The German Environmental Survey for Children and Adolescents 2014-2017 (GerES V) - Study population, response rates and representativeness.

The German Environmental Survey (GerES) is a population-representative, cross-sectional study on environmental exposures of the general population of Germany. GerES has repeatedly been conducted since 1985 by the German Environment Agency (UBA) in close collaboration with the Health Interview and Examination Surveys of the Robert Koch Institute (RKI). In the German Environmental Survey for Children and adolescents 2014-2017 (GerES V) pollutants and other environmental stressors were measured in human samples as well as in the homes of 3- to 17-year-old children and adolescents. Interviews were conducted about health-related behaviors and living conditions. The GerES V basic program encompassed examinations of whole blood, blood plasma, morning urine and drinking water samples, measurements of ultrafine particles and noise levels, comprehensive standardized interviews, and self-administrated questionnaires. Additional modules on volatile organic compounds and aldehydes, particulate matter (PM2.5) in indoor air, organic compounds in drinking water and pollutants in house dust were conducted in subsamples. Potential GerES V participants were identified and attained by the RKI from those participants who were examined and interviewed for the cross-sectional component of the second follow-up to the German Health Interview and Examination Survey for Children and Adolescents (KiGGS Wave 2). The gross sample of GerES V comprised 3031 children and adolescents of which 2294 finally took part in the survey. This equals a total response rate of 75.7 %. Response rates varied, depending on region, type of municipality, age and sex, from 66.0 % to 78.3 %. By calculating individual case weights, discrepancies due to sample design and non-response between the GerES V sample and the whole population could be considered in statistical analysis. Therefore, the representativeness of the GerES V results with regard to age, sex, community size and region was assured.

Converged Structural and Spectroscopic Properties for Refined QM/MM Models of Azurin.

Blue copper proteins continue to challenge experiment and theory with their electronic structure and spectroscopic properties that respond sensitively to the coordination environment of the copper ion. In this work, we report state-of-the art electronic structure studies for geometric and spectroscopic properties of the archetypal "Type I" copper protein azurin in its Cu(II) state. A hybrid quantum mechanics/molecular mechanics (QM/MM) approach is used, employing both density functional theory (DFT) and coupled cluster with singles, doubles, and perturbative triples (CCSD(T)) methods for the QM region, the latter method making use of the domain-based local pair natural orbital (DLPNO) approach. Models of increasing QM size are employed to investigate the convergence of critical geometric parameters. It is shown that convergence is slow and that a large QM region is critical for reproducing the short experimental Cu-SCys112 distance. The study of structural convergence is followed by investigation of spectroscopic parameters using both DFT and DLPNO-CC methods and comparing these to the experimental spectrum using simulations. The results allow us to examine for the first time the distribution of spin densities and hyperfine coupling constants at the coupled cluster level, leading us to revisit the experimental assignment of the 33S hyperfine splitting. The wavefunction-based approach to obtain spin-dependent properties of open-shell systems demonstrated here for the case of azurin is transferable and applicable to a large array of bioinorganic systems.

Structure-Spectroscopy Correlations for Intermediate Q of Soluble Methane Monooxygenase: Insights from QM/MM Calculations.

The determination of the diiron core intermediate structures involved in the catalytic cycle of soluble methane monooxygenase (sMMO), the enzyme that selectively catalyzes the conversion of methane to methanol, has been a subject of intense interest within the bioinorganic scientific community. Particularly, the specific geometry and electronic structure of the intermediate that precedes methane binding, known as intermediate Q (or MMOHQ), has been debated for over 30 years. Some reported studies support a bis-µ-oxo-bridged Fe(IV)2O2 closed-core conformation Fe(IV)2O2 core, whereas others favor an open-core geometry, with a longer Fe-Fe distance. The lack of consensus calls for a thorough re-examination and reinterpretation of the spectroscopic data available on the MMOHQ intermediate. Herein, we report extensive simulations based on a hybrid quantum mechanics/molecular mechanics approach (QM/MM) approach that takes into account the complete enzyme to explore possible conformations for intermediates MMOHox and MMOHQ of the sMMOH catalytic cycle. High-level quantum chemical approaches are used to correlate specific structural motifs with geometric parameters for comparison with crystallographic and EXAFS data, as well as with spectroscopic data from Mössbauer spectroscopy, Fe K-edge high-energy resolution X-ray absorption spectroscopy (HERFD XAS), and resonance Raman 16O-18O difference spectroscopy. The results provide strong support for an open-core-type configuration in MMOHQ, with the most likely topology involving mono-oxo-bridged Fe ions and alternate terminal Fe-oxo and Fe-hydroxo groups that interact via intramolecular hydrogen bonding. The implications of an open-core intermediate Q on the reaction mechanism of sMMO are discussed.

Carbene-Induced Rescue of Catalytic Activity in Deactivated Nitrite Reductase Mutant.

The role of His145 in the T1 copper center of nitrite reductase (NiR) is pivotal for the activity of the enzyme. Mutation to a glycine at this position enables the reconstitution of the T1 center by the addition of imidazole as exogenous ligands, however the catalytic activity is only marginally rescued. Here, we demonstrate that the uptake of 1,3-dimethylimidazolylidene as N-heterocyclic carbene (NHC) by the H145G NiR mutant instead of imidazole yields a significantly more active catalyst, suggesting a beneficial role of such C-bonding. Spectroscopic analyses of the formed H145G≈NHC variant as well as an analogue without the catalytic T2 copper center reveal no significant alteration of the T1 site compared to the wild type or the variant containing imidazole as exogenous N-bound surrogate of H145. However, the presence of the carbene doubles the catalytic activity of the mutant compared to the imidazole variant. This enhanced activity has been attributed to a faster electron transfer to the T1 center in the NHC variant and a concomitant change of the rate-limiting step.

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.

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

The production and use of the plasticisers Hexamoll® DINCH (di-(iso-nonyl)-cyclohexane-1,2-dicarboxylate) and DPHP (di-(2-propylheptyl) phthalate) have increased after both chemicals were introduced into the market in the early 2000s as substitutes for restricted high molecular weight phthalates. During the population representative German Environmental Survey (GerES) of Children and Adolescents (GerES V, 2014-2017), we collected urine samples and measured the concentrations of DINCH and DPHP metabolites in 2228 and in a subsample of 516 participants, respectively. We detected DINCH and DPHP metabolites in 100% and 62% of the 3-17 years old children and adolescents, respectively. Geometric means of DINCH metabolites were 2.27 µg/L for OH-MINCH, 0.93 µg/L for oxo-MINCH, 1.14 µg/L for cx-MINCH and 3.47 µg/L for DINCH (Σ of OH-MINCH + cx-MINCH). Geometric means of DPHP metabolites were 0.30 µg/L for OH-MPHP, 0.32 µg/L for oxo-MPHP and 0.64 µg/L for DPHP (Σ of OH-MPHP + oxo-MPHP). The 3-5 years old children had almost 3-fold higher DINCH biomarkers levels than adolescents (14-17 years). Higher concentrations of DPHP biomarkers among young children only became apparent after creatinine adjustment. Urinary levels of DINCH but not of DPHP biomarkers were associated with the levels of the respective plasticisers in house dust. When compared to HBM health-based guidance values, we observed no exceedance of the HBM-I value of 1 mg/L for DPHP (Σ of OH-MPHP + oxo-MPHP). However, 0.04% of the children exceeded the health based guidance value HBM-I of 3 mg/L for DINCH (Σ of OH-MINCH + cx-MINCH). This finding shows that even a less toxic replacement of restricted chemicals can reach exposures in some individuals, at which, according to current knowledge, health impacts cannot be excluded with sufficient certainty. In conclusion, we provide representative data on DINCH and DPHP exposure of children and adolescents in Germany. Further surveillance is warranted to assess the substitution process of plasticisers, and to advise exposure reduction measures, especially for highly exposed children and adolescents. Providing the results to the European HBM Initiative HBM4EU will support risk assessment and risk management not only in Germany but also in Europe.

Systematic High-Accuracy Prediction of Electron Affinities for Biological Quinones.

Quinones play vital roles as electron carriers in fundamental biological processes; therefore, the ability to accurately predict their electron affinities is crucial for understanding their properties and function. The increasing availability of cost-effective implementations of correlated wave function methods for both closed-shell and open-shell systems offers an alternative to density functional theory approaches that have traditionally dominated the field despite their shortcomings. Here, we define a benchmark set of quinones with experimentally available electron affinities and evaluate a range of electronic structure methods, setting a target accuracy of 0.1 eV. Among wave function methods, we test various implementations of coupled cluster (CC) theory, including local pair natural orbital (LPNO) approaches to canonical and parameterized CCSD, the domain-based DLPNO approximation, and the equations-of-motion approach for electron affinities, EA-EOM-CCSD. In addition, several variants of canonical, spin-component-scaled, orbital-optimized, and explicitly correlated (F12) Møller-Plesset perturbation theory are benchmarked. Achieving systematically the target level of accuracy is challenging and a composite scheme that combines canonical CCSD(T) with large basis set LPNO-based extrapolation of correlation energy proves to be the most accurate approach. Methods that offer comparable performance are the parameterized LPNO-pCCSD, the DLPNO-CCSD(T0 ), and the orbital optimized OO-SCS-MP2. Among DFT methods, viable practical alternatives are only the M06 and the double hybrids, but the latter should be employed with caution because of significant basis set sensitivity. A highly accurate yet cost-effective DLPNO-based coupled cluster approach is used to investigate the methoxy conformation effect on the electron affinities of ubiquinones found in photosynthetic bacterial reaction centers. © 2018 Wiley Periodicals, Inc.

[Epidemiological studies with environmental relevance in Germany]. / Epidemiologische Studien mit Umweltbezug in Deutschland.

Our environment is a major factor in determining health and well-being throughout life, from conception into old age. This overview illustrates the most important epidemiological studies and health monitoring systems in Germany, which investigate environmental influences in various population subgroups and estimate related health effects. Environmental factors examined in each study are described. The mentioned studies in children and adults build the basis for predictions and preventive measures. The number of the assessed environmental factors, the depth of the examinations as well as the (phenotypical) characterization of the study participants differ. Still, the obtained data build a base for important future research. However, for this, a permanent and Germany-wide assessment of environmental factors is necessary.The proportion of the European population living in urban areas is projected to increase in the future. Therefore, environmental factors such as air pollution, air temperature, and noise, but also social inequality, are likely to have a negative effect on health and quality of life of the population. The challenge of the aging population as well as potential adaptation processes to the diverse environmental stimuli requires multidisciplinary approaches. From an environmental epidemiology view, the collected data from the described studies are of immense value because only with this data can associations between environment and health be investigated and public health-relevant preventive measures be identified.The NAKO health study will be the largest resource of health data and should therefore be included in future activities related to the investigation of environmental health effects in Germany.

THP-1-derived macrophages render lung epithelial cells hypo-responsive to Legionella pneumophila - a systems biology study.

Immune response in the lung has to protect the huge alveolar surface against pathogens while securing the delicate lung structure. Macrophages and alveolar epithelial cells constitute the first line of defense and together orchestrate the initial steps of host defense. In this study, we analysed the influence of macrophages on type II alveolar epithelial cells during Legionella pneumophila-infection by a systems biology approach combining experimental work and mathematical modelling. We found that L. pneumophila-infected THP-1-derived macrophages provoke a pro-inflammatory activation of neighboring lung epithelial cells, but in addition render them hypo-responsive to direct infection with the same pathogen. We generated a kinetic mathematical model of macrophage activation and identified a paracrine mechanism of macrophage-secreted IL-1ß inducing a prolonged IRAK-1 degradation in lung epithelial cells. This intercellular crosstalk may help to avoid an overwhelming inflammatory response by preventing excessive local secretion of pro-inflammatory cytokines and thereby negatively regulating the recruitment of immune cells to the site of infection. This suggests an important but ambivalent immunomodulatory role of macrophages in lung infection.

Legionella pneumophila infection activates bystander cells differentially by bacterial and host cell vesicles.

Extracellular vesicles from eukaryotic cells and outer membrane vesicles (OMVs) released from gram-negative bacteria have been described as mediators of pathogen-host interaction and intercellular communication. Legionella pneumophila (L. pneumophila) is a causative agent of severe pneumonia. The differential effect of bacterial and host cell vesicles in L. pneumophila infection is unknown so far. We infected THP-1-derived or primary human macrophages with L. pneumophila and isolated supernatant vesicles by differential centrifugation. We observed an increase of exosomes in the 100 k pellet by nanoparticle tracking analysis, electron microscopy, and protein markers. This fraction additionally contained Legionella LPS, indicating also the presence of OMVs. In contrast, vesicles in the 16 k pellet, representing microparticles, decreased during infection. The 100 k vesicle fraction activated uninfected primary human alveolar epithelial cells, A549 cells, and THP-1 cells. Epithelial cell activation was reduced by exosome depletion (anti-CD63, or GW4869), or blocking of IL-1ß in the supernatant. In contrast, the response of THP-1 cells to vesicles was reduced by a TLR2-neutralizing antibody, UV-inactivation of bacteria, or - partially - RNase-treatment of vesicles. Taken together, we found that during L. pneumophila infection, neighbouring epithelial cells were predominantly activated by exosomes and cytokines, whereas myeloid cells were activated by bacterial OMVs.

microRNA-125a-3p is regulated by MyD88 in Legionella pneumophila infection and targets NTAN1.

BACKGROUND: Legionella pneumophila (L. pneumophila) is a causative agent of severe pneumonia. It is highly adapted to intracellular replication and manipulates host cell functions like vesicle trafficking and mRNA translation to its own advantage. However, it is still unknown to what extent microRNAs (miRNAs) are involved in the Legionella-host cell interaction. METHODS: WT and MyD88-/- murine bone marrow-derived macrophages (BMM) were infected with L. pneumophila, the transcriptome was analyzed by high throughput qPCR array (microRNAs) and conventional qPCR (mRNAs), and mRNA-miRNA interaction was validated by luciferase assays with 3´-UTR mutations and western blot. RESULTS: L. pneumophila infection caused a pro-inflammatory reaction and significant miRNA changes in murine macrophages. In MyD88-/- cells, induction of inflammatory markers, such as Ccxl1/Kc, Il6 and miR-146a-5p was reduced. Induction of miR-125a-3p was completely abrogated in MyD88-/- cells. Target prediction analyses revealed N-terminal asparagine amidase 1 (NTAN1), a factor from the n-end rule pathway, to be a putative target of miR-125a-3p. This interaction could be confirmed by luciferase assay and western blot. CONCLUSION: Taken together, we characterized the miRNA regulation in L. pneumophila infection with regard to MyD88 signaling and identified NTAN1 as a target of miR-125a-3p. This finding unravels a yet unknown feature of Legionella-host cell interaction, potentially relevant for new treatment options.

Legionella pneumophila Outer Membrane Vesicles: Isolation and Analysis of Their Pro-inflammatory Potential on Macrophages.

Bacteria are able to secrete a variety of molecules via various secretory systems. Besides the secretion of molecules into the extracellular space or directly into another cell, Gram-negative bacteria can also form outer membrane vesicles (OMVs). These membrane vesicles can deliver their cargo over long distances, and the cargo is protected from degradation by proteases and nucleases. Legionella pneumophila (L. pneumophila) is an intracellular, Gram-negative pathogen that causes a severe form of pneumonia. In humans, it infects alveolar macrophages, where it blocks lysosomal degradation and forms a specialized replication vacuole. Moreover, L. pneumophila produces OMVs under various growth conditions. To understand the role of OMVs in the infection process of human macrophages, we set up a protocol to purify bacterial membrane vesicles from liquid culture. The method is based on differential ultracentrifugation. The enriched OMVs were subsequently analyzed with regard to their protein and lipopolysaccharide (LPS) amount and were then used for the treatment of a human monocytic cell line or murine bone marrow-derived macrophages. The pro-inflammatory responses of those cells were analyzed by enzyme-linked immunosorbent assay. Furthermore, alterations in a subsequent infection were analyzed. To this end, the bacterial replication of L. pneumophila in macrophages was studied by colony-forming unit assays. Here, we describe a detailed protocol for the purification of L. pneumophila OMVs from liquid culture by ultracentrifugation and for the downstream analysis of their pro-inflammatory potential on macrophages.

German Environmental Survey for Children and Adolescents 2014-2017 (GerES V) - the environmental module of KiGGS Wave 2.

Health-relevant exposures to environmental pollutants, fungi, bacteria, noise, and air pollution have to be identified at an early stage. At the same time, impacts on health and their potential environmental causes need to be investigated and documented. The German Environmental Survey for Children and Adolescents 2014-2017 (GerES V) is the environmental module of KiGGS Wave 2 of the Robert Koch Institute and takes a deeper look at the sections living conditions and health status of the KiGGS study. GerES V collects up-to-date information on the exposure of children and adolescents in Germany aged 3 to 17 to chemicals and investigates chemical and physical environmental pollutants in their living environments. The survey contributes to identifying environmental hazards and measures that effectively reduce or prevent such hazards in order to protect and promote the health of the young generation.

Legionella pneumophila-Derived Outer Membrane Vesicles Promote Bacterial Replication in Macrophages.

The formation and release of outer membrane vesicles (OMVs) is a phenomenon of Gram-negative bacteria. This includes Legionella pneumophila (L. pneumophila), a causative agent of severe pneumonia. Upon its transmission into the lung, L. pneumophila primarily infects and replicates within macrophages. Here, we analyzed the influence of L. pneumophila OMVs on macrophages. To this end, differentiated THP-1 cells were incubated with increasing doses of Legionella OMVs, leading to a TLR2-dependent classical activation of macrophages with the release of pro-inflammatory cytokines. Inhibition of TLR2 and NF-κB signaling reduced the induction of pro-inflammatory cytokines. Furthermore, treatment of THP-1 cells with OMVs prior to infection reduced replication of L. pneumophila in THP-1 cells. Blocking of TLR2 activation or heat denaturation of OMVs restored bacterial replication in the first 24 h of infection. With prolonged infection-time, OMV pre-treated macrophages became more permissive for bacterial replication than untreated cells and showed increased numbers of Legionella-containing vacuoles and reduced pro-inflammatory cytokine induction. Additionally, miRNA-146a was found to be transcriptionally induced by OMVs and to facilitate bacterial replication. Accordingly, IRAK-1, one of miRNA-146a's targets, showed prolonged activation-dependent degradation, which rendered THP-1 cells more permissive for Legionella replication. In conclusion, L. pneumophila OMVs are initially potent pro-inflammatory stimulators of macrophages, acting via TLR2, IRAK-1, and NF-κB, while at later time points, OMVs facilitate L. pneumophila replication by miR-146a-dependent IRAK-1 suppression. OMVs might thereby promote spreading of L. pneumophila in the host.

Atom-Precise Organometallic Zinc Clusters.

The bottom-up synthesis of organometallic zinc clusters is described. The cation {[Zn10](Cp*)6 Me}(+) (1) is obtained by reacting [Zn2 Cp*2] with [FeCp2][BAr4 (F)] in the presence of ZnMe2. In the presence of suitable ligands, the high reactivity of 1 enables the controlled abstraction of single Zn units, providing access to the lower-nuclearity clusters {[Zn9 ](Cp*)6} (2) and {[Zn8 ](Cp*)5 ((t) BuNC)3}(+) (3). According to DFT calculations, 1 and 2 can be described as closed-shell species that are electron-deficient in terms of the Wade-Mingos rules because the apical ZnCp* units that constitute the cluster cage do not have three, but only one, frontier orbitals available for cluster bonding. Zinc behaves flexibly in building the skeletal metal-metal bonds, sometimes providing one major frontier orbital (like Group 11 metals) and sometimes providing three frontier orbitals (like Group 13 elements).

Population variation in biomonitoring data for persistent organic pollutants (POPs): an examination of multiple population-based datasets for application to Australian pooled biomonitoring data.

BACKGROUND: Australian national biomonitoring for persistent organic pollutants (POPs) relies upon age-specific pooled serum samples to characterize central tendencies of concentrations but does not provide estimates of upper bound concentrations. This analysis compares population variation from biomonitoring datasets from the US, Canada, Germany, Spain, and Belgium to identify and test patterns potentially useful for estimating population upper bound reference values for the Australian population. METHODS: Arithmetic means and the ratio of the 95th percentile to the arithmetic mean (P95:mean) were assessed by survey for defined age subgroups for three polychlorinated biphenyls (PCBs 138, 153, and 180), hexachlorobenzene (HCB), p,p-dichlorodiphenyldichloroethylene (DDE), 2,2',4,4' tetrabrominated diphenylether (PBDE 47), perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). RESULTS: Arithmetic mean concentrations of each analyte varied widely across surveys and age groups. However, P95:mean ratios differed to a limited extent, with no systematic variation across ages. The average P95:mean ratios were 2.2 for the three PCBs and HCB; 3.0 for DDE; 2.0 and 2.3 for PFOA and PFOS, respectively. The P95:mean ratio for PBDE 47 was more variable among age groups, ranging from 2.7 to 4.8. The average P95:mean ratios accurately estimated age group-specific P95s in the Flemish Environmental Health Survey II and were used to estimate the P95s for the Australian population by age group from the pooled biomonitoring data. CONCLUSIONS: Similar population variation patterns for POPs were observed across multiple surveys, even when absolute concentrations differed widely. These patterns can be used to estimate population upper bounds when only pooled sampling data are available.

Utility of two novel multiplexing assays for the detection of gastrointestinal pathogens - a first experience.

BACKGROUND: Cause for gastroenteritis range from viral, bacterial to parasitic pathogens. Rapid Multiplexing techniques like ProGastro_SSCS and xTAG_GPP can detect broad panels of pathogens simultaneously. We performed a field test with a total number of 347 stool samples from adult hospitalized patients that were tested with the Luminex xTAG GPP assay; of the 157 samples positively tested for at least one pathogen by xTAG GPP a total number of 30 samples was retested with the ProGastro SSCS assay. Assays were compared to standard routine diagnostics. FINDINGS: Multiplexing significantly reduced the time to the initial identification of a pathogen. Moreover, multiplexing detected pathogens for which a diagnostic assays was not requested by the physician and thus may be an important tool for avoiding nosocomial outbreaks. CONCLUSION: This first frontline approach with these assays approves their utility compared to conventional microbiological methods.

Levels and predictors of urinary nickel concentrations of children in Germany: results from the German Environmental Survey on children (GerES IV).

Human biomonitoring of nickel has gained interest in environmental medicine due to its wide distribution in the environment and its allergenic potential. There are indications that the prevalence of nickel sensitization in children is increased by nickel exposure and that oral uptake of nickel can exacerbate nickel dermatitis in nickel-sensitive individuals. Urinary nickel measurement is a good indicator of exposure. However, data on nickel levels in urine of children are rare. For the first time, the German Environmental Survey on children (GerES IV) 2003-2006 provided representative data to describe the internal nickel exposure of children aged 3-14 years in Germany. Nickel was measured after enrichment in the organic phase of urine by graphite furnace atomic absorption spectrometry with Zeeman background correction. Nickel levels (n=1576) ranged from <0.5 to 15 µg/l. Geometric mean was 1.26 µg/l. Multivariate regression analysis showed that gender, age, socio-economic status, being overweighted, consumption of hazelnut spread, nuts, cereals, chocolate and urinary creatinine were significant predictors for urinary nickel excretion of children who do not smoke. 20.2% of the variance could be explained by these variables. With a contribution of 13.8% the urinary creatinine concentration was the most important predictor. No influence of nickel intake via drinking water and second hand smoke exposure was observed.

Overview of the study design, participation and field work of the German Environmental Survey on Children 2003-2006 (GerES IV).

The German Federal Environment Agency carried out its fourth German Environmental Survey (GerES IV), which is the first survey on children only and the environment-related module of the German Health Interview and Examination Survey for Children and Adolescents (German acronym: KiGGS), conducted by the Robert Koch Institute (RKI). The German Environmental Surveys are nationwide population studies conducted to determine the exposure to environmental pollutants, to explore exposure pathways and to identify sub-groups with higher exposure. GerES IV was conducted on randomly selected 1790 children aged 3-14 years from the cross-sectional sample of KiGGS. The participants of GerES IV lived in 150 sampling locations all over Germany. Field work was carried out from May 2003 to May 2006. The response rate in GerES IV was 77.3%. Due to the fact that participation in GerES IV was limited to children that had previously participated in the KiGGS study, the total response rate in GerES IV resulted in 52.6%. Response rates did neither differ significantly between West and East Germany, nor between different community sizes, age groups and gender. The basic study programme included blood samples, morning urine, tap water and house dust as well as comprehensive questionnaire-based interviews. In addition, subgroups were studied with regard to "noise, hearing capacity and stress hormones", "chemical contamination of indoor air" and "biogenic indoor contamination". A key element of the field work in GerES IV was a home visit to carry out interviews, conduct measurements and collect samples. An exception was blood sampling which was carried out within KiGGS. The quality of field work, data collection, evaluation, and chemical, biological and physical analyses was successfully evaluated by internal and external quality assurance. This comprehensive overview aims at giving other research groups the opportunity to compare different study designs or to adapt their own design to get comparable results.

Reprint of "Update of the reference and HBM values derived by the German Human Biomonitoring Commission".

In 2007, we reviewed the working principles and working procedures of the German Human Biomonitoring Commission together with the reference values and human biomonitoring (HBM) values derived up to that time. Since then, the Commission has decided to derive additionally HBM I values on the basis of tolerable daily intakes and has used and evaluated this new approach on the metabolites of (2-ethylhexyl) phthalate (DEHP) in urine. Furthermore, the Commission has derived a HBM I value for thallium in urine, has recinded the HBM values for lead in blood, and has updated the HBM values for cadmium in urine. Based on the representative data of the German Environmental Survey on Children from 2003 to 2006 (GerES IV), the Commission has updated the reference values for a large number of environmental pollutants in urine and blood of children in Germany. Since 2007, the Commission has derived new and updated reference values for PFOS and PFOA in human plasma, for thallium in urine, for aromatic amines in urine, for a comprehensive number of phthalate metabolites in urine, and for organochlorine pesticides in human breast milk. Furthermore, the Commission has evaluated background exposure levels for two naphthalene metabolites and acrylamide (using acrylamide-haemoglobin adduct) for the general population. This paper reports the new values, including those already published, in order to provide an updated overview.