Levels of phthalate metabolites in urine among mother-child-pairs - results from the Duisburg birth cohort study, Germany.

Phthalates are used ubiquitously and human exposure is widespread. Some phthalates are anti-androgens and have to be regarded as reproductive and developmental toxicants. In the Duisburg birth cohort study we examine the associations between hormonally active environmental agents and child development. Here we report the concentrations of 21 primary and secondary phthalate metabolites from seven low molecular weight (LMW) phthalates (DMP, DEP, BBzP, DiBP, DnBP, DCHP, DnPeP) and five high-molecular weight (HMW) phthalates (DEHP, DiNP, DiDP, DPHP, DnOP) in 208 urine samples from 104 mothers and their school-aged children. Analysis was performed by multidimensional liquid chromatography coupled to tandem mass spectrometry (LC/LC-MS/MS), using internal isotope-labeled standards. In both children and mothers, 18 out of 21 phthalate metabolites were detected above the limits of quantification (between 0.2 and 1.0 μg/l) in nearly all urine samples. Among the LMW phthalates, the excretion level (geometric mean) of the ΣDiBP metabolites was most prominent in children (103.9 μg/l), followed by ΣDnBP (56.5 μg/l), and MEP (39.1 μg/l). In mothers ΣDiBP (66.6 μg/l) was highest, followed by MEP (50.5 μg/l), and ΣDnBP (36.0 μg/l). Among the HMW phthalates, ΣDEHP was highest in children and mothers (55.7/28.9 μg/l). Compared to reference values derived from the German Human Biomonitoring Commission, children's metabolite concentrations were within background levels, whereas for mothers considerably higher exposure to the LMW phthalates DnBP and DiBP, and the HMW phthalate DEHP was detected (MiBP: 10.7%; MnBP: 11.7%; ΣDEHP: 23.3% of the samples were above the reference values). The LMW metabolites from DMP, DiBP, and DnBP, and the HMW metabolites from DEHP and DiNP were correlated between the mothers and children, probably indicating shared exposure in the immediate surrounding environment. Children showed higher excretion levels for most of the secondary metabolites than mothers, confirming previous findings on higher oxidized metabolite levels in children. The LMW metabolites ΣDiBP, ΣDnBP, and MMP, and the HMW metabolites ΣDEHP were negatively associated with children's age. The LMW metabolites ΣDiBP, ΣDnBP, and MBzP were inversely associated with body mass index of the children. The LMW ΣDiBP metabolites revealed a significant association with nicotine metabolites in urine from both children and mothers. Further analyses are ongoing to study long-term phthalate exposure and the associations with puberty outcome in these children.

Kasper-Sonnenberg M ，Koch HM ，Wittsiepe J ，Wilhelm M ... -  《-》

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, 24h-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.

Göen T ，Dobler L ，Koschorreck J ，Müller J ，Wiesmüller GA ，Drexler H ，Kolossa-Gehring M ... -  《-》

Identifying sources of phthalate exposure with human biomonitoring: results of a 48h fasting study with urine collection and personal activity patterns.

Human biomonitoring studies measuring phthalate metabolites in urine have shown widespread exposure to phthalates in the general population. Diet is thought to be a principle route of exposure to many phthalates. Therefore, we studied urinary phthalate metabolite patterns over a period of strict fasting and additionally recorded personal activity patterns with a diary to investigate non-dietary routes of exposure. Five individuals (3 female, 2 male, 27-47 years of age) fasted on glass-bottled water only over a 48-h period. All urine void events were captured in full, and measured for metabolites of the high molecular weight (HMW) di-(2-ethylhexyl) phthalate (DEHP), di-isononyl phthalate (DINP) and di-isodecyl phthalate (DiDP), and the low molecular weight (LMW) di-n-butyl phthalate (DnBP), di-iso-butyl phthalate (DiBP), butylbenzyl phthalate (BBzP), dimethyl phthalate (DMP), and diethyl phthalate (DEP). In all, 21 metabolites were measured in a total of 118 urine events, including events before and after the fasting period. At the onset of the study all phthalate metabolite concentrations were consistent with levels found in previous general population studies. Metabolites of the HMW phthalates (DEHP, DiNP and DiDP) showed a rapid decline to levels 5-10 times lower than initial levels within 24h of the fast and remained low thereafter. After food consumption resumed, levels rose again. By contrast, metabolites of the LMW phthalates including DMP, DEP, BBzP, DnBP and DiBP showed a cyclical pattern of rising and declining concentrations suggestive of ongoing non-food exposures. Furthermore, metabolites of most of the LMW phthalates (BBzP, DnBP and DiBP) tracked each other remarkably well, suggesting concurrent exposures. Diary entries could not help explain exposure sources for these phthalates, with one exception: rises in MEP concentrations around males' showers suggest personal care products as a major source of DEP. Exposure to HMW phthalates in this cohort appears to be driven by dietary intake, while non-dietary routes such as use of personal care products and ubiquitous sources including dust and indoor air appear to explain exposure to LMW phthalates.

Koch HM ，Lorber M ，Christensen KL ，Pälmke C ，Koslitz S ，Brüning T ... -  《-》

Biomonitoring of phthalate metabolites in the Canadian population through the Canadian Health Measures Survey (2007-2009).

Human exposure to phthalates occurs through multiple sources and pathways. In the Canadian Health Measures Survey 2007-2009, 11 phthalate metabolites, namely, MMP, MEP, MnBP, MBzP, MCHP, MCPP, MEHP, MEOHP, MEHHP, MnOP, and MiNP were measured in urine samples of 6-49 year old survey respondents (n=3236). The phthalate metabolites biomonitoring data from this nationally-representative Canadian survey are presented here. The metabolites MEP, MnBP, MBzP, MCPP, MEHP, MEOHP and MEHHP were detected in >90% of Canadians while MMP, MCHP, MnOP and MiNP were detected in <20% of the Canadian population. Step-wise regression analyses were carried out to identify important predictors of volumetric concentrations (μg/L) of the metabolites in the general population. Individual multiple regression models with covariates age, sex, creatinine, fasting status, and the interaction terms age×creatinine, age×sex and fasting status×creatinine were constructed for MEP, MnBP, MBzP, MCPP, MEHP, MEOHP and MEHHP. The least square geometric mean (LSGM) estimates for volumetric concentration (μg/L) of the metabolites derived from respective regression models were used to assess the patterns in the metabolite concentrations among population sub-groups. The results indicate that children had significantly higher urinary concentrations of MnBP, MBzP, MEHP, MEHHP, MEOHP and MCPP than adolescents and adults. Moreover, MEP, MBzP, MnBP and MEOHP concentrations in females were significantly higher than in males. We observed that fasting status significantly affects the concentrations of MEHP, MEHHP, MEOHP, and MCPP metabolites analyzed in this study. Moreover, our results indicate that the sampling time could affect the DEHP metabolite concentrations in the general Canadian population.

Saravanabhavan G ，Guay M ，Langlois É ，Giroux S ，Murray J ，Haines D ... -  《-》

Phthalate metabolites in urine of children and adolescents in Germany. Human biomonitoring results of the German Environmental Survey GerES V, 2014-2017.

During the population representative German Environmental Survey of Children and Adolescents (GerES V, 2014-2017) 2256 first-morning void urine samples from 3 to 17 years old children and adolescents were analysed for 21 metabolites of 11 different phthalates (di-methyl phthalate (DMP), di-ethyl phthalate (DEP), butylbenzyl phthalate (BBzP), di-iso-butyl phthalate (DiBP), di-n-butyl phthalate (DnBP), di-cyclohexyl phthalate (DCHP), di-n-pentyl phthalate (DnPeP), di-(2-ethylhexyl) phthalate (DEHP), di-iso-nonyl phthalate (DiNP), di-iso-decyl phthalate (DiDP) and di-n-octyl phthalate (DnOP)). Metabolites of DMP, DEP, BBzP, DiBP, DnBP, DEHP, DiNP and DiDP were found in 97%-100% of the participants, DCHP and DnPeP in 6%, and DnOP in none of the urine samples. Geometric means (GM) were highest for metabolites of DiBP (MiBP: 26.1 μg/L), DEP (MEP: 25.8 μg/L), DnBP (MnBP: 20.9 μg/L), and DEHP (cx-MEPP: 11.9 μg/L). For all phthalates but DEP, GMs were consistently higher in the 3-5 years old children than in the 14-17 years old adolescents. For DEHP, the age differences were most pronounced. All detectable phthalate biomarker concentrations were positively associated with the levels of the respective phthalate in house dust. In GerES V we found considerably lower phthalate biomarker levels than in the preceding GerES IV (2003-2006). GMs of biomarker levels in GerES V were only 18% (BBzP), 23% (MnBP), 23% (DEHP), 29% (MiBP) and 57% (DiNP) of those measured a decade earlier in GerES IV. However, some children and adolescents still exceeded health-based guidance values in the current GerES V. 0.38% of the participants had levels of DnBP, 0.08% levels of DEHP and 0.007% levels of DiNP which were higher than the respective health-based guidance values. Accordingly, for these persons an impact on health cannot be excluded with sufficient certainty. The ongoing and substantial exposure of vulnerable children and adolescents to many phthalates confirms the need of a continued monitoring of established phthalates, whether regulated or not, as well as of potential substitutes. With this biomonitoring approach we provide a picture of current individual and cumulative exposure developments and body burdens to phthalates, thus providing support for timely and effective chemicals policies and legislation.

Schwedler G ，Rucic E ，Lange R ，Conrad A ，Koch HM ，Pälmke C ，Brüning T ，Schulz C ，Schmied-Tobies MIH ，Daniels A ，Kolossa-Gehring M ... -  《-》