A walk in the PARC: developing and implementing 21st century chemical risk assessment in Europe.

Current approaches for the assessment of environmental and human health risks due to exposure to chemical substances have served their purpose reasonably well. Nevertheless, the systems in place for different uses of chemicals are faced with various challenges, ranging from a growing number of chemicals to changes in the types of chemicals and materials produced. This has triggered global awareness of the need for a paradigm shift, which in turn has led to the publication of new concepts for chemical risk assessment and explorations of how to translate these concepts into pragmatic approaches. As a result, next-generation risk assessment (NGRA) is generally seen as the way forward. However, incorporating new scientific insights and innovative approaches into hazard and exposure assessments in such a way that regulatory needs are adequately met has appeared to be challenging. The European Partnership for the Assessment of Risks from Chemicals (PARC) has been designed to address various challenges associated with innovating chemical risk assessment. Its overall goal is to consolidate and strengthen the European research and innovation capacity for chemical risk assessment to protect human health and the environment. With around 200 participating organisations from all over Europe, including three European agencies, and a total budget of over 400 million euro, PARC is one of the largest projects of its kind. It has a duration of seven years and is coordinated by ANSES, the French Agency for Food, Environmental and Occupational Health & Safety.

Approaches to mixture risk assessment of PFASs in the European population based on human hazard and biomonitoring data.

Per- and polyfluoroalkyl substances (PFASs) are a highly persistent, mobile, and bioaccumulative class of chemicals, of which emissions into the environment result in long-lasting contamination with high probability for causing adverse effects to human health and the environment. Within the European Biomonitoring Initiative HBM4EU, samples and data were collected in a harmonized way from human biomonitoring (HBM) studies in Europe to derive current exposure data across a geographic spread. We performed mixture risk assessments based on recent internal exposure data of PFASs in European teenagers generated in the HBM4EU Aligned Studies (dataset with N = 1957, sampling years 2014-2021). Mixture risk assessments were performed based on three hazard-based approaches: the Hazard Index (HI) approach, the sum value approach as used by the European Food Safety Authority (EFSA) and the Relative Potency Factor (RPF) approach. The HI approach resulted in the highest risk estimates, followed by the RPF approach and the sum value approach. The assessments indicate that PFAS exposure may result in a health risk in a considerable fraction of individuals in the HBM4EU teenager study sample, thereby confirming the conclusion drawn in the recent EFSA scientific opinion. This study underlines that HBM data are of added value in assessing the health risks of aggregate and cumulative exposure to PFASs, as such data are able to reflect exposure from different sources and via different routes.

PFAS levels and determinants of variability in exposure in European teenagers - Results from the HBM4EU aligned studies (2014-2021).

BACKGROUND: Perfluoroalkyl substances (PFAS) are man-made fluorinated chemicals, widely used in various types of consumer products, resulting in their omnipresence in human populations. The aim of this study was to describe current PFAS levels in European teenagers and to investigate the determinants of serum/plasma concentrations in this specific age group. METHODS: PFAS concentrations were determined in serum or plasma samples from 1957 teenagers (12-18 years) from 9 European countries as part of the HBM4EU aligned studies (2014-2021). Questionnaire data were post-harmonized by each study and quality checked centrally. Only PFAS with an overall quantification frequency of at least 60% (PFOS, PFOA, PFHxS and PFNA) were included in the analyses. Sociodemographic and lifestyle factors were analysed together with food consumption frequencies to identify determinants of PFAS exposure. The variables study, sex and the highest educational level of household were included as fixed factors in the multivariable linear regression models for all PFAS and each dietary variable was added to the fixed model one by one and for each PFAS separately. RESULTS: The European exposure values for PFAS were reported as geometric means with 95% confidence intervals (CI): PFOS [2.13 µg/L (1.63-2.78)], PFOA ([0.97 µg/L (0.75-1.26)]), PFNA [0.30 µg/L (0.19-0.45)] and PFHxS [0.41 µg/L (0.33-0.52)]. The estimated geometric mean exposure levels were significantly higher in the North and West versus the South and East of Europe. Boys had significantly higher concentrations of the four PFAS compared to girls and significantly higher PFASs concentrations were found in teenagers from households with a higher education level. Consumption of seafood and fish at least 2 times per week was significantly associated with 21% (95% CI: 12-31%) increase in PFOS concentrations and 20% (95% CI: 10-31%) increase in PFNA concentrations as compared to less frequent consumption of seafood and fish. The same trend was observed for PFOA and PFHxS but not statistically significant. Consumption of eggs at least 2 times per week was associated with 11% (95% CI: 2-22%) and 14% (95% CI: 2-27%) increase in PFOS and PFNA concentrations, respectively, as compared to less frequent consumption of eggs. Significantly higher PFOS concentrations were observed for participants consuming offal (14% (95% CI: 3-26%)), the same trend was observed for the other PFAS but not statistically significant. Local food consumption at least 2 times per week was associated with 40% (95% CI: 19-64%) increase in PFOS levels as compared to those consuming local food less frequently. CONCLUSION: This work provides information about current levels of PFAS in European teenagers and potential dietary sources of exposure to PFAS in European teenagers. These results can be of use for targeted monitoring of PFAS in food.

Human biomonitoring guidance values (HBM-GVs) for priority substances under the HBM4EU initiative - New values derivation for deltamethrin and cyfluthrin and overall results.

The European Initiative HBM4EU aimed to further establish human biomonitoring across Europe as an important tool for determining population exposure to chemicals and as part of health-related risk assessments, thus making it applicable for policy advice. Not only should analytical methods and survey design be harmonized and quality assured, but also the evaluation of human biomonitoring data. For the health-related interpretation of the data within HBM4EU, a strategy for deriving health-based human biomonitoring guidance values (HBM-GVs) for both the general population and workers was agreed on. On this basis, HBM-GVs for exposure biomarkers of 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH), phthalates (diethyl hexyl phthalate (DEHP), di-n-butyl phthalate (DnBP), diisobutyl phthalate (DiBP), butyl benzyl phthalate (BBzP), and bis-(2-propylheptyl) phthalate (DPHP)), bisphenols A and S, pyrethroids (deltamethrin and cyfluthrin), solvents (1-methyl-2-pyrrolidone (NMP), 1-ethylpyrrolidin-2-one (NEP), N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC)), the heavy metal cadmium and the mycotoxin deoxynivalenol (DON) were developed and assigned a level of confidence. The approach to HBM-GV derivations, results, and limitations in data interpretation with special focus on the pyrethroids are presented in this paper.

German Environmental Specimen Bank: 24-hour urine samples from 1999 to 2017 reveal rapid increase in exposure to the para-phthalate plasticizer di(2-ethylhexyl) terephthalate (DEHTP).

The worldwide plasticizer markets are facing constant substitution processes. Many classic ortho-phthalate plasticizers like di(2-ethylhexyl) phthalate (DEHP) are phased out, due to their proven toxicity to reproduction. Assumedly less critical, less regulated plasticizers such as di(2-ethylhexyl) terephthalate (DEHTP) are increasingly applied in consumer near products like toys, food contact materials, and medical devices. With the increasing use of DEHTP, increasing exposures of the general population have to be expected likewise. Human biomonitoring is a well-established tool to determine population exposures. In the present study we investigate the time trend of exposure to DEHTP using 24-hour urine samples of the German Environmental Specimen Bank (ESB) collected from 1999 to 2017. In these samples (60 per odd-numbered year, 600 samples in total) collected from young German adults (20-29 years, equal gender distribution) we determined four specific urinary metabolites as biomarkers of DEHTP exposure. From 1999 to 2009, the main specific urinary metabolite 5cx-MEPTP was quantifiable in <10% of the samples. Thereafter, detection rates and levels constantly increased, in line with rapidly increasing DEHTP consumption volumes. In 2017, all samples had 5cx-MEPTP levels above the limit of quantification (LOQ) with a median concentration of 3.35 µg/L (95th percentile: 12.8 µg/L). The other metabolites were detected less frequently and at lower levels but correlated well with 5cx-MEPTP robustly confirming the increasing DEHTP exposure. All 5cx-MEPTP concentrations were well below the German health based guidance value (HBM-I) of 2800 µg/L for adults. Likewise, the median calculated daily intake, based on 5cx-MEPTP measured in 2017, was 0.74 µg/kg bw∗d (95th percentile: 3.86 µg/kg bw∗d), still well below the tolerable daily intake (TDI) of 1000 µg/kg bw∗d. Based on current toxicological knowledge we can hence conclude that for the population investigated, DEHTP exposure gives no reason for immediate concern. However, the steep ongoing increase of DEHTP exposure warrants further close monitoring in the future, preferably also in sub-populations with known higher exposures to plasticizers, especially children.

The German approach to regulate indoor air contaminants.

Indoor air quality (IAQ) and exposure to indoor chemicals are widely discussed in terms of personal discomfort and health risks. In contrast to ambient air and working environments, legally binding regulations are only partially established for indoor contaminants, and other available European guidelines are limited. To correct these deficits, the German Committee on Indoor Guide Values (AIR), formerly known as the Ad hoc Working Group (Ad hoc AG), performed health assessments of indoor air contaminants. The main tasks were to develop toxicologically based indoor air guide values, health-based guideline values, and reference values largely based on the 95th percentile of the concentrations found in a reference population. Here, we provide a comprehensive overview of the indoor air values set in Germany and discuss the basis of their derivation. This overview includes a description of legally binding standards, indoor air guide values for 38 substances or groups, and guidelines for TVOC (total volatile organic compounds), particulate matter, and carbon dioxide as well as risk-related guidelines for carcinogenic substances.

Bis-(2-propylheptyl)phthalate (DPHP) metabolites emerging in 24h urine samples from the German Environmental Specimen Bank (1999-2012).

Bis-(2-propylheptyl)-phthalate (DPHP) has been introduced as a substitute for other high molecular weight phthalates primarily used in high temperature applications (e.g. cable wires, roofing membranes). The aim of this study was to investigate how the increased usage of DPHP is reflected in urine samples collected over the last 14 years and to evaluate the current extent of exposure. We analyzed 300 urine samples (24h voids) from the German Environmental Specimen Bank collected in the years 1999, 2003, 2006, 2009 and 2012, 60 samples per year, from 30 male and 30 female volunteers (age: 20-30 years) for three specific, secondary oxidized DPHP metabolites (with hydroxy, oxo and carboxy modifications of the alkyl side chain). We determined DPHP metabolites with a previously developed GC-HRMS method, enabling us to unambiguously distinguish DPHP metabolites from co-eluting, structurally isomeric di-iso-decyl phthalate (DIDP) metabolites. All samples were blinded before analysis. We detected no DPHP metabolites in urine samples from the years 1999, 2003 and 2006. Thereafter, detection rates increased from 3.3% in 2009 to 21.7% in 2012. Mono-oxo-propylheptylphthalate (oxo-MPHP) was the most abundant metabolite, with concentrations between

A pilot study on the feasibility of European harmonized human biomonitoring: Strategies towards a common approach, challenges and opportunities.

In 2004 the European Commission and Member States initiated activities towards a harmonized approach for Human Biomonitoring surveys throughout Europe. The main objective was to sustain environmental health policy by building a coherent and sustainable framework and by increasing the comparability of data across countries. A pilot study to test common guidelines for setting up surveys was considered a key step in this process. Through a bottom-up approach that included all stakeholders, a joint study protocol was elaborated. From September 2011 till February 2012, 17 European countries collected data from 1844 mother-child pairs in the frame of DEMOnstration of a study to COordinate and Perform Human Biomonitoring on a European Scale (DEMOCOPHES).(1) Mercury in hair and urinary cadmium and cotinine were selected as biomarkers of exposure covered by sufficient analytical experience. Phthalate metabolites and Bisphenol A in urine were added to take into account increasing public and political awareness for emerging types of contaminants and to test less advanced markers/markers covered by less analytical experience. Extensive efforts towards chemo-analytical comparability were included. The pilot study showed that common approaches can be found in a context of considerable differences with respect to experience and expertize, socio-cultural background, economic situation and national priorities. It also evidenced that comparable Human Biomonitoring results can be obtained in such context. A European network was built, exchanging information, expertize and experiences, and providing training on all aspects of a survey. A key challenge was finding the right balance between a rigid structure allowing maximal comparability and a flexible approach increasing feasibility and capacity building. Next steps in European harmonization in Human Biomonitoring surveys include the establishment of a joint process for prioritization of substances to cover and biomarkers to develop, linking biomonitoring surveys with health examination surveys and with research, and coping with the diverse implementations of EU regulations and international guidelines with respect to ethics and privacy.

Interpreting biomarker data from the COPHES/DEMOCOPHES twin projects: Using external exposure data to understand biomarker differences among countries.

In 2011 and 2012, the COPHES/DEMOCOPHES twin projects performed the first ever harmonized human biomonitoring survey in 17 European countries. In more than 1800 mother-child pairs, individual lifestyle data were collected and cadmium, cotinine and certain phthalate metabolites were measured in urine. Total mercury was determined in hair samples. While the main goal of the COPHES/DEMOCOPHES twin projects was to develop and test harmonized protocols and procedures, the goal of the current paper is to investigate whether the observed differences in biomarker values among the countries implementing DEMOCOPHES can be interpreted using information from external databases on environmental quality and lifestyle. In general, 13 countries having implemented DEMOCOPHES provided high-quality data from external sources that were relevant for interpretation purposes. However, some data were not available for reporting or were not in line with predefined specifications. Therefore, only part of the external information could be included in the statistical analyses. Nonetheless, there was a highly significant correlation between national levels of fish consumption and mercury in hair, the strength of antismoking legislation was significantly related to urinary cotinine levels, and we were able to show indications that also urinary cadmium levels were associated with environmental quality and food quality. These results again show the potential of biomonitoring data to provide added value for (the evaluation of) evidence-informed policy making.

Gender differences in cadmium and cotinine levels in prepubertal children.

Susceptibility to environmental stressors has been described for fetal and early childhood development. However, the possible susceptibility of the prepubertal period, characterized by the orchestration of the organism towards sexual maturation and adulthood has been poorly investigated and exposure data are scarce. In the current study levels of cadmium (Cd), cotinine and creatinine in urine were analyzed in a subsample 216 children from 12 European countries within the DEMOCOPHES project. The children were divided into six age-sex groups: boys (6-8 years, 9-10 years and 11 years old), and girls (6-7 years, 8-9 years, 10-11 years). The number of subjects per group was between 23 and 53. The cut off values were set at 0.1 µg/L for Cd, and 0.8 µg/L for cotinine defined according to the highest limit of quantification. The levels of Cd and cotinine were adjusted for creatinine level. In the total subsample group, the median level of Cd was 0.180 µg/L (range 0.10-0.69 µg/L), and for cotinine the median wet weight value was 1.50 µg/L (range 0.80-39.91 µg/L). There was no significant difference in creatinine and cotinine levels between genders and age groups. There was a significant correlation between levels of cadmium and creatinine in all children of both genders. This shows that even at such low levels the possible effect of cadmium on kidney function was present and measurable. An increase in Cd levels was evident with age. Cadmium levels were significantly different between 6-7 year old girls, 11 year old boys and 10-11 year old girls. As there was a balanced distribution in the number of subjects from countries included in the study, bias due to data clustering was not probable. The impact of low Cd levels on kidney function and gender differences in Cd levels needs further investigation.

German health-related environmental monitoring: assessing time trends of the general population's exposure to heavy metals.

The German system of a health-related environmental monitoring is based upon two instruments: The German Environmental Survey (GerES) and the Environmental Specimen Bank (ESB). The ESB is a tool to describe time trends of human exposure. Each year approx. 500 students from 4 sampling locations are analysed for their heavy metal contents in blood, blood plasma, and urine. GerES is a nationwide representative cross-sectional study that has been conducted four times up to now. Both instruments have been used to measure heavy metals over the last decades and thus provide complementary information. Both instruments are useful to describe time trends. However, combining the two has an added value, which is demonstrated for heavy metals for the first time in this paper. Major results and the changing importance of sources of exposure to heavy metals (Pb, Cd, Hg, Au, Pt, U and Ni) are shown. This leads to the following conclusion about the today's relevance of exposure in Germany. For the study participants of the city of Muenster, lead in whole blood decreased from about 70 µg/l in 1981 to levels below 15 µg/l in 2009. GerES data of young adults confirmed this time trend and GerES IV on children revealed the decreasing relevance of lead in outdoor air and in drinking water. The concentrations of mercury in urine decreased because in Germany it is no longer recommended to use amalgam fillings for children. However, GerES IV and ESB data also demonstrate that despite the decline of these heavy metals exposures to nickel and uranium originating from drinking water are still of importance.

[Concept for a German national birth cohort for environmental health research]. / Konzept für eine umweltepidemiologische Geburtskohorte des Bundes.

The German Federal Environment Agency has commissioned the conceptual work for a birth cohort study to investigate environmental health problems in children. The recruitment is intended to start as early as possible in pregnancy and to take place in several regions of Germany. To detect health risks for exposures and outcomes with low prevalence as well as gene-environment interactions, a cohort size of 100,000-200,000 parent-child pairs is needed. The concept focuses on five health issues: neurodevelopment; reproductive development; pregnancy and birth outcomes; asthma, allergies and respiratory disease; obesity, insulin resistance and diabetes. The examination of additional health conditions will be possible. The exposure assessment will cover chemical, biological and physical exposures; psychosocial factors and genetics will be assessed as well. Biological and environmental samples will be stored in a repository for future analyses. The birth cohort study will contribute to the detection of associations between environmental exposures and health conditions over the course of life, which in turn will have an impact on environmental and health policies.

[German Environmental Survey for Children (GerES IV) in the German Health Interview and Examination Survey for Children and Adolescents (KiGGS). First results]. / Kinder-Umwelt-Survey (KUS) im Rahmen des Kinder- und Jugendgesundheitssurveys (KiGGS). Erste Ergebnisse.

The German Environmental Survey for Children (GerES IV) is the environment-related module of the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) of the Robert Koch Institute and the fourth GerES of the Federal Environment Agency. The main objective of GerESs is to analyse and document the extent, distribution and determinants of exposure to environmental pollutants of the German general population. GerES IV was performed from 2003 to 2006. A total of 1.790 children aged 3-14 years from 150 sampling locations participated in GerES IV. Samples of blood, urine, tap water, house dust and indoor air were analysed. Hearing tests, measurements of traffic noise and interviews to get exposure-related information were conducted. First results indicate a clear decrease of the exposure to arsenic, lead and mercury. Cotinine concentrations in urine can be used to classify the exposure of children to environmental tobacco smoke. The examination of the tap water used in the subjects' households indicates that in some households the guideline values of the German Drinking Water Ordinance were not always met. This is the case for nickel, copper and lead which are used as pipe material for domestic plumbing.

The German Human Biomonitoring Commission.

In Germany, the Human Biomonitoring Commission of the German Federal Environment Agency was established in 1992 to develop scientifically based criteria for the application of human biomonitoring (HBM). The goal is to clarify fundamental and practical issues related to HBM. Following the assessment of pollutants in body fluids, the commission derives two different kinds of guideline values: reference values and HBM values (HBM I and HBM II values). This article gives a review of the current reference values, HBM values, and the work of the German Human Biomonitoring Commission.

Twenty years of the German Environmental Survey (GerES): human biomonitoring--temporal and spatial (West Germany/East Germany) differences in population exposure.

The German Environmental Surveys (GerESs) are nationwide population studies, which have repeatedly been carried out in Germany since the mid-1980s. The subjects were representatively selected from the regional registration offices with regard to age, gender and community size. The first survey for adults (GerES I) was carried out in 1985/1986 (West Germany) followed by GerES IIa in 1990/1991 (West Germany) and GerES IIb in 1991/1992 (East Germany). In GerES II children were also included to some extent. In 1998, the third GerES for adults was conducted in both parts of Germany (GerES III). The current survey 2003/2006 (GerES IV) is focussing exclusively on children. A 1-year pilot study was conducted in 2001-2002 to collect information on parameters influencing the response rate and to test the suitability of the different instruments intended to be used for the main study. The main goal of the surveys is to analyse and document the extent, distribution and determinants of exposure to environmental pollutants of the German general population. Three main instruments of investigation were comprised in GerES: human biomonitoring (HBM), monitoring of the domestic environment, and collecting information on exposure pathways and living conditions via questionnaires. This paper is focussed on the general design of the GerESs, the trend over time and spatial differences (West Germany and East Germany) for HBM data on arsenic, cadmium, lead, mercury, pentachlorophenol (PCP), and polycyclic aromatic hydrocarbons (PAH). These substances have been determined in blood and/or morning urine of adults and children. All GerESs have been conducted in close connection with the National Health Interview and Examination Surveys performed by the Robert Koch-Institute, Berlin.

German Environmental Survey (GerES): human biomonitoring as a tool to identify exposure pathways.

The German Environmental Survey (GerES) is a representative population study and has been repeatedly carried out since the mid-1980s. The currently run survey (GerES IV) is the first one solely targeted on children. The GerES IV Pilot Study resulted in first insights into major exposure pathways relevant to children. These insights were made possible by the determination of pollutant concentrations in blood and urine and the additional consideration of their occurrence in the indoor environment and by using questionnaire data. The results of the GerES IV Pilot Study are presented according to major exposure pathways such as house dust, food and environmental tobacco smoke (ETS). An overview on relevant pilot study results is given. The results of GerES IV will permit the verification and substantiation of the pilot study results.