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Background Bisphenol A (BPA) is an industrial chemical mostly used in the manufacture of plastics, resins and thermal paper. Several studies have reported adverse health effects with BPA exposures, namely metabolic disorders and altered neurodevelopment in children, among others. The aim of this study was to explore BPA exposure, its socio-demographic and life-style related determinants, and its association with neurodevelopmental outcomes in early school age children from Poland. Methods A total of 250 urine samples of 7 year-old children from the Polish Mother and Child Cohort Study (REPRO_PL) were analyzed for BPA concentrations using high performance liquid chromatography with online sample clean-up coupled to tandem mass spectrometry (online-SPE-LC-MS/MS). Socio-demographic and lifestyle-related data was collected by questionnaires or additional biomarker measurements. Emotional and behavioral symptoms in children were assessed using mother-reported Strengths and Difficulties Questionnaire (SDQ). Cognitive and psychomotor development was evaluated by Polish adaptation of the Intelligence and Development Scales (IDS) performed by trained psychologists. Results Urinary BPA concentrations and back-calculated daily intakes (medians of 1.8 μg/l and 46.3 ng/kg bw/day, respectively) were similar to other European studies. Urinary cotinine levels and body mass index, together with maternal educational level and socio-economic status, were the main determinants of BPA levels in Polish children. After adjusting for confounding factors, BPA has been found to be positively associated with emotional symptoms (β: 0.14, 95% CI: 0.022; 0.27). Cognitive and psychomotor development were not found to be related to BPA levels. Conclusions This study represents the first report of BPA levels and their determinants in school age children in Poland. The exposure level was found to be related to child emotional condition, which can have long-term consequences including social functioning and scholastic achievements. Further monitoring of this population in terms of overall chemical exposure is required.

E-mail addresses: kvo@envs.au.dk (K. Vorkamp), Castano@isciii.es (A. Castaño), Jean-Philippe.Antignac@oniris-nantes.fr (J.-P. Antignac), Luis.Boada@ulpgc.es (L.D. Boada), ECequier@quimica.udl.cat (E. Cequier), Adrian.Covaci@uantwerpen.be (A. Covaci), M.Esteban@isciii.es (M. Esteban López), LineSmastuen.Haug@fhi.no (L.S. Haug), Kasper@ipa-dguv.de (M. Kasper-Sonnenberg), Koch@ipa-dguv.de (H.M. Koch), Octavio.Perez@ulpgc.es (O. Pérez Luzardo), Agnese.Osite@lu.lv (A. Osīte), Loic.Rambaud@santepubliquefrance.fr (L. Rambaud), mtpin@ticino.com (M.-T. Pinorini), Gabriele.Sabbioni@bluewin.ch (G. Sabbioni), Cathrine.Thomsen@fhi.no (C. Thomsen).; International audience; The major purpose of human biomonitoring is the mapping and assessment of human exposure to chemicals. The European initiative HBM4EU has prioritized seven substance groups and two metals relevant for human exposure: Phthalates and substitutes (1,2-cyclohexane dicarboxylic acid diisononyl ester, DINCH), bisphenols, perand polyfluoroalkyl substances (PFASs), halogenated and organophosphorous flame retardants (HFRs and OPFRs), polycyclic aromatic hydrocarbons (PAHs), arylamines, cadmium and chromium. As a first step towards comparable European-wide data, the most suitable biomarkers, human matrices and analytical methods for each substance group or metal were selected from the scientific literature, based on a set of selection criteria. The biomarkers included parent compounds of PFASs and HFRs in serum, of bisphenols and arylamines in urine, metabolites of phthalates, DINCH, OPFRs and PAHs in urine as well as metals in blood and urine, with a preference to measure Cr in erythrocytes representing Cr (VI) exposure. High performance liquid chromatographytandem mass spectrometry (LC-MS/MS) was the method of choice for bisphenols, PFASs, the HFR hexabromocyclododecane (HBCDD), phenolic HFRs as well as the metabolites of phthalates, DINCH, OPFRs and PAHs in urine. Gas chromatographic (GC) methods were selected for the remaining compounds, e.g. GC-low resolution MS with electron capture negative ionization (ECNI) for HFRs. Both GC-MS and LC-MS/MS were suitable for arylamines. New developments towards increased applications of GC-MS/MS may offer alternatives to GC-MS or LC-MS/MS approaches, e.g. for bisphenols. The metals were best determined by inductively coupled plasma (ICP)-MS, with the particular challenge of avoiding interferences in the Cd determination in urine. The evaluation process revealed research needs towards higher sensitivity and non-invasive sampling as well as a need for more stringent quality assurance/quality control applications and assessments.

N-methyl-2-pyrrolidone (NMP) and its substitute N-ethyl-2-pyrrolidone (NEP) are aprotic solvents used in many technical applications, but also in carpets, and consumer products such as cleaning agents, and cosmetics. NMP and NEP are classified as reproductive toxicants. As a substance of very high concern (SVHC), NMP is included in the European REACH (Registration, Evaluation, Authorisation of Chemicals) candidate list for authorisation. NMP and NEP metabolites were measured in more than 2100 urine samples of 3- to 17-year-old children and adolescents, participating in the population-representative German Environmental Survey for Children and Adolescents 2014–2017 (GerES V). The two NMP metabolites 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP) and 2-hydroxy-N-methylsuccinimide (2-HMSI) could be detected and quantified in all urine samples, and the two NEP metabolites 5-hydroxy-N-ethylpyrrolidone (5-HNEP) and 2-hydroxy-N-ethylsuccinimide (2-HESI) in 32% and 87% of the urine samples. Geometric mean concentrations were 103.1 µg/L (88.21 µg/gcreatinine) for the sum of NMP metabolites and 11.86 µg/L (10.15 µg/gcreatinine) for the sum of NEP metabolites, thus remaining below the current health-based human biomonitoring values. For NMP, highest exposure was found in young children, but exposure pathways could not be revealed. Exposure to NEP was highest in adolescents and participants with low socio-economic status or migration background. Associations to usage of personal care products suggested the choice of products to have a distinct impact on NEP exposure. The presented data can be used by the German Human Biomonitoring Commission to derive new reference values (RV95) for NMP and NEP for children and adolescents in Germany. This will facilitate to recognise changing exposure levels in this population group in Germany.

The aim of this interdisciplinary research project in North Rhine-Westphalia (NRW), Germany, entitled “Elimination of pharmaceuticals and organic micropollutants from waste water” involved the conception of cost-effective and innovative waste-water cleaning methods. In this project in vitro assays, in vivo assays and chemical analyses were performed on three municipal waste-water treatment plants (WWTP). This publication focuses on the study of the in vitro bioassays. Cytotoxic, estrogenic, genotoxic and mutagenic effects of the original as well as enriched water samples were monitored before and after wastewater treatment steps using MTT and PAN I, ER Calux and A-YES, micronucleus and Comet assays as well as AMES test. In most cases, the measured effects were reduced after ozonation, but in general, the biological response depended upon the water composition of the WWTP, in particular on the formed by-products and concentration of micropollutants. In order to be able to assess the genotoxic and/or mutagenic potential of waste-water samples using bioassays like Ames test, Comet assay or micronucleus test an enrichment of the water sample via solid-phase extraction is recommended. This is in agreement with previous studies such as the “ToxBox”-Project of the Environmental Agency in Germany.

Exposure to environmental phenols such as bisphenol A, benzophenones, 2-phenylphenol, triclosan, and triclocarban is of concern, because of their endocrine disrupting properties and broad application in consumer products. The current body burden of the 3–17-year-old population in Germany to these substances was assessed in first-morning void urine samples (N = 515–516) collected within the population-representative German Environmental Survey for Children and Adolescents 2014–2017 (GerES V). Bisphenol A was the most prominent phenol analysed here, ubiquitously found in almost all samples with a geometric mean (GM) concentration of 1.905 μg/L (1.669 μg/gcreatinine) and a maximum (MAX) urinary concentration of 399 μg/L. Benzophenone-3 and benzophenone-1 were quantified in 35% and 41% of the samples. GM was below the limit of quantification (LOQ) for benzophenone-3 and 0.559 μg/L (0.489 μg/gcrea) for benzophenone-1, MAX concentrations were 845 μg/L and 202 μg/L, respectively. In 16% of the samples triclosan was found in quantifiable amounts resulting in a GM below LOQ and a MAX concentration of 801 μg/L. Benzophenone-8, 2-phenylphenol and triclocarban were quantified in none or only 1% of the samples. Benzophenone-1 and -3 concentrations were found to be associated with frequent application of personal care products. A comparison with the previous cycle of the survey, GerES IV (2003–2006), showed a decrease of urinary bisphenol A concentrations, mainly in young children. Despite this decrease, the concentration of bisphenol A exceeded the human biomonitoring (HBM) value HBM-I of 0.1 mg/L in 0.11% of the samples. For triclosan, all urinary concentrations were well below the HBM-I value of 2 mg/L. To minimise environmental health risks, it is therefore necessary to maintain a further declining trend for bisphenol A and continue monitoring the exposure to environmental phenols, as well as to monitor substitutes such as bisphenol F and S.

Parabens are antimicrobial preservatives used in a wide range of consumer products such as personal care products, cosmetics, pharmaceuticals, and food. Consequently, the general population is ubiquitously exposed to these substances via dermal absorption, ingestion, and inhalation. Parabens promote estrogenic activity and are hence under assessment as endocrine disrupting substances. Urine samples from 3- to 17-year-old children and adolescents (N = 516) living in Germany were analysed for concentrations of nine parabens in the population representative German Environmental Survey for Children and Adolescents 2014–2017 (GerES V). Detection rates and urinary concentrations of the parabens decreased with increasing length of the alkyl chain. Methyl paraben was quantified in 97% of the samples with a geometric mean (GM) concentration of 7.724 μg/L (6.714 μg/gcreatinine), ethyl paraben was quantified in 69% (GM: 0.943 μg/L and 0.825 μg/gcrea), and n-propyl paraben in 31% (GM: 0.563 μg/L and 0.493 μg/gcrea). Concentrations of iso-propyl paraben, butyl paraben, iso-butyl paraben, and benzyl paraben were below the limit of quantification in most samples. Pentyl paraben and heptyl paraben were not detected in any of the samples. Paraben concentrations in urine were found to be associated with frequent usage of leave-on personal care products and cosmetics. Cumulative exposure to parabens (back-calculated daily intakes, expressed as hazard index) was found to be on a level raising concern in up to 14% of the population, mainly driven by n-propyl paraben, and depending on the level of conservativeness and point-of departures used for calculation.

In several human biomonitoring surveys, changes in the usage patterns of phthalates have come to light, but their influence on the risks associated with combined exposures is insufficiently understood. Based on the largest study to date, the 27-year survey of urinary phthalate metabolite levels in 24-hour urine samples from the German Environmental Specimen Bank, we present a deep analysis of changing phthalate exposures on mixture risks. This analysis adopts the Hazard Index (HI) approach based on the five phthalates DBP, DIBP, BBP, DEHP and DINP. Calculations of the hazard index for each study participant included updated phthalate reference doses for anti-androgenicity (RfDAAs) that take account of new evidence of phthalates’ developmental toxicity. The Maximum Cumulative Ratio (MCR) approach was used to establish whether a subject’s combined exposure was dominated by one phthalate or was influenced by several phthalates simultaneously. Generally, over the years there was a shift towards lower HIs and higher MCRs, reflecting an increased complexity of the combined exposures. The decade from 1988 to about 1999 was characterised by rather high HIs of between 3 and 7 (95th percentile) which were driven by exposure to DBP and DEHP, often exceeding their single acceptable exposures. Traditional single phthalate risk assessments would have underestimated these risks by up to 50%. From 2006 onwards, no study participant experienced exposures above acceptable levels for a single phthalate, but combined exposures were still in excess of HI = 1. From 2011 onwards most individuals stayed below HI = 1. In interpreting these results, we caution against the use of HI = 1 as an acceptable limit and develop proposals for improved and more realistic mixture risk assessments that take account of co-exposures to other anti-androgenic substances also capable of disrupting the male reproductive system. From this perspective, we regard HIs between 0.1 and 0.2 as more appropriate for evaluating combined phthalate exposures. Assessed against lowered HIs of 0.1 – 0.2, the combined phthalate exposures of most study participants exceeded acceptable levels in all study years, including 2015. Continued monitoring efforts for phthalate combinations are required to provide the basis for appropriate risk management measures. Federal Ministry for the Environment, Nature Conservation, and Nuclear Safety (BMU), Germany; Horizon 2020 research and innovation programme

DINCH (cyclohexane-1,2-dicarboxylic acid-diisononyl ester) is a phthalate plasticizer substitute introduced into the market in 2002. It is increasingly used especially in the production of toys, food contact materials and medical devices. In this measurement campaign on 24-h urine samples of young adults (20–29 years) from the German Environmental Specimen Bank (ESB) collected in 2010, 2011, 2013, 2015 and 2017 (in total 300 samples, 60 samples/year) we analyzed three specific, oxidized DINCH metabolites (OH-MINCH: cyclohexane-1,2-dicarboxylic acid-mono(hydroxy-isononyl) ester; cx-MINCH: cyclohexane-1,2-dicarboxylic acid-mono(carboxy-isooctyl) ester, oxo-MINCH: cyclohexane-1,2-dicarboxylic acid-mono(oxo-isononyl) ester). We merged these data with earlier data of the ESB from the years 1999–2012 and are now able to report levels and time trends of internal DINCH exposure from 1999 to 2017. After first detections of the major oxidized DINCH metabolite OH-MINCH in 2006 (6.7%) detection rates rapidly increased to 43.3% in 2009, 80% in 2010 and 98.3% in 2011 and 2012. From the year 2013 on we could detect OH-MINCH in every urine sample analyzed. The median concentrations of OH-MINCH rapidly increased from 0.15 μg/L in 2010 to twice the concentration in 2011 (0.31 μg/L) with further increases in 2013 (0.37 μg/L), 2015 (0.59 μg/L) and 2017 (0.70 μg/L). Similar increases, albeit at lower detection rates and concentration levels, could be observed for cx-MINCH and oxo-MINCH. All metabolites strongly correlate with each other. For the ESB study population, DINCH exposures are still far below health based guidance values such as the German Human Biomonitoring Value (HBM-I; 4,500 μg/L for the sum of OH-MINCH and cx-MINCH) or the tolerable daily intake (TDI) of EFSA (1 mg/kg bw/d). The median daily DINCH intake (DI) calculated for 2017 was 0.23 μg/kg bw/d, thus 4,310-times lower than the TDI. The maximum DI calculated for one individual in 2012 (42.60 μg/kg bw/d) was a factor of more than 20 below the TDI. The ongoing increase in DINCH exposure needs to be closely monitored in the future, including populations with potentially higher exposures such as children. This close monitoring will enable timely exposure and risk reduction measures if exposures reached critical levels, or if new toxicological data lead to lower health based guidance values. DINCH belongs to the European Human Biomonitoring Initiative (HBM4EU) priority substances for which policy relevant questions still have to be answered.

In this study we analyzed one of the most comprehensive sets of 21 urinary phthalate metabolites representing exposure to 11 parent phthalates (DEP, DMP, DiBP, DnBP, BBzP, DEHP, DiNP, DiDP, DCHP, DnPeP, DnOP) in first morning urine samples of 112 Portuguese children (4-18 years) sampled in 2014/15. The study population consisted of two groups: group 1 with normal weight/underweight children (N = 43) following their regular diet and group 2 with obese/overweight children (N = 69) following a healthy diet (with nutritional counselling). Most of the metabolites were above the limits quantification (81-100%) except for MCHP, MnPEP and MnOP. Metabolite levels were generally comparable to other recent child and general populations sampled worldwide, confirming the steady decline in exposures to most phthalates. Compared to Portuguese children sampled in 2011/2012, median urinary metabolite levels decreased by approximately 50% for DEHP, DnBP, DiBP and BBzP. Risk assessments for individual phthalates and the sum of the anti-androgenic phthalates did not indicate to attributable health risks, also at the upper percentiles of exposure. In the healthy diet group the median concentration of the DEHP metabolites was significant lower, while all phthalate metabolites except MEP tended to be lower compared to the regular diet group. Multiple log-linear regression analyses revealed significantly lower daily intakes (DIs) for all phthalates in the healthy diet group compared to the regular diet group (geometric mean ratios (gMR) between 0.510-0.618; p ≤ 0.05), except for DEP (gMR: 0.811; p = 0.273). The same analyses with the continuous variable body mass index instead of the diet groups also showed effects on the DIs (gMRs between 0.926-0.951; p ≤ 0.05), however much smaller than the effects of the diet. The results indicate that obese children following a healthy diet composed of fresh and less packaged/processed food can considerably reduce their intake for most phthalates and can have lower phthalate intakes than regular weight/regular diet children., Luísa Correia-Sá is grateful to Fundação para a Ciência e a Tecnologia (FCT) by the grant (SFRH/BD/87019/2012), financed by POCH, subsidized by Fundo Social Europeu and Ministério da Ciência, Tecnologia e Ensino Superior. The authors are thankful to the project Qualidade e Segurança Alimentar – uma abordagem (nano)tecnológica, reference NORTE-01-0145-FEDER-000011.

Background Infant exposure to persistent organic pollutants (POPs) may contribute to obesity. However, many studies so far have been small, focused on transplacental exposure, used an inappropriate measure to assess postnatal exposure through breastfeeding if any, or did not discern between prenatal and postnatal effects. Objectives We investigated prenatal and postnatal exposure to POPs and infant growth (a predictor of obesity). Methods We pooled data from seven European birth cohorts with biomarker concentrations of polychlorinated biphenyl 153 (PCB-153) (n = 2,487), and p,p´-dichlorodiphenyldichloroethylene (p,p´-DDE) (n = 1,864), estimating prenatal and postnatal POPs exposure using a validated pharmacokinetic model. Growth was change in weight-for-age z-score between birth and 24 months. Per compound, multilevel models were fitted with either POPs total exposure from conception to 24 months or prenatal or postnatal exposure. Results We found a significant increase in growth associated with p,p´-DDE, seemingly due to prenatal exposure (per interquartile increase in exposure, adjusted β = 0.12; 95% CI: 0.03, 0.22). Due to heterogeneity across cohorts, this estimate cannot be considered precise, but does indicate that an association with infant growth is present on average. In contrast, a significant decrease in growth was associated with postnatal PCB-153 exposure (β = –0.10; 95% CI: –0.19, –0.01). Conclusion To our knowledge, this is the largest study to date of POPs exposure and infant growth, and it contains state-of-the-art exposure modeling. Prenatal p,p´-DDE was associated with increased infant growth, and postnatal PCB-153 with decreased growth at European exposure levels. Citation Iszatt N, Stigum H, Verner MA, White RA, Govarts E, Palkovicova Murinova L, Schoeters G, Trnovec T, Legler J, Pelé F, Botton J, Chevrier C, Wittsiepe J, Ranft U, Vandentorren S, Kasper-Sonnenberg M, Klümper C, Weisglas-Kuperus N, Polder A, Eggesbø M, OBELIX. 2015. Prenatal and postnatal exposure to persistent organic pollutants and infant growth: a pooled analysis of seven European birth cohorts. Environ Health Perspect 123:730–736; http://dx.doi.org/10.1289/ehp.1308005

\(\bf Objective\) Epidemiological studies indicate associations between childhood exposure with phthalates and bisphenol A (BPA) and the pubertal development. We examined associations between the pre-pubertal phthalate and BPA body burden and the longitudinally assessed sexual maturation of eight- to thirteen-year-old children. \(\bf Methods\) We started with eight- to ten-year-old children in the baseline study and quantified phthalate metabolites and BPA in 472 urine samples (250 boys; 222 girls; mean age: 8.8 years). Associations between the pubertal development, assessed in three annual follow-up studies by Puberty Development scale questionnaires (PD scales), and the chemical exposure from the baseline visit were longitudinally analyzed with generalized estimation equations. \(\bf Results\) The number of children with both chemical measures and PD scores (calculated from the PD scales) was 408. In the third follow-up, 49% of the girls and 18% of the boys had reached mid-puberty. For girls, we observed a delayed pubertal development with the di-hexyl-ethyl phthalate (DEHP) metabolites (\(\beta\): -0.16 to -0.23; p \(\leq\) 0.05 or p \(\leq\) 0.1), mono-n-butyl phthalate (\(\beta\): -0.15; 95% CI: -0.31; 0.01), mono-benzyl phthalate (\(\beta\): -0.11; 95% CI: -0,24; -0,01),and mono-ethyl phthalate (MEP) (\(\beta\): -0.15; 95% CI: -0.28; -0.01). In addition, significant non-linear associations of the DEHP metabolites and BPA with the PD scores were found, when their quadratic effects were included in the GEE models. In boys, no consistent relationships between the PD scores and the chemicals were detected except of an accelerated development with the \(\sum\)DEHP metabolites (\(\beta\): 0.16; 95% CI: -0.02; -0.34) \(\bf Conclusion\) We found indications that pre-pubertal exposures with phthalates and BPA were associated with pubertal timing in children, particularly in girls. For boys, associations were inconsistent, and not necessarily in line with the known anti-androgenicity of some phthalates during prenatal exposure.

Exposure to bisphenol A (BPA) is known to be widespread and available data suggests that BPA can act as an endocrine disruptor. Diet is generally regarded as the dominant BPA exposure source, namely through leaching to food from packaging materials. The aim of this study was to evaluate the exposure of 110 Portuguese children (4-18 years old), divided in two groups: the regular diet group (n = 43) comprised healthy normal weight/underweight children with no dietary control; the healthy diet group (n = 67) comprised children diagnosed for obesity/overweight (without other known associated diseases) that were set on a healthy diet for weight control. First morning urine samples were collected and total urinary BPA was analyzed after enzymatic hydrolysis via on-line HPLC-MS/MS with isotope dilution quantification. Virtually, all the children were exposed to BPA, with 91% of the samples above the LOQ (limit of quantification) of 0.1 μg/L. The median (95th percentile) urinary BPA levels for non-normalized and creatinine-corrected values were 1.89 μg/L (16.0) and 1.92 μg/g creatinine (14.4), respectively. BPA levels in the regular diet group were higher than in the healthy diet group, but differences were not significant. Calculated daily BPA intakes, however, were significantly higher in children of the regular diet group than in children of healthy diet group. Median (95th percentile) daily intakes amounted to 41.6 (467) ng/kg body weight/day in the regular diet group, and 23.2 (197) ng/kg body weight/day in the healthy diet group. Multiple logistic regression analysis revealed that children in the healthy diet group had 33% lower intakes than children in the regular diet group (OR 0.67; 95% CI 0.51-0.89). For both groups, however, urinary BPA levels and daily BPA intakes were within the range reported for other children's populations and were well below health guidance values such as the European Food Safety Authority (EFSA) temporary tolerable daily intake (t-TDI) of 4 μg/kg body weight/day. In addition, lower daily BPA intakes were more likely linked with the inherent dietary approach rather than with high BMI or obesity.

In the context of the Duisburg Birth Cohort, this retrospective cohort study provides results of internal exposure to perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), and perfluorohexanesulfonic acid (PFHxS) in 156 mother-child pairs, and investigates whether and to what extent in utero exposure of these chemicals at German background levels exerts an effect on newborn and infant weight and length, and weight in relation to length expressed by ponderal index, in order to examine whether any reduction in weight is disproportionate to length. The levels of PFOA, PFOS, and PFHxS were determined in 81 maternal and 83 umbilical cord stored frozen plasma samples and 105 umbilical cord blood samples. Calculated factors were used to convert umbilical cord values to maternal levels. Weights and lengths were retrieved at birth and at 1, 4, 6, and 12 mo from examination booklets and ponderal index (kg/m3) was calculated. Subsequently, correlations were assessed using multiple linear regressions and generalized estimation equations with each of the measures as a continuous outcome variable and with PFOA, PFOS, and PFHxS concentration quartiles as categorized predictor variables, while adjusting for relevant covariates. PFOA, PFOS, and PFHxS were generally within German background exposure levels. There was a significant association between PFOA, PFOS, and PFHxS concentration quartiles and decrease in ponderal index at birth but not weight or height. A nonsignificant negative association between exposure to all three compounds and birth weight was noted. Follow-up showed no sustained effect of the PFAA on anthropometric measures during the first year.

Polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/F) and polychlorinated biphenyls (PCB) are postulated to act as endocrine disrupters. In the ongoing Duisburg birth cohort study, started in 2000-2002, influence of persistent organic pollutants (POP) on child development was monitored. For the first time, associations were reported between prenatal and postnatal PCDD/F and PCB exposures and early endocrinological changes concerning adrenarchal development. PCDD/F and PCB concentrations were measured in blood samples taken in wk 32 of pregnancy and in breast milk using gas chromatography and high-resolution mass spectrometry (GC/HRMS). At the age of 6-7 and 8-9 yr, serum samples were collected from 111 children. The samples were assayed for the sex hormones testosterone, estradiol, dehydroepiandrosterone sulfate (DHEA-S), and 17-OH-progesterone (17-OHP) by using an automated chemiluminescence assay system. Analyses of repeated measurements of DHEA-S serum levels were performed by linear regression analysis using generalized estimating equations (GEE). Linear regression analysis showed a positive association between DHEA-S and breast milk levels of PCDD/F and PCB expressed as toxicity equivalents according to toxicity equivalent factors published by the World Health Organization (WHO) in 2005 (WHO(2005)-TEq) (increase of 29%, geometric mean ratio, GMR: 1.29, 95% CI 1.06-1. 58 per doubling of PCDD/F + PCB WHO(2005)-TEq levels). Results for the association with the WHO(2005)-TEq levels in blood of mothers were in the same direction (increase of 15%, GMR 1.15, 95% CI 0.93-1.42 per doubling of PCDD/F + PCB WHO(2005)-TEq levels), but not significant. Data indicate that PCDD/F and PCB exposure in infancy may influence DHEA-S serum levels in prepubertal children. Increased DHEA-S serum levels are considered to indicate acceleration of the adrenal maturation.

Bisphenol A (BPA) may alter endocrine functions, and human exposure is widespread. In the Duisburg birth cohort study the influence of several contaminants was examined on the neuropsychological and pubertal development of children. This study reports the biomonitoring results on BPA within the 6-yr follow-up study (children's age 6-8 yr). Total BPA and free (unconjugated) BPA concentrations in 208 urine samples of 104 mother-child pairs were measured. For quality control, total BPA was analyzed by two independent laboratories. BPA was detected in all urine samples, while free BPA was observed above the limit of quantification (LOQ) in only 33 samples. Total BPA concentrations were significantly associated between the two laboratories. BPA concentrations (median; range) tended to be higher in children than in mothers but the difference was not significant. Total BPA levels in children and mothers correlated at low levels but significantly to each other. Multivariate linear regression analysis revealed positive associations between creatinine and the BPA concentrations and a negative association with German nationality (mothers only). Evidence indicates that BPA exposure is omnipresent but levels in mother-child pairs are low. Only small amounts (less than 16%) were detectable as free (unconjugated) BPA. Analytical reliability is high even at such low levels, provided that external contamination is minimized.

In a cross-sectional study performed in 2000, an unexpected positive association between nickel (Ni) in ambient air, urinary Ni content and the prevalence of Ni sensitization in a subgroup of 6-yr-old children living near a steel mill was observed. Between 2005 and 2006, in a different and larger study population, we examined if Ni from ambient air or urinary Ni concentration was related to Ni sensitization in children living next to Ni-emitting steel mills. We studied 749 school beginners living in four Ni-polluted industrial areas of North Rhine-Westphalia, Germany. We assessed Ni in ambient air, Ni in urine from children and mothers, and Ni in tap water, conducted patch tests in children (including the NiSO(4)-dilution test) and collected questionnaire data. Statistics were done by linear and logistic regression analyses, adjusted for covariates. At increased Ni concentration in ambient air (unit of increase: 10 ng/m(3)), urinary Ni concentrations rose in both mothers (9.1%; 95% CI: 6.8-11.4%) and children (2.4%; 95% CI: 0.4-4.4%). The prevalence of Ni sensitization in children was associated with increased Ni from ambient air (unit of increase: 18 ng/m(3); odds ratio 1.28; 95% CI: 1.25-1.32) and urinary Ni concentration (unit of increase: 7.1 μg/L; odds ratio 2.4; 95% CI: 1.20-4.48). Ni in ambient air of areas with Ni-emitting factories contributes to internal Ni exposure in residents via inhalation and, furthermore, is a risk factor for the development of Ni sensitization in children.

Multidomain scaffolding proteins organize the molecular machinery of neurotransmitter vesicle dynamics during synaptogenesis and synaptic activity. We find that domains of five active zone proteins converge on an interaction node that centers on the N-terminal region of Munc13-1 and includes the zinc-finger domain of Rim1, the C-terminal region of Bassoon, a segment of CAST1/ELKS2, and the third coiled-coil domain (CC3) of either Aczonin/Piccolo or Bassoon. This multidomain complex may constitute a center for the physical and functional integration of the protein machinery at the active zone. An additional connection between Aczonin and Bassoon is mediated by the second coiled-coil domain of Aczonin. Recombinant Aczonin-CC3, expressed in cultured neurons as a green fluorescent protein fusion protein, is targeted to synapses and suppresses vesicle turnover, suggesting involvements in synaptic assembly as well as activity. Our findings show that Aczonin, Bassoon, CAST1, Munc13, and Rim are closely and multiply interconnected, they indicate that Aczonin-CC3 can actively participate in neurotransmitter vesicle dynamics, and they highlight the N-terminal region of Munc13-1 as a hub of protein interactions by adding three new binding partners to its mechanistic potential in the control of synaptic vesicle priming.

Low-level exposure to polychlorinated biphenyl-153 (PCB-153) and dichlorodiphenyldichloroethylene (p-p′-DDE) can impair fetal growth; however, the exposure–response relationship and effect modifiers of such association are not well established. This study is an extension of an earlier European meta-analysis. Our aim was to explore exposure–response relationship between PCB-153 and p-p′-DDE and birth outcomes; to evaluate whether any no exposure–effect level and susceptible subgroups exist; and to assess the role of maternal gestational weight gain (GWG). We used a pooled dataset of 9377 mother–child pairs enrolled in 14 study populations from 11 European birth cohorts. General additive models were used to evaluate the shape of the relationships between organochlorine compounds and birth outcomes. We observed an inverse linear exposure–response relationship between prenatal exposure to PCB-153 and birth weight [decline of 194 g (95% CI −314, −74) per 1 μg/L increase in PCB-153]. We showed effects on birth weight over the entire exposure range, including at low levels. This reduction seems to be stronger among children of mothers who were non-Caucasian or had smoked during pregnancy. The most susceptible subgroup was girls whose mothers smoked during pregnancy. After adjusting for absolute GWG or estimated fat mass, a reduction in birth weight was still observed. This study suggests that the association between low-level exposure to PCB-153 and birth weight exists and follows an inverse linear exposure–response relationship with effects even at low levels, and that maternal smoking and ethnicity modify this association. Keywords: Biomarkers of exposure, Persistent organic pollutants, Polychlorinated biphenyls (PCBs), Dichlorodiphenyldichloroethylene (DDE), Birth weight

Some phthalates and also bisphenol A (BPA) interfere with the human endocrine system and are labelled as reproductive toxicants. Children's exposure to these contaminants is suspected to be associated with developmental disorders and other health impairments. We provide biomonitoring data on 21 urinary phthalate metabolite and BPA levels in first morning urine of 8-10 year old children. Participants were children born between 1999 and 2002 of the Duisburg birth cohort (8-9 years, N=113) and of the Bochum cohort study (8-10 years, N=352). Additionally, for the Duisburg birth cohort we compare current data of children from Duisburg (8-9 years) with data from 2 years earlier when the children were 6-7 years old. We analyzed influences of important covariates on exposure levels by multiple regression analysis and those from two sampling time points by generalized equation estimation models adjusted for important covariates. Compared to recently published studies the phthalate metabolite and BPA concentrations were within the range of background levels. There were no significant differences between children from Bochum and Duisburg. Comparison between the two Duisburg birth cohort data sets (2007-2008 and 2009-2010) showed significant correlations for most of the phthalate metabolites (r Spearman between 0.25 and 0.51; p ≤ 0.05) but not for BPA (r Spearman=0.162; p=0.143). Most of the phthalate metabolites in the groups of the 6-7 and 8-9 years old Duisburg children were negatively associated with higher age, except for BPA concentrations with nearly constant levels. Exposure levels may be influenced by changes in child specific exposure patterns with age but also by the rapidly changing phthalate market.

International audience; BACKGROUND: Persistent organic pollutants may affect the immune and respiratory systems, but available evidence is based on small study populations. We studied the association between prenatal exposure to dichlorodiphenyldichloroethylene (DDE) and polychlorinated biphenyl 153 (PCB 153) and children's respiratory health in European birth cohorts. METHODS: We included 4608 mothers and children enrolled in 10 birth cohort studies from 7 European countries. Outcomes were parent-reported bronchitis and wheeze in the first 4 years of life. For each cohort, we performed Poisson regression analyses, modeling occurrences of the outcomes on the estimates of cord-serum concentrations of PCB 153 and DDE as continuous variables (per doubling exposure) and as cohort-specific tertiles. Summary estimates were obtained through random-effects meta-analyses. RESULTS: The risk of bronchitis or wheeze (combined variable) assessed before 18 months of age increased with increasing DDE exposure (relative risk [RR] per doubling exposure = 1.03 [95% confidence interval = 1.00-1.07]). When these outcomes were analyzed separately, associations appeared stronger for bronchitis. We also found an association between increasing PCB 153 exposure and bronchitis in this period (RR per doubling exposure = 1.06 [1.01-1.12]) but not between PCB 153 and wheeze. No associations were found between either DDE or PCB 153 and ever-wheeze assessed after 18 months. Inclusion of both compounds in the models attenuated risk estimates for PCB 153 tertiles of exposure, whereas DDE associations were more robust. CONCLUSION: This large meta-analysis suggests that prenatal DDE exposure may be associated with respiratory health symptoms in young children (below 18 months), whereas prenatal PCB 153 levels were not associated with such symptoms.

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.