Urinary concentrations of phthalate/DINCH metabolites and body mass index among European children and adolescents in the HBM4EU Aligned Studies: A cross-sectional multi-country study.

BACKGROUND: Phthalates are ubiquitous in the environment. Despite short half-lives, chronic exposure can lead to endocrine disruption. The safety of phthalate substitute DINCH is unclear. OBJECTIVE: To evaluate associations between urinary concentrations of phthalate/DINCH metabolites and body mass index (BMI) z-score among children and adolescents. METHOD: We used Human Biomonitoring for Europe Aligned Studies data from 2876 children (12 studies, 6-12 years, 2014-2021) and 2499 adolescents (10 studies, 12-18 years, 2014-2021) with up to 14 phthalate/DINCH urinary metabolites. We used multilevel linear regression to assess associations between phthalate/DINCH concentrations and BMI z-scores, testing effect modification by sex. In a subset, Bayesian kernel machine regression (BKMR) and quantile-based g-computation assessed important predictors and mixture effects. RESULTS: In children, we found few associations in single pollutant models and no interactions by sex (p-interaction > 0.1). BKMR detected no relevant exposures (posterior inclusion probabilities, PIPs < 0.25), nor joint mixture effect. In adolescent single pollutant analysis, mono-ethyl phthalate (MEP) concentrations were associated with higher BMI z-score in males (ß = 0.08, 95 % CI: 0.001,0.15, per interquartile range increase in ln-transformed concentrations, p-interaction = 0.06). Conversely, mono-isobutyl phthalate (MiBP) was associated with a lower BMI z-score in both sexes (ß = -0.13, 95 % CI: -0.19, -0.07, p-interaction = 0.74), as was sum of di(2-ethylhexyl) phthalate (∑DEHP) metabolites in females only (ß = -0.08, 95 % CI: -0.14, -0.02, p-interaction = 0.01). In BKMR, higher BMI z-scores were predicted by MEP (PIP=0.90) and MBzP (PIP=0.84) in males. Lower BMI z-scores were predicted by MiBP (PIP=0.999), OH-MIDP (PIP=0.88) and OH-MINCH (PIP=0.72) in both sexes, less robustly by DEHP (PIP=0.61) in females. In quantile g-computation, the overall mixture effect was null for males, and trended negative for females (ß = -0.11, 95 % CI: -0.25, 0.03, per joint exposure quantile). CONCLUSION: In this large Europe-wide study, we found age/sex-specific differences between phthalate metabolites and BMI z-score, stronger in adolescents. Longitudinal studies with repeated phthalate measurements are needed.

Determinants of exposure to acrylamide in European children and adults based on urinary biomarkers: results from the "European Human Biomonitoring Initiative" HBM4EU participating studies.

Little is known about exposure determinants of acrylamide (AA), a genotoxic food-processing contaminant, in Europe. We assessed determinants of AA exposure, measured by urinary mercapturic acids of AA (AAMA) and glycidamide (GAMA), its main metabolite, in 3157 children/adolescents and 1297 adults in the European Human Biomonitoring Initiative. Harmonized individual-level questionnaires data and quality assured measurements of AAMA and GAMA (urine collection: 2014-2021), the short-term validated biomarkers of AA exposure, were obtained from four studies (Italy, France, Germany, and Norway) in children/adolescents (age range: 3-18 years) and six studies (Portugal, Spain, France, Germany, Luxembourg, and Iceland) in adults (age range: 20-45 years). Multivariable-adjusted pooled quantile regressions were employed to assess median differences (ß coefficients) with 95% confidence intervals (95% CI) in AAMA and GAMA (µg/g creatinine) in relation to exposure determinants. Southern European studies had higher AAMA than Northern studies. In children/adolescents, we observed significant lower AA associated with high socioeconomic status (AAMA:ß = - 9.1 µg/g creatinine, 95% CI - 15.8, - 2.4; GAMA: ß = - 3.4 µg/g creatinine, 95% CI - 4.7, - 2.2), living in rural areas (AAMA:ß = - 4.7 µg/g creatinine, 95% CI - 8.6, - 0.8; GAMA:ß = - 1.1 µg/g creatinine, 95% CI - 1.9, - 0.4) and increasing age (AAMA:ß = - 1.9 µg/g creatinine, 95% CI - 2.4, - 1.4; GAMA:ß = - 0.7 µg/g creatinine, 95% CI - 0.8, - 0.6). In adults, higher AAMA was also associated with high consumption of fried potatoes whereas lower AAMA was associated with higher body-mass-index. Based on this large-scale study, several potential determinants of AA exposure were identified in children/adolescents and adults in European countries.

A revised concept for deriving reference values for internal exposures to chemical substances and its application to population-representative biomonitoring data in German children and adolescents 2014-2017 (GerES V).

HBM reference values, in contrast to toxicologically derived values, are statistically derived values that provide information on the exposure of the population. The exceedance frequency (if applicable for individual population groups) is often a first assessment standard for the local exposure situation for municipalities. More than 25 years have passed since the German Human Biomonitoring Commission (HBMC) formulated the first recommendations for the derivation of population-based reference values (HBM reference values, RV95) for substance concentrations based on HBM studies. A fundamental revision is timely, for several reasons. There have been considerable advances in relevant statistical methods, which meant that previously time-consuming and inaccessible procedures and calculations are now widely available. Furthermore, not all steps for the derivation of HBM reference values were clearly elaborated in the first recommendations. With this revision we intended to achieve a rigorous standardization of the entire process of deriving HBM reference values, also to realise a higher degree of transparency. In accordance with established international practice, it is recommended to use the 95th percentile of the reference distribution as the HBM reference value. To this end, the empirical 95th percentile of a suitable sample should be rounded, ensuring that the rounded value is within the two-sided 95% confidence interval of the percentile. All estimates should be based on distribution-free methods, and the confidence interval should be estimated using a bootstrap approach, if possible, according to the BCa ("bias-corrected and accelerated bootstrap"). A minimum sample size of 80 observations is considered necessary. The entire procedure ensures that the derived HBM reference value is robust against at least two extreme values and can also be used for underlying mixed distributions. If it is known in advance that certain subgroups (different age groups, smokers, etc.) show differing internal exposures, it is recommended that group-specific HBM reference values should be derived. Especially when the sample sizes for individual subgroups are too small, individual datasets with potential outliers can be excluded in advance to homogenize the reference value population. In the second part, new HBM reference values based on data of the German Environmental Survey for Children and Adolescents (GerES V, 2014-2017) were derived in accordance with the revised recommendations. The GerES V is the most recent population-representative monitoring of human exposure to pollutants in Germany on children and adolescents aged 3-17 years (N = 2294). RV95 for GerES V are reported for four subgroups (males/females and 3-11/12-17 years) for 108 different substances including phthalates and alternative plasticisers, metals, organochlorine pesticides, polychlorinated biphenyls (PCB), per- and polyfluoroalkyl substances (PFAS), parabens, aprotic solvents, chlorophenols, polycyclic aromatic hydrocarbons (PAH) and UV filter, in total 135 biomarkers. Algorithms implemented in R were used for the statistics and the determination of the HBM reference values. To facilitate a quality control of the study data, the corresponding R source code is given, together with graphical representations of results. The HBM reference values listed in this article replace earlier RV95 values derived by the HBMC for children and adolescents from data of precedent GerES studies (e.g. published in Apel et al., 2017).

Exposure to Phthalates in European Children, Adolescents and Adults since 2005: A Harmonized Approach Based on Existing HBM Data in the HBM4EU Initiative.

Phthalates are mainly used as plasticizers and are associated inter alia with adverse effects on reproductive functions. While more and more national programs in Europe have started monitoring internal exposure to phthalates and its substitute 1,2-Cyclohexanedicarboxylic acid (DINCH), the comparability of results from such existing human biomonitoring (HBM) studies across Europe is challenging. They differ widely in time periods, study samples, degree of geographical coverage, design, analytical methodology, biomarker selection, and analytical quality assurance level. The HBM4EU initiative has gathered existing HBM data of 29 studies from participating countries, covering all European regions and Israel. The data were prepared and aggregated by a harmonized procedure with the aim to describe-as comparably as possible-the EU-wide general population's internal exposure to phthalates from the years 2005 to 2019. Most data were available from Northern (up to 6 studies and up to 13 time points), Western (11; 19), and Eastern Europe (9; 12), e.g., allowing for the investigation of time patterns. While the bandwidth of exposure was generally similar, we still observed regional differences for Butyl benzyl phthalate (BBzP), Di(2-ethylhexyl) phthalate (DEHP), Di-isononyl phthalate (DiNP), and Di-isobutyl phthalate (DiBP) with pronounced decreases over time in Northern and Western Europe, and to a lesser degree in Eastern Europe. Differences between age groups were visible for Di-n-butyl phthalate (DnBP), where children (3 to 5-year olds and 6 to 11-year olds) had lower urinary concentrations than adolescents (12 to 19-year-olds), who in turn had lower urinary concentrations than adults (20 to 39-year-olds). This study is a step towards making internal exposures to phthalates comparable across countries, although standardized data were not available, targeting European data sets harmonized with respect to data formatting and calculation of aggregated data (such as developed within HBM4EU), and highlights further suggestions for improved harmonization in future studies.

Current exposure to phthalates and DINCH in European children and adolescents - Results from the HBM4EU Aligned Studies 2014 to 2021.

Phthalates are mainly used as plasticizers for polyvinyl chloride (PVC). Exposure to several phthalates is associated with different adverse effects most prominently on the development of reproductive functions. The HBM4EU Aligned Studies (2014-2021) have investigated current European exposure to ten phthalates (DEP, BBzP, DiBP, DnBP, DCHP, DnPeP, DEHP, DiNP, DiDP, DnOP) and the substitute DINCH to answer the open policy relevant questions which were defined by HBM4EU partner countries and EU institutions as the starting point of the programme. The exposure dataset includes ∼5,600 children (6-11 years) and adolescents (12-18 years) from up to 12 countries per age group and covering the North, East, South and West European regions. Study data from participating studies were harmonised with respect to sample size and selection of participants, selection of biomarkers, and quality and comparability of analytical results to provide a comparable perspective of European exposure. Phthalate and DINCH exposure were deduced from urinary excretions of metabolites, where concentrations were expressed as their key descriptor geometric mean (GM) and 95th percentile (P95). This study aims at reporting current exposure levels and differences in these between European studies and regions, as well as comparisons to human biomonitoring guidance values (HBM-GVs). GMs for children were highest for ∑DEHP metabolites (33.6 µg/L), MiBP (26.6 µg/L), and MEP (24.4 µg/L) and lowest for∑DiDP metabolites (1.91 µg/L) and ∑DINCH metabolites (3.57 µg/L). In adolescents highest GMs were found for MEP (43.3 µg/L), ∑DEHP metabolites (28.8 µg/L), and MiBP (25.6 µg/L) and lowest for ∑DiDP metabolites (= 2.02 µg/L) and ∑DINCH metabolites (2.51 µg/L). In addition, GMs and P95 stratified by European region, sex, household education level, and degree of urbanization are presented. Differences in average biomarker concentrations between sampling sites (data collections) ranged from factor 2 to 9. Compared to the European average, children in the sampling sites OCC (Denmark), InAirQ (Hungary), and SPECIMEn (The Netherlands) had the lowest concentrations across all metabolites and ESTEBAN (France), NAC II (Italy), and CROME (Greece) the highest. For adolescents, comparably higher metabolite concentrations were found in NEB II (Norway), PCB cohort (Slovakia), and ESTEBAN (France), and lower concentrations in POLAES (Poland), FLEHS IV (Belgium), and GerES V-sub (Germany). Multivariate analyses (Survey Generalized Linear Models) indicate compound-specific differences in average metabolite concentrations between the four European regions. Comparison of individual levels with HBM-GVs revealed highest rates of exceedances for DnBP and DiBP, with up to 3 and 5%, respectively, in children and adolescents. No exceedances were observed for DEP and DINCH. With our results we provide current, detailed, and comparable data on exposure to phthalates in children and - for the first time - in adolescents, and - for the first time - on DINCH in children and adolescents of all four regions of Europe which are particularly suited to inform exposure and risk assessment and answer open policy relevant questions.

Interpreting biomonitoring data: Introducing the international human biomonitoring (i-HBM) working group's health-based guidance value (HB2GV) dashboard.

Human biomonitoring (HBM) data measured in specific contexts or populations provide information for comparing population exposures. There are numerous health-based biomonitoring guidance values, but to locate these values, interested parties need to seek them out individually from publications, governmental reports, websites and other sources. Until now, there has been no central, international repository for this information. Thus, a tool is needed to help researchers, public health professionals, risk assessors, and regulatory decision makers to quickly locate relevant values on numerous environmental chemicals. A free, on-line repository for international health-based guidance values to facilitate the interpretation of HBM data is now available. The repository is referred to as the "Human Biomonitoring Health-Based Guidance Value (HB2GV) Dashboard". The Dashboard represents the efforts of the International Human Biomonitoring Working Group (i-HBM), affiliated with the International Society of Exposure Science. The i-HBM's mission is to promote the use of population-level HBM data to inform public health decision-making by developing harmonized resources to facilitate the interpretation of HBM data in a health-based context. This paper describes the methods used to compile the human biomonitoring health-based guidance values, how the values can be accessed and used, and caveats with using the Dashboard for interpreting HBM data. To our knowledge, the HB2GV Dashboard is the first open-access, curated database of HBM guidance values developed for use in interpreting HBM data. This new resource can assist global HBM data users such as risk assessors, risk managers and biomonitoring programs with a readily available compilation of guidance values.

Urinary cotinine and exposure to passive smoke in children and adolescents in Germany - Human biomonitoring results of the German Environmental Survey 2014-2017 (GerES V).

Passive smoking is a preventable and significant cause of many serious health problems, with children being particularly at risk. In the fifth German Environmental Survey (GerES V), conducted from 2014 to 2017, information reflecting the extent of passive smoke exposure in children and adolescents was collected by interview-based questionnaires and human biomonitoring (HBM) analyses of cotinine in urine from 2260 participants, aged 3-17 years. Based on these population-representative data, we describe current passive smoke exposure stratified by different subgroups and identify specific exposure determinants using multivariate logistic regression. The questionnaire data revealed that 42% of children and adolescents lived with at least one smoker in the household. Quantifiable concentrations of cotinine could be detected in 56% of the participants. The overall median concentration of cotinine was 0.2 µg/L, with children and adolescents of low socioeconomic status found to be a group particularly affected by passive smoke with higher cotinine concentrations (median = 1.2 µg/L). In the multiple analysis, the most significant predictor of cotinine levels derived from the questionnaire was passive smoking at home (odds ratio (OR) 13.07 [95CI: 4.65, 36.70]). However, parental smoking and passive smoking among friends and relatives could also be identified as independent factors influencing elevated cotinine levels. The comparison between the previous cycle GerES IV (2003-2006) on 3-14-year-olds and GerES V shows that tobacco smoke exposure of children decreased significantly. This decrease is likely an effect of extensive non-smoker protection laws being enforced 2007-2008 on federal and state level. This is reflected by a halving of urinary cotinine concentrations. Nevertheless, our results indicate that passive smoke is still a relevant source of harmful pollutants for many children and adolescents in Germany, and thus support the need for further efforts to reduce passive smoke exposure, especially in the private environment.

A Human Biomonitoring Study Assessing Glyphosate and Aminomethylphosphonic Acid (AMPA) Exposures among Farm and Non-Farm Families.

Glyphosate-based pesticides are the highest-volume used herbicides worldwide. International concerns regarding the potential human adverse effects of glyphosate exposures have heightened since IARC classified glyphosate as probably carcinogenic to humans. Human biomonitoring (HBM) studies have identified ubiquitous exposure to glyphosate and its main breakdown product, aminomethylphosphonic acid (AMPA), from environmental exposures. The IMAGE research project aimed to investigate farm and non-farm families' exposure to glyphosate while aligning with the Human Biomonitoring for Europe (HBM4EU) initiative. The study recruited non-farm and farm families (who use glyphosate on their farms). Each family member provided a urine sample that was analysed using gas chromatography coupled with tandem mass spectrometry, with a limit of quantification of 0.05 µg/L for glyphosate and AMPA. In addition to general information on background exposures in farm and non-farm families, we investigated relationships in exposure between families and family members. We recruited 68 families, including 54 non-farm and 14 farm families (180 vs. 45 individuals). Some pesticide users (n = 14, all male farmers) had slightly elevated AMPA levels compared to other adult participants but, overall, we observed no significant differences between farm and non-farm families. The main metabolite, AMPA, was quantifiable in twice as many samples as glyphosate (61% vs. 32%), with a maximum concentration of 7.24 µg/L vs. 3.21 µg/L. Compared to previous studies, exposure levels were relatively low and far below current health-based guidance values (3% or less for glyphosate and AMPA). Study results suggest potential exposures from residential co-exposures or living with a pesticide user. This is the first study internationally to investigate glyphosate and AMPA across family members (farm and non-farm). We found comparably low glyphosate and AMPA exposures among these families. These results enhance our understanding of glyphosate exposures for different demographic groups and contribute to the scientific knowledge on exposures required for regulatory risk assessments and the re-evaluation of glyphosate in 2022 by the European Commission.

Trends of Exposure to Acrylamide as Measured by Urinary Biomarkers Levels within the HBM4EU Biomonitoring Aligned Studies (2000-2021).

Acrylamide, a substance potentially carcinogenic in humans, represents a very prevalent contaminant in food and is also contained in tobacco smoke. Occupational exposure to higher concentrations of acrylamide was shown to induce neurotoxicity in humans. To minimize related risks for public health, it is vital to obtain data on the actual level of exposure in differently affected segments of the population. To achieve this aim, acrylamide has been added to the list of substances of concern to be investigated in the HBM4EU project, a European initiative to obtain biomonitoring data for a number of pollutants highly relevant for public health. This report summarizes the results obtained for acrylamide, with a focus on time-trends and recent exposure levels, obtained by HBM4EU as well as by associated studies in a total of seven European countries. Mean biomarker levels were compared by sampling year and time-trends were analyzed using linear regression models and an adequate statistical test. An increasing trend of acrylamide biomarker concentrations was found in children for the years 2014-2017, while in adults an overall increase in exposure was found to be not significant for the time period of observation (2000-2021). For smokers, represented by two studies and sampling for, over a total three years, no clear tendency was observed. In conclusion, samples from European countries indicate that average acrylamide exposure still exceeds suggested benchmark levels and may be of specific concern in children. More research is required to confirm trends of declining values observed in most recent years.

Lead, cadmium, mercury, and chromium in urine and blood of children and adolescents in Germany - Human biomonitoring results of the German Environmental Survey 2014-2017 (GerES V).

Metals reach humans through food and drinking water intake and inhalation of airborne particles and can have detrimental health effects in particular for children. The metals presented here (lead, cadmium, chromium, and mercury) could lead to toxic effects such as neurotoxicity, mutagenicity, and have been classified as (possible) carcinogens. Using population representative data from the German Environmental Survey 2014-2017 (GerES V) from 3- to 17-year-old children on lead and cadmium in blood (n = 720) and on cadmium, chromium, and mercury in urine (n = 2250) we describe current internal exposure levels, and socio-demographic and substance-specific exposure determinants. Average internal exposure (geometric means) in blood was 9.47 µg/L for lead and below 0.06 µg/L (limit of quantification) for cadmium, and in urine 0.072 µg/L for cadmium, 0.067 µg/L for mercury, and 0.393 µg/L for chromium, respectively. Younger children have higher concentrations of lead and chromium compared to 14-17-year-old adolescents, and boys have slightly higher mercury concentrations than girls. With respect to substance specific determinants, higher lead concentrations emerged in participants with domestic fuel and in non-smoking children with smokers in the household, higher levels of cadmium were associated with smoking and vegetarian diet and higher levels of mercury with the consumption of seafood and amalgam teeth fillings. No specific exposure determinants emerged for chromium. The health based guidance value HBM-I was not exceeded for mercury and for cadmium in urine it was exceeded by 0.6% of the study population. None of the exceedances was related to substantial tobacco smoke exposure. Comparisons to previous GerES cycles (GerES II, 1990-1992; GerES IV, 2003-2006) indicate continuously lower levels.

Determination of trace elements in urine by inductively coupled plasma-tandem mass spectrometry - Biomonitoring of adults in the German capital region.

A method was developed and validated for multi-element analyses of human urine samples using inductively coupled plasma-tandem mass spectrometry. The combination of a simple sample preparation and the state-of-the-art technique allows high-throughput and lowest limits of quantification up to 1 ng/L. Thereby coefficients of variation ranges from 0.4% (V) to 3.7% (Be), and 0.9% (Cd) to 4.8% (Ni) for intraday and interday precision, respectively. The method's performance is demonstrated by successful participation in international interlaboratory comparison programs as external quality assurance. Moreover, the method was applied for the analysis of first-morning void urine samples of adults (N = 77) living in the German capital region. 15 metals and metalloids (Astotal, Be, Bi, Cd, Co, Cr, In, Mn, Mo, Ni, Pb, Sn, Tl, V, and Zn) were determined. With exception of indium, all elements were found in urine samples above the limit of quantification, demonstrating the suitability to measure the general population's exposure to these metals and metalloids. The method presented here shall be used for analysis of urine samples collected in the upcoming German Environmental Survey, GerES VI, a cross-sectional, population-representative study.

Glyphosate and aminomethylphosphonic acid (AMPA) in urine of children and adolescents in Germany - Human biomonitoring results of the German Environmental Survey 2014-2017 (GerES V).

Since the 1970s, glyphosate has become the most used herbicide of the world. The general population is ubiquitously exposed to glyphosate. Its long-term toxicity, carcinogenic potential and other health effects are controversially discussed. Even though the possible health impacts of glyphosate are of global concern, no population-wide monitoring of glyphosate was done yet. This study presents the worldwide first population-representative data on glyphosate and its metabolite aminomethylphosphonic acid (AMPA) for children and adolescents. 2144 first-morning void urine samples of 3-17-year-old children and adolescents living in Germany were analysed for concentrations of glyphosate and AMPA in the German Environmental Survey for Children and Adolescents 2014-2017 (GerESV). In 52 % of the samples (46 % for AMPA) the urinary glyphosate concentrations were above the limit of quantification of 0.1 µg/L. The geometric mean concentrations were 0.107 µg/L (0.090 µg/gcreatinine) for glyphosate and 0.100 µg/L (0.085 µg/gcreatinine) for AMPA. No clear association between exposure to glyphosate or AMPA and vegetarian diet or consumption of cereals, pulses, or vegetables could be identified. The low quantification rate and the 95th percentiles for glyphosate and AMPA of around 0.5 µg/L demonstrate an overall low exposure of the young population in Germany.

Substitutes mimic the exposure behaviour of REACH regulated phthalates - A review of the German HBM system on the example of plasticizers.

The population is constantly exposed to potentially harmful substances present in the environment, including inter alia food and drinking water, consumer products, and indoor air. Human biomonitoring (HBM) is a valuable tool to determine the integral, internal exposure of the general population, including vulnerable subgroups, to provide the basis for risk assessment and policy advice. The German HBM system comprises of five pillars: (1) the development of suitable analytical methods for new substances of concern, (2) cross-sectional population-representative German Environmental Surveys (GerES), (3) time trend analyses using archived samples from the Environmental Specimen Bank (ESB), (4) the derivation of health-based guidance values as a risk assessment tool, and (5) transfer of data into the European cooperation network HBM4EU. The goal of this paper is to present the complementary elements of the German HBM system and to show its strengths and limitations on the example of plasticizers. Plasticizers have been identified by EU services and HBM4EU partners as priority substances for chemical policy at EU level. Using the complementary elements of the German HBM system, the internal exposure to classical phthalates and novel alternative plasticizers can be reliably monitored. It is shown that market changes, due to regulation of certain phthalates and the rise of substitutes, are rapidly reflected in the internal exposure of the population. It was shown that exposure to DEHP, DiBP, DnBP, and BBzP decreased considerably, whereas exposure to the novel substitutes such as DPHP, DEHTP, and Hexamoll®DINCH has increased significantly. While health-based guidance values for several phthalates (esp. DnBP, DiBP, DEHP) were exceeded quite often at the turn of the millennium, exceedances today have become rarer. Still, also the latest GerES reveals the ubiquitous and concurrent exposures to many plasticizers. Of concern is that the youngest children showed the highest exposures to most of the investigated plasticizers and in some cases their levels of DiBP and DnBP still exceeded health-based guidance values. Over the last years, mixture exposures are increasingly recognized as relevant, especially if the toxicological modes of action are similar. This is supported by a cumulative risk assessment for four endocrine active phthalates which confirms the still concerning cumulative exposure in many young children. Given the adverse health effects of some phthalates and the limited toxicological knowledge of substitutes, exposure reduction and surveillance are needed on German and EU-level. Substitutes need to be monitored, to intervene if exposures are threatening to exceed acceptable levels, or if new toxicological data question their appropriateness. It is strongly recommended to reconsider the use of plastics and plasticizers.

Pentachlorophenol and nine other chlorophenols in urine of children and adolescents in Germany - Human biomonitoring results of the German Environmental Survey 2014-2017 (GerES V).

Chlorophenols comprise of a large group of chemicals used inter alia for the production of biocides, pharmaceuticals, other industrial products and are used e.g. as antiseptics or wood preservatives due to their biocidal properties. Several of them are classified as toxic to aquatic life and harmful to humans by ingestion, inhalation, or dermal contact, causing skin and eye irritation. Moreover, chlorophenols are possibly carcinogenic to humans. The most prominent chlorophenol - pentachlorophenol - is carcinogenic to humans, was banned in Germany in 1989 and further regulated by the European Commission in 2006 and included in the Stockholm Convention in 2017. Some chlorophenols are persistent in the environment and are also biodegradation products of precursor substances. To evaluate the health-relevance of recent exposure and monitor the effectiveness of regulatory measures, chlorophenols were analysed in the population-representative German Environmental Survey on Children and Adolescents 2014-2017 (GerES V). First-morning void urine samples of 485 3-17-year-old children and adolescents were analysed for ten chlorophenols. Pentachlorophenol was still quantified in 87% of the children and adolescents with a geometric mean (GM) concentration of 0.19 µg/L (0.16 µg/gcrea) and a maximum concentration of 6.7 µg/L (5.4 µg/gcrea). The maximum concentration was well below the health-based guidance value HBM-I of 25 µg/L (20 µg/gcrea). 4-Monochlorophenol was quantified in all samples with a GM concentration of 1.38 µg/L (1.14 µg/gcrea). 2-Monochlorophenol, 2,4-dichlorophenol, and 2,5-dichlorophenol were quantified in 97%, 98%, and 95% of the samples, with GMs of 0.26 µg/L (0.21 µg/gcrea), 0.24 µg/L (0.20 µg/gcrea), and 0.26 µg/L (0.21 µg/gcrea). 2,6-dichlorophenol, 2,3,4-trichlorophenol, and 2,4,5-trichlorophenol were quantified in 17-25% of the samples with GMs below the limit of quantification (LOQ) of 0.1 µg/L 2,4,6-trichlorophenol was quantified in 72% of the samples (GM: 0.13 µg/L, 0.11 µg/gcrea), 2,3,4,6-tetrachlorophenol in 44% of the samples (GM < LOQ). Comparison to previous cycles of GerES revealed substantially lower exposure to most of the chlorophenols in GerES V. Exposure levels found in Germany were comparatively low in contrast to North American results.

Metabolites of 4-methylbenzylidene camphor (4-MBC), butylated hydroxytoluene (BHT), and tris(2-ethylhexyl) trimellitate (TOTM) in urine of children and adolescents in Germany - human biomonitoring results of the German Environmental Survey GerES V (2014-2017).

The UV filter 4-methylbenzylidene camphor (4-MBC), used in cosmetics, the antioxidant butylated hydroxytoluene (BHT), used inter alia as a food additive and in cosmetics, and the plasticizer tris(2-ethylhexyl) trimellitate (TOTM), used mainly in medical devices as substitute for di-(2-ethylhexyl) phthalate (DEHP), are suspected to have endocrine disrupting effects. Human biomonitoring methods that allow for assessing the internal exposure of the general population to these substances were recently developed in a German cooperation to enhance the use of human biomonitoring. First-morning void urine samples from 3- to 17-year-old children and adolescents living in Germany were analysed for metabolites of 4-MBC (N = 447), BHT (N = 2091), and TOTM (N = 431) in the population-representative German Environmental Survey on Children and Adolescents 2014-2017 (GerES V). 4-MBC metabolites were found in quantifiable amounts only in single cases and exposure levels remained well below health-based guidance values. In contrast, ubiquitous exposure to BHT became evident with a geometric mean (GM) urinary concentration of the metabolite BHT acid of 2.346 µg/L (1.989 µg/gcreatinine) and a maximum concentration of 248 µg/L (269 µg/gcrea). The highest GM concentration was found in young children aged 3-5 years, yet no specific sources of exposure could be identified. Also, TOTM metabolites were found in quantifiable amounts only in very few samples. None of these findings could be related to previous hospital treatment or exposure via house dust. The presented results will be the basis to derive reference values for exposure of children and adolescents in Germany to BHT and will facilitate to identify changing exposure levels in the general population.

Benzene metabolite SPMA and acrylamide metabolites AAMA and GAMA in urine of children and adolescents in Germany - human biomonitoring results of the German Environmental Survey 2014-2017 (GerES V).

Benzene and acrylamide are carcinogenic substances contained inter alia in tobacco smoke. The mercapturic acid metabolites of benzene, N-acetyl-S-phenyl-L-cysteine (SPMA), and of acrylamide, N-acetyl-S-(3-amino-3-oxopropyl)-cysteine (AAMA) and N-acetyl-S-(3-amino-2-hydroxy-3-oxopropyl)-cysteine (GAMA), were analysed in 2260 first-morning void urine samples from children and adolescents aged 3-17 years, participating in the population-representative German Environmental Survey on Children and Adolescents, GerES V 2014-2017. SPMA was detected in 98% of the participants with a geometric mean (GM) of 0.097 µg/L urine. Smokers had about 10-fold higher levels of the benzene metabolite SPMA than non-smokers. The sample comprises of 48 self-reported smokers, mainly in the oldest age group (14-17-year-olds). Second-hand smoke exposure, living near busy or very busy roads, and using domestic fuels for heating were additionally associated with higher benzene metabolite levels. SPMA levels in GerES V were lower compared to levels found in other countries, which in part however may reflect different proportions of smokers. The acrylamide metabolites AAMA and GAMA were detected in 100% of the participants with a GM of 72.6 µg/L urine for AAMA and 15.0 µg/L urine for GAMA. Smoking children and adolescents had about 2.5-fold higher AAMA levels than non-smoking ones. The frequency of consumption of french-fried potatoes and potato crisps consumption was also positively associated with urinary AAMA and GAMA levels. Compared to the urinary AAMA and GAMA levels in Germany and other countries, levels in GerES V tended to be higher than in the few studies reported. The urinary levels of the benzene biomarker SPMA, and the acrylamide biomarkers AAMA and GAMA build the basis to derive reference values for the exposure of children and adolescents in Germany. The results reveal options for exposure reduction mainly in personal choices regarding smoking and diet, but also requiring policy to maintain efforts in non-smoking regulations and improving ambient air quality. Providing these results also to the European HBM Initiative HBM4EU will contribute to gain knowledge on the exposure of the European population, the health impact of carcinogens and thus providing support for substantiated exposure assessment.

Alkyl pyrrolidone solvents N-methyl-2-pyrrolidone (NMP) and N-ethyl-2-pyrrolidone (NEP) in urine of children and adolescents in Germany - human biomonitoring results of the German Environmental Survey 2014-2017 (GerESV).

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 listfor 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 (GerESV). 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.

Parabens in urine of children and adolescents in Germany - human biomonitoring results of the german environmental survey 2014-2017 (GerES V).

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.