates in urine. Therefore, 24 h-urine samples from the German Environmental Specimen Bank (ESB) collected from 240 subjects (predominantly students, age range 19–29 years, 120 females, 120 males) in the years 2002, 2004, 2006 and 2008 (60 individuals each), were analysed for the concentrations of mono-n-butyl phthalate (MnBP) as metabolite of di-n-butyl phthalate (DnBP), mono-iso-butyl phthalate (MiBP) as metabolite of di-iso-butyl phthalate (DiBP), mono-benzyl phthalate (MBzP) as metabolite of butylbenzyl phthalate (BBzP), mono-(2-ethylhexyl) phthalate (MEHP), 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-MMHxP) as metabolites of di(2-ethylhexyl) phthalate (DEHP), monohydroxylated (OH-MiNP), monooxidated (oxo-MiNP) and monocarboxylated (cx-MiNP) mono-iso-nonylphthalates as metabolites of di-iso-nonyl phthalates (DiNP). Based on the urinary metabolite excretion, together with results of a previous study, which covered the years 1988–2003, we investigated the chronological sequences of the phthalate exposure over two decades. In more than 98% of the urine samples metabolites of all five phthalates were detectable indicating a ubiquitous exposure of people living in Germany to all five phthalates throughout the period investigated. The medians in samples from the different years investigated are 65.4 (2002), 38.5 (2004), 29.3 (2006) and 19.6 μg/l (2008) for MnBP, 31.4 (2002), 25.4 (2004), 31.8 (2006) and 25.5 μg/l (2008) for MiBP, 7.8 (2002), 6.3 (2004), 3.6 (2006) and 3.8 μg/l (2008) for MBzP, 7.0 (2002), 5.6 (2004), 4.1 (2006) and 3.3 μg/l (2008) for MEHP, 19.6 (2002), 16.2 (2004), 13.2 (2006) and 9.6 μg/l (2008) for 5OH-MEHP, 13.9 (2002), 11.8 (2004), 8.3 (2006) and 6.4 μg/l (2008) for 5oxo-MEHP, 18.7 (2002), 16.5 (2004), 13.8 (2006) and 10.2 μg/l (2008) for 5cx-MEPP, 7.2 (2002), 6.5 (2004), 5.1 (2006) and 4.6 μg/l (2008) for 2cx-MMHxP, 3.3 (2002), 2.8 (2004), 3.5 (2006) and 3.6 μg/l (2008) for OH-MiNP, 2.1 (2002), 2.1 (2004), 2.2 (2006) and 2.3 μg/l (2008) for oxo-MiNP and 4.1 (2002), 3.2 (2004), 4.1 (2006) and 3.6 μg/l (2008) for cx-MiNP. The investigation of the time series 1988–2008 indicates a decrease of the internal exposure to DnBP by the factor of 7–8 and to DEHP and BzBP by the factor of 2–3. In contrast, an increase of the internal exposure by the factor of 4 was observed for DiNP over the study period. The exposure to DiBP was found to be stable. In summary, we found decreases of the internal human exposure for legally restricted phthalates whereas the exposure to their substitutes increased. Future investigations should verify these trends. This is of increasing importance since the European Commission decided to require ban or authorization from 1.1.2015 for DEHP, DnBP, DiBP and BzBP according to REACh Annex XIV.     

Mono(2-ethyl-5-hydroxyhexyl) phthalate and mono-(2-ethyl-5-oxohexyl) phthalate as biomarkers for human exposure assessment to di-(2-ethylhexyl) phthalate

Exposure to di-(2-ethylhexyl) phthalate (DEHP) is prevalent based on the measurement of its hydrolytic metabolite mono-(2-ethylhexyl) phthalate (MEHP) in the urine of 78% of the general U.S. population studied in the 1999-2000 National Health and Nutrition Examination Survey (NHANES). However, despite the high level of production and use of DEHP, the urinary MEHP levels in the NHANES samples were lower than the monoester metabolites of phthalates less commonly used than DEHP, suggesting metabolic differences between phthalates. We measured MEHP and two oxidative DEHP metabolites, mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) and mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) to verify whether these other metabolites account for a greater proportion of DEHP metabolic products in 127 paired human urine and serum samples. We found that the urinary levels of MEHHP and MEOHP were 10-fold higher than levels of MEHP; concentrations of urinary MEOHP and MEHHP were strongly correlated (r = 0.928). We also found that the serum levels of MEOHP and MEHHP were comparatively lower than those in urine. Furthermore, the glucuronide-bound conjugates of the oxidative metabolites were the predominant form in both urine and serum. MEOHP and MEHHP cannot be formed by serum enzymes from the hydrolysis of any contamination from DEHP potentially introduced during blood collection and storage. Therefore, concentrations of MEHHP and MEOHP in serum may be a more selective measure of DEHP exposure than is MEHP. However, additional data on the absorption, distribution, metabolism, and elimination of these oxidative metabolites are needed to completely understand the extent of DEHP exposure from the serum concentrations of oxidative DEHP metabolites.     

Austrian reference values for phthalate metabolite exposure in children/adolescents and adults

Reference values (RV₉₅) are statistically derived values comprising the rounded 95th percentiles within the 95% confidence interval and indicate the upper margin of background exposure to chemical substances in a population at a given time period. Based on representative national human biomonitoring data on several urinary phthalate metabolites in children, adolescents and adults from 2010 to 2011, RV₉₅ were derived for the Austrian population based on a IUPAC guideline and the recommendation of the German Human Biomonitoring Commission. The RV₉₅ (rounded values) for phthalate metabolites in children and adolescents aged 6–15 years are 110?μg/l (confidence interval of 95th population percentile: 83.7–163) for mono-ethyl phthalate (MEP), 45?μg/l (40.9–60.6) for mono-n-butyl phthalate (MnBP), 130?μg/l (126–161) for mono-isobutyl phthalate (MiBP), 25?μg/l (17.8–33.6) for mono-benzyl phthalate (MBzP), 100?μg/l (94.0–126) for the sum of the di(2-ethylhexyl) phthalate (DEHP) metabolites including mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (5OH-MEHP), mono(2-ethyl-5-oxohexyl) phthalate (5oxo-MEHP) and mono(2-ethyl-5-carboxypentyl) phthalate (5cx-MEPP), and 1.5?μg/l (0.64–1.6) for mono-cyclohexyl phthalate (MCHP). In adults aged 18–81 years, RV₉₅ are 440?μg/l (353–636) for MEP, 40?μg/l (33.1–52.1) for MnBP, 110?μg/l (87.3–118) for MiBP, 10?μg/l (7.2–11.8) for MBzP, 50?μg/l (44.6–68.3) for the sum of MEHP, 5OH-MEHP, 5oxo-MEHP and 5cx-MEPP, and 1.5?μg/l (0.95–1.8) for MCHP. For almost all investigated metabolites, children and adolescents exhibit higher RV₉₅ than adults, with the exceptions being MEP and MCHP. Compared to available RV₉₅ for Germany and Canada, Austrian values are lower for all investigated population groups.     

Trends of the internal phthalate exposure of young adults in Germany—Follow-up of a retrospective human biomonitoring study

The exposure of the general population to phthalates is of increasing public health concern. Variations in the internal exposure of the population are likely, because the amounts, distribution and application characters of the phthalate use change over time. Estimating the chronological sequences of the phthalate exposure, we performed a retrospective human biomonitoring study by investigating the metabolites of the five most prominent phthalates in urine. Therefore, 24 h-urine samples from the German Environmental Specimen Bank (ESB) collected from 240 subjects (predominantly students, age range 19–29 years, 120 females, 120 males) in the years 2002, 2004, 2006 and 2008 (60 individuals each), were analysed for the concentrations of mono-n-butyl phthalate (MnBP) as metabolite of di-n-butyl phthalate (DnBP), mono-iso-butyl phthalate (MiBP) as metabolite of di-iso-butyl phthalate (DiBP), mono-benzyl phthalate (MBzP) as metabolite of butylbenzyl phthalate (BBzP), mono-(2-ethylhexyl) phthalate (MEHP), 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-MMHxP) as metabolites of di(2-ethylhexyl) phthalate (DEHP), monohydroxylated (OH-MiNP), monooxidated (oxo-MiNP) and monocarboxylated (cx-MiNP) mono-iso-nonylphthalates as metabolites of di-iso-nonyl phthalates (DiNP). Based on the urinary metabolite excretion, together with results of a previous study, which covered the years 1988–2003, we investigated the chronological sequences of the phthalate exposure over two decades. In more than 98% of the urine samples metabolites of all five phthalates were detectable indicating a ubiquitous exposure of people living in Germany to all five phthalates throughout the period investigated. The medians in samples from the different years investigated are 65.4 (2002), 38.5 (2004), 29.3 (2006) and 19.6 μg/l (2008) for MnBP, 31.4 (2002), 25.4 (2004), 31.8 (2006) and 25.5 μg/l (2008) for MiBP, 7.8 (2002), 6.3 (2004), 3.6 (2006) and 3.8 μg/l (2008) for MBzP, 7.0 (2002), 5.6 (2004), 4.1 (2006) and 3.3 μg/l (2008) for MEHP, 19.6 (2002), 16.2 (2004), 13.2 (2006) and 9.6 μg/l (2008) for 5OH-MEHP, 13.9 (2002), 11.8 (2004), 8.3 (2006) and 6.4 μg/l (2008) for 5oxo-MEHP, 18.7 (2002), 16.5 (2004), 13.8 (2006) and 10.2 μg/l (2008) for 5cx-MEPP, 7.2 (2002), 6.5 (2004), 5.1 (2006) and 4.6 μg/l (2008) for 2cx-MMHxP, 3.3 (2002), 2.8 (2004), 3.5 (2006) and 3.6 μg/l (2008) for OH-MiNP, 2.1 (2002), 2.1 (2004), 2.2 (2006) and 2.3 μg/l (2008) for oxo-MiNP and 4.1 (2002), 3.2 (2004), 4.1 (2006) and 3.6 μg/l (2008) for cx-MiNP. The investigation of the time series 1988–2008 indicates a decrease of the internal exposure to DnBP by the factor of 7–8 and to DEHP and BzBP by the factor of 2–3. In contrast, an increase of the internal exposure by the factor of 4 was observed for DiNP over the study period. The exposure to DiBP was found to be stable. In summary, we found decreases of the internal human exposure for legally restricted phthalates whereas the exposure to their substitutes increased. Future investigations should verify these trends. This is of increasing importance since the European Commission decided to require ban or authorization from 1.1.2015 for DEHP, DnBP, DiBP and BzBP according to REACh Annex XIV.     

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 microg/kgbody weight (bw)/day and a 95th percentile of 25.2 or 15.2 microg/kgbw/day. Three children (1%) exceeded the value of the tolerable daily intake (TDI) of the European Food Safety Authority of 50 microg/kgbw/day, while 7.5% or 3% (depending on the calculation model) exceeded the reference dose (RfD) of 20 microg/kgbw/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.     

Exposure to phthalates in neonatal intensive care unit infants: urinary concentrations of monoesters and oxidative metabolites

OBJECTIVE: We previously demonstrated that among 54 infants in neonatal intensive care units, exposure to polyvinyl chloride plastic medical devices containing the plasticizer di(2-ethylhexyl) phthalate (DEHP) is associated with urinary concentrations of mono(2-ethylhexyl) phthalate (MEHP) , a DEHP metabolite. In this follow-up report, we studied the neonates' exposure to DEHP-containing devices in relation to urinary concentrations of two other DEHP metabolites, and to urinary concentrations of metabolites of dibutyl phthalate (DBP) and benzylbutyl phthalate (BzBP) , phthalates found in construction materials and personal care products. MEASUREMENTS: A priori, we classified the intensiveness of these 54 infants' exposure to DEHP-containing medical products. We measured three metabolites of DEHP in infants' urine: MEHP and two of its oxidative metabolites, mono(2-ethyl-5-hydroxylhexyl) phthalate (MEHHP) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) . We also measured monobutyl phthalate (MBP) , a metabolite of DBP, and monobenzyl phthalate (MBzP), a metabolite of BzBP. RESULTS: Intensiveness of DEHP-containing product use was monotonically associated with all three DEHP metabolites. Urinary concentrations of MEHHP and MEOHP among infants in the high-DEHP-intensiveness group were 13-14 times the concentrations among infants in the low-intensiveness group (p相似文献   

Metabolites of the plasticizer di (2-ethylhexyl) phthalate in urine samples of workers in polyvinylchloride processing industries

Summary Little is known about occupational exposure to the plasticizer di(2-ethylhexyl)phthalate (CAS number 117-81-7), a compound widely used in polyvinylchloride (PVC) plastics. We have studied the uptake of DEHP in workers by determining the concentrations of four metabolites of DEHP in urine samples, i.e., mono(2-ethylhexyl)phthalate (MEHP), mono (5-carboxy-2-ethylpentyl)phthalate, mono(2-ethyl-5-oxohexyl)phthalate, and mono(2-ethyl-5-hydroxyhexyl)phthalate. In addition DEHP concentrations in the air were determined by personal air sampling. Nine workers in a PVC boot factory exposed to a maximum of 1.2 mg/m³ DEHP showed an increase in the urinary concentrations of all four metabolites over the workshift. These results were obtained on both the first and the last day of the workweek. With the exception of MEHP, the increases in the concentrations of the metabolites during a workday were statistically significant. Six workers from a PVC cable factory exposed to a maximum of 1.2 mg/m³ DEHP showed a one-to fourfold increase in the concentrations of the four metabolites over the workshift, but these increases were not statistically significant. These results indicate that measurement of DEHP metabolites in urine samples may be of use for monitoring the occupational exposure to DEHP.     

Determination of four metabolites of the plasticizer di (2-ethylhexyl) phthalate in human urine samples

Summary A method for biological monitoring of exposure to the plasticizer di(2-ethylhexyl)phthalate (DEHP) is described. In this method the four main metabolites of DEHP [i.e., mono (2-ethylhexyl) phthalate (MEHP), mono (5-carboxy-2-ethylpentyl)phthalate, mono(2-ethyl-5-oxohexyl)phthalate, and mono(2-ethyl-5-hydroxyhexyl)-phthalate] are determined in urine samples. The procedure includes enzymatic hydrolysis, ether extraction, and derivatization with triethyloxonium tetrafluoroborate. Analysis is performed by gas chromatography electron impact mass spectrometry. The detection limit for all four metabolites is less than 25 g/l urine. The coefficient of variation based on duplicate determinations of urine samples of workers occupationally exposed to DEHP was 16% for MEHP (mean concentration 0.157 mg/l) and 6% -9% for the other three metabolites (mean concentrations 0.130-0.175 mg/1). The method described here was used to study DEHP metabolism in man. Most persons excrete mono(2-ethyl-5-oxohexyl)-phthalate and mono (2-ethyl-5-hydroxyhexyl)phthalate as a (glucuronide) conjugate. Mono (5-carboxy-2-ethyl-pentyl)phthalate is mainly excreted in free form, while for MEHP a large interindividual variation in conjugation status was observed. Of the four metabolites quantified, 52% are products of a ((-l)-hydroxylation reaction of MEHP [i.e., mono (2-ethyl-5-oxohexyl)phthalate and mono (2-ethyl-5-hydroxyhexyl)phthalate], 22% is the product of a -hydroxylation reaction of MEHP [i.e., mono (5-carboxy-2-ethylpentyl)phthalate], and 26% is not oxidized further (i.e., MEHP). A good correlation is obtained when the amount of MEHP -hydroxylation products is compared with the amount of MEHP (-1)hydroxylation products in urine samples. When the internal dose of DEHP has to be established we recommend that the levels of all four metabolites of DEHP be studied in urine samples.     

Estimation of intake level of di (2-ethyhexyl) phthalate (DEHP) in Japanese pregnant women based on measurement of concentrations of three urinary metabolites

OBJECTIVES: [corrected] The daily intake level of di (2-ethyhexyl) phthalate (DEHP) of Japanese pregnant women was estimated on the basis of the measurement of the urinary concentrations of three DEHP metabolites. METHODS: Spot urine samples were collected from 42 pregnant women who visited the gynecology division of a hospital for routine health check between June and October, 2003. The urinary concentrations of three DEHP metabolites, namely, mono (2-ethyhexyl) phthalate (MEHP), mono (2-ethy-5-hydroxyhexyl) phthalate (MEHHP), and mono (2-ethyl-5-oxohexyl) phthalate (MEOHP) were measured by HPLC/MS/MS. RESULTS: The concentrations of urinary MEHP, MEOHP and MEHHP (n=40) were 3.27-39.5 (median 9.83), 1.51-41.0 (median 10.4) and 4.6-26.6 (median 10.9) microg/g cre, respectively. The ranges of the estimated daily intake of DEHP per body weight based on the MEHP, MEOHP and MEHHP concentrations (n=40) were 3.45-41.6 (median 10.4), 0.66-17.9 (median 4.55) and 1.47-8.57 (median 3.51) microg/kg/day, respectively. The maximum estimated intake level per body weight (41.6 microg/kg/day) reached the Tolerable Daily Intake (TDI) level of 40-140 microg/kg/day set by the Ministry of Health and Welfare (now the Ministry of Health, Labour and Welfare). CONCLUSIONS: The health risk of DEHP exposure of our study subjects was found to be minimum from the viewpoint of the current knowledge of its risk level, although the human health effects of low-level DEHP exposure have to be studied further.     

Fetal exposure to phthalates – a pilot study

The fetus is considered to be the most sensitive stage of life to the potential developmental and reproductive toxicity of the phthalates. But, data on human fetal exposure to phthalates is still scarce. In this pilot study we collected 11 pairs of amniotic fluid (AF) and corresponding maternal urine (MU) samples during Caesarean section and analysed them for several phthalate metabolites by LC-MS/MS. In all AF samples, metabolites of di-n-butyl phthalate (DnBP), diisobutyl phthalate (DiBP), butylbenzyl phthalate (BBzP), di(2-ethylhexyl) phthalate (DEHP) were detectable. For the first time, we were able to detect also oxidative phthalate metabolites in AF, with two carboxy metabolites of DEHP showing the highest abundance. In the MU samples, the concentrations of the phthalate metabolites were generally much higher than in the AF samples. There was a statistically significant linear correlation for the DiBP monoester (MiBP) (r=0.93; p<0.001) in the AF and MU samples. We also found a significant correlation for the DEHP monoester (MEHP) (r=0.91; p<0.001), although there was a most likely external contamination with MEHP in the MU samples. Our results suggest that several phthalates or their metabolites, respectively, reach the human fetus, which might be able to affect fetal health. Further research is needed to elucidate fetal metabolism of phthalates and to evaluate the in utero phthalate exposure and the potential effects on fetal reproductive development. Due to the continuous turn over of AF, urinary levels may be most appropriate for assessing both maternal and fetal phthalate exposure.     

Relationship between Environmental Phthalate Exposure and the Intelligence of School-Age Children

Background

Concern over phthalates has emerged because of their potential toxicity to humans.

Objective

We investigated the relationship between the urinary concentrations of phthalate metabolites and children’s intellectual functioning.

Methods

This study enrolled 667 children at nine elementary schools in five South Korean cities. A cross-sectional examination of urine phthalate concentrations was performed, and scores on neuropsychological tests were obtained from both the children and their mothers.

Results

We measured mono-2-ethylhexyl phthalate (MEHP) and mono(2-ethyl-5-oxohexyl)phthalate (MEOHP), both metabolites of di(2-ethylhexyl)phthalate (DEHP), and mono-n-butyl phthalate (MBP), a metabolite of dibutyl phthalate (DBP), in urine samples. The geometric mean (ln) concentrations of MEHP, MEOHP, and MBP were 21.3 μg/L [geometric SD (GSD) = 2.2 μg/L; range, 0.5–445.4], 18.0 μg/L (GSD = 2.4; range, 0.07–291.1), and 48.9 μg/L (GSD = 2.2; range, 2.1–1645.5), respectively. After adjusting for demographic and developmental covariates, the Full Scale IQ and Verbal IQ scores were negatively associated with DEHP metabolites but not with DBP metabolites. We also found a significant negative relationship between the urine concentrations of the metabolites of DEHP and DBP and children’s vocabulary subscores. After controlling for maternal IQ, a significant inverse relationship between DEHP metabolites and vocabulary subscale score remained. Among boys, we found a negative association between increasing MEHP phthalate concentrations and the sum of DEHP metabolite concentrations and Wechsler Intelligence Scale for Children vocabulary score; however, among girls, we found no significant association between these variables.

Conclusion

Controlling for maternal IQ and other covariates, the results show an inverse relationship between phthalate metabolites and IQ scores; however, given the limitations in cross-sectional epidemiology, prospective studies are needed to fully explore these associations.     

Assessing human exposure to phthalates using monoesters and their oxidized metabolites as biomarkers

Phthalates are a group of industrial chemicals with many commercial uses, such as solvents, additives, and plasticizers. For example, di-(2-ethylhexyl) phthalate (DEHP) is added in varying amounts to certain plastics, such as polyvinyl chloride, to increase their flexibility. In humans, phthalates are metabolized to their respective monoesters, conjugated, and eliminated. However, despite the high production and use of DEHP, we have recently found that the urinary levels of the DEHP metabolite mono-(2-ethylhexyl) phthalate (MEHP) in 2,541 persons in the United States were lower than we anticipated, especially when compared with urinary metabolite levels of other commonly used phthalates. This finding raised questions about the sensitivity of this biomarker for assessing DEHP exposure. We explored the utility of two other DEHP metabolites, mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) and mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), as additional DEHP biomarkers. These metabolites are formed by oxidative metabolism of MEHP. In urine from 62 people, both the range and the mean urinary levels of MEOHP and MEHHP were on average 4-fold higher than those of MEHP; the mean of the individual ratios of MEHHP/MEOHP, MEHHP/MEHP, and MEOHP/MEHP were 1.4, 8.2, and 5.9, respectively. These data suggest that MEOHP and MEHHP are more sensitive biomarkers of exposure to DEHP than is MEHP. These findings also suggest a predominant human metabolic route for DEHP hydrolysis to MEHP followed by oxidation of MEHP; they also imply that a similar mechanism may be relevant for other high-molecular-weight phthalates, such as di-n-octyl, di-isononyl, and di-isodecyl phthalates.     

Internal phthalate exposure over the last two decades--a retrospective human biomonitoring study

In a retrospective human biomonitoring study we analyzed 24h urine samples taken from the German Environmental Specimen Bank for Human Tissues (ESBHum), which were collected from 634 subjects (predominantly students, age range 20-29 years, 326 females, 308 males) in 9 years between 1988 and 2003 (each n >or= 60), for the concentrations of primary and/or secondary metabolites of di-n-butyl phthalate (DnBP), di-iso-butyl phthalate (DiBP), butylbenzyl phthalate (BBzP), di(2-ethylhexyl) phthalate (DEHP) and di-iso-nonyl phthalate (DiNP). Based on the urinary metabolite excretion we estimated daily intakes of the parent phthalates and investigated the chronological course of the phthalate exposure. In over 98% of the urine samples metabolites of all five phthalates were detectable indicating a ubiquitous exposure of the German population to all five phthalates throughout the last 20 years. The median daily intakes in the subsets between 1988 and 1993 were quite constant for DnBP (approx. 7 microg/kg bw/d) and DEHP (approx. 4 microg/kg bw/d). However, from 1996 the median levels of both phthalates decreased continuously until 2003 (DnBP 1.9 microg/kg bw/d; DEHP 2.4 microg/kg bw/d). By contrast, the daily intake values for DiBP were slightly increasing over the whole time frame investigated (median 1988: 1.1 microg/kg bw/d; median 2003: 1.4 microg/kg bw/d), approximating the levels for DnBP and DEHP. For BBzP we observed slightly decreasing values, even though the medians as of 1998 levelled off at around 0.2 microg/kg bw/d. Regarding daily DiNP exposure we found continuously increasing values, with the lowest median being 0.20 microg/kg bw/d for the subset of 1988 and the highest median for 2003 being twice as high. The trends observed in phthalate exposure may be associated with a change in production and usage pattern. Female subjects exhibited significantly higher daily intakes for the dibutyl phthalates (DnBP p=0.013; DiBP p=0.004). Compared to data from US National Health and Nutrition Examination Surveys (NHANES) exposure levels of the dibutyl phthalates were generally higher in our German study population, while levels of BBzP were somewhat lower. Overall, for a considerable 14% of the subjects we observed daily DnBP intakes above the tolerable daily intake (TDI) value deduced by the European Food Safety Authority (EFSA) (10 microg/kg bw/d). However, the frequency of exceedance decreased during the years and was beneath 2% in the 2003 subset. Even though transgressions of the exposure limit values of the EFSA and the US Environmental Protection Agency (US EPA) occurred only in a relatively small share of the subjects, one has to take into account the cumulative exposure to all phthalates investigated and possible dose-additive endocrine effects of these phthalates.     

Prenatal exposures to phthalates among women in New York City and Krakow, Poland

Experimental evidence has shown that certain phthalates can disrupt endocrine function and induce reproductive and developmental toxicity. However, few data are available on the extent of human exposure to phthalates during pregnancy. As part of the research being conducted by the Columbia Center for Children's Environmental Health, we have measured levels of phthalates in 48-hr personal air samples collected from parallel cohorts of pregnant women in New York, New York, (n = 30) and in Krakow, Poland (n = 30). Spot urine samples were collected during the same 48-hr period from the New York women (n = 25). The following four phthalates or their metabolites were measured in both personal air and urine: diethyl phthalate (DEP), dibutyl phthalate (DBP), diethylhexyl phthalate (DEHP), and butyl benzyl phthalate (BBzP). All were present in 100% of the air and urine samples. Ranges in personal air samples were as follows: DEP (0.26-7.12 microg/m3), DBP (0.11-14.76 microg/m3), DEHP (0.05-1.08 microg/m3), and BBzP (0.00-0.63 microg/m3). The mean personal air concentrations of DBP, di-isobutyl phthalate, and DEHP are higher in Krakow, whereas the mean personal air concentration of DEP is higher in New York. Statistically significant correlations between personal air and urinary levels were found for DEP and monoethyl phthalate (r = 0.42, p < 0.05), DBP and monobutyl phthalate (r = 0.58, p < 0.01), and BBzP and monobenzyl phthalate (r = 0.65, p < 0.01). These results demonstrate considerable phthalate exposures during pregnancy among women in these two cohorts and indicate that inhalation is an important route of exposure.     

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

Objectives

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.

Methods

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.

Results

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.

Conclusion

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.