Phthalates and substitute plasticizers: Main achievements from the European human biomonitoring initiative HBM4EU.

Phthalates and the substitute plasticizer DINCH belong to the first group of priority substances investigated by the European Human Biomonitoring Initiative (HBM4EU) to answer policy-relevant questions and safeguard an efficient science-to-policy transfer of results. Human internal exposure levels were assessed using two data sets from all European regions and Israel. The first collated existing human biomonitoring (HBM) data (2005-2019). The second consisted of new data generated in the harmonized "HBM4EU Aligned Studies" (2014-2021) on children and teenagers for the ten most relevant phthalates and DINCH, accompanied by a quality assurance/quality control (QA/QC) program for 17 urinary exposure biomarkers. Exposures differed between countries, European regions, age groups and educational levels. Toxicologically derived Human biomonitoring guidance values (HBM-GVs) were exceeded in up to 5% of the participants of the HBM4EU Aligned Studies. A mixture risk assessment (MRA) including five reprotoxic phthalates (DEHP, DnBP, DiBP, BBzP, DiNP) revealed that for about 17% of the children and teenagers, health risks cannot be excluded. Concern about male reproductive health emphasized the need to include other anti-androgenic substances for MRA. Contaminated food and the use of personal care products were identified as relevant exposure determinants paving the way for new regulatory measures. Time trend analyses verified the efficacy of regulations: especially for the highly regulated phthalates exposure dropped significantly, while levels of the substitutes DINCH and DEHTP increased. The HBM4EU e-waste study, however, suggests that workers involved in e-waste management may be exposed to higher levels of restricted phthalates. Exposure-effect association studies indicated the relevance of a range of endpoints. A set of HBM indicators was derived to facilitate and accelerate science-to-policy transfer. Result indicators allow different groups and regions to be easily compared. Impact indicators allow health risks to be directly interpreted. The presented results enable successful science-to-policy transfer and support timely and targeted policy measures.

Time Patterns in Internal Human Exposure Data to Bisphenols, Phthalates, DINCH, Organophosphate Flame Retardants, Cadmium and Polyaromatic Hydrocarbons in Europe.

Human biomonitoring (HBM) data in Europe are often fragmented and collected in different EU countries and sampling periods. Exposure levels for children and adult women in Europe were evaluated over time. For the period 2000-2010, literature and aggregated data were collected in a harmonized way across studies. Between 2011-2012, biobanked samples from the DEMOCOPHES project were used. For 2014-2021, HBM data were generated within the HBM4EU Aligned Studies. Time patterns on internal exposure were evaluated visually and statistically using the 50th and 90th percentiles (P50/P90) for phthalates/DINCH and organophosphorus flame retardants (OPFRs) in children (5-12 years), and cadmium, bisphenols and polycyclic aromatic hydrocarbons (PAHs) in women (24-52 years). Restricted phthalate metabolites show decreasing patterns for children. Phthalate substitute, DINCH, shows a non-significant increasing pattern. For OPFRs, no trends were statistically significant. For women, BPA shows a clear decreasing pattern, while substitutes BPF and BPS show an increasing pattern coinciding with the BPA restrictions introduced. No clear patterns are observed for PAHs or cadmium. Although the causal relations were not studied as such, exposure levels to chemicals restricted at EU level visually decreased, while the levels for some of their substitutes increased. The results support policy efficacy monitoring and the policy-supportive role played by HBM.

How to use human biomonitoring in chemical risk assessment: Methodological aspects, recommendations, and lessons learned from HBM4EU.

One of the aims of the European Human Biomonitoring Initiative, HBM4EU, was to provide examples of and good practices for the effective use of human biomonitoring (HBM) data in human health risk assessment (RA). The need for such information is pressing, as previous research has indicated that regulatory risk assessors generally lack knowledge and experience of the use of HBM data in RA. By recognising this gap in expertise, as well as the added value of incorporating HBM data into RA, this paper aims to support the integration of HBM into regulatory RA. Based on the work of the HBM4EU, we provide examples of different approaches to including HBM in RA and in estimations of the environmental burden of disease (EBoD), the benefits and pitfalls involved, information on the important methodological aspects to consider, and recommendations on how to overcome obstacles. The examples are derived from RAs or EBoD estimations made under the HBM4EU for the following HBM4EU priority substances: acrylamide, o-toluidine of the aniline family, aprotic solvents, arsenic, bisphenols, cadmium, diisocyanates, flame retardants, hexavalent chromium [Cr(VI)], lead, mercury, mixture of per-/poly-fluorinated compounds, mixture of pesticides, mixture of phthalates, mycotoxins, polycyclic aromatic hydrocarbons (PAHs), and the UV-filter benzophenone-3. Although the RA and EBoD work presented here is not intended to have direct regulatory implications, the results can be useful for raising awareness of possibly needed policy actions, as newly generated HBM data from HBM4EU on the current exposure of the EU population has been used in many RAs and EBoD estimations.

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.

Harmonized human biomonitoring in European children, teenagers and adults: EU-wide exposure data of 11 chemical substance groups from the HBM4EU Aligned Studies (2014-2021).

As one of the core elements of the European Human Biomonitoring Initiative (HBM4EU) a human biomonitoring (HBM) survey was conducted in 23 countries to generate EU-wide comparable HBM data. This survey has built on existing HBM capacity in Europe by aligning national or regional HBM studies, referred to as the HBM4EU Aligned Studies. The HBM4EU Aligned Studies included a total of 10,795 participants of three age groups: (i) 3,576 children aged 6-12 years, (ii) 3,117 teenagers aged 12-18 years and (iii) 4,102 young adults aged 20-39 years. The participants were recruited between 2014 and 2021 in 11-12 countries per age group, geographically distributed across Europe. Depending on the age group, internal exposure to phthalates and the substitute DINCH, halogenated and organophosphorus flame retardants, per- and polyfluoroalkyl substances (PFASs), cadmium, bisphenols, polycyclic aromatic hydrocarbons (PAHs), arsenic species, acrylamide, mycotoxins (deoxynivalenol (total DON)), benzophenones and selected pesticides was assessed by measuring substance specific biomarkers subjected to stringent quality control programs for chemical analysis. For substance groups analyzed in different age groups higher average exposure levels were observed in the youngest age group, i.e., phthalates/DINCH in children versus teenagers, acrylamide and pesticides in children versus adults, benzophenones in teenagers versus adults. Many biomarkers in teenagers and adults varied significantly according to educational attainment, with higher exposure levels of bisphenols, phthalates, benzophenones, PAHs and acrylamide in participants (from households) with lower educational attainment, while teenagers from households with higher educational attainment have higher exposure levels for PFASs and arsenic. In children, a social gradient was only observed for the non-specific pyrethroid metabolite 3-PBA and di-isodecyl phthalate (DiDP), with higher levels in children from households with higher educational attainment. Geographical variations were seen for all exposure biomarkers. For 15 biomarkers, the available health-based HBM guidance values were exceeded with highest exceedance rates for toxicologically relevant arsenic in teenagers (40%), 3-PBA in children (36%), and between 11 and 14% for total DON, Σ (PFOA + PFNA + PFHxS + PFOS), bisphenol S and cadmium. The infrastructure and harmonized approach succeeded in obtaining comparable European wide internal exposure data for a prioritized set of 11 chemical groups. These data serve as a reference for comparison at the global level, provide a baseline to compare the efficacy of the European Commission's chemical strategy for sustainability and will give leverage to national policy makers for the implementation of targeted measures.

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.

Urinary excretion of phthalates and the substitutes DINCH and DEHTP in Danish young men and German young adults between 2000 and 2017 - A time trend analysis.

Over the last twenty-five years it has become evident that exposure to several phthalates can have adverse effects on human health, such as endocrine disruption. This led to a series of EU regulations that resulted in a decrease in the production volumes of the restricted phthalates and an increased production of substitutes. The current study describes the impact of regulations and changes in production and use of phthalates and their substitutes on internal exposure patterns in two European populations since the beginning of the 2000'ies. Using harmonised data from young adults in Denmark (Danish Young Men Study, n = 1,063, spot urine) and Germany (Environmental Specimen Bank, n = 878, 24-h urine) with repeated cross-sectional design (3-11 cycles per biomarker) we applied Locally Estimated Scatterplot Smoothing (LOESS) and Generalized Linear Models (GLMs) to estimate time trends and the role of covariates on the trend (e.g. age, BMI). Time trends of daily excretion (µg/24h) are comparable between the two samples for the regulated (DEHP, BBzP, DiNP, DnBP, DiBP, DiDP/DPHP) as well as the non-regulated substances (DMP, DEP, DINCH, DEHTP) although the rate of change differ for some of the compounds. GLM results indicate that the daily excretion of the most regulated phthalates has decreased over time (DEHP yearly about 12-16%, BBzP 5%, DnBP 0.3-17%, and DiBP 4-12%). Interestingly, also the non-regulated phthalates DMP and DEP decreased by 6-18% per year. In sharp contrast, the phthalate substitutes DINCH and DEHTP show very steep annual increases (∼10-68% and ∼100%, respectively) between 2009 and 2017. We did not find an effect of age, sex, BMI, or education on the time trend. The present study provides comparable insights into how exposure to phthalates and two of their substitutes have changed over the last two decades in Germany and Denmark.

Concurrent Assessment of Phthalates/HEXAMOLL® DINCH Exposure and Wechsler Intelligence Scale for Children Performance in Three European Cohorts of the HBM4EU Aligned Studies.

Information about the effects of phthalates and non-phthalate substitute cyclohexane-1,2-dicarboxylic acid diisononyl ester (HEXAMOLL® DINCH) on children's neurodevelopment is limited. The aim of the present research is to evaluate the association between phthalate/HEXAMOLL® DINCH exposure and child neurodevelopment in three European cohorts involved in HBM4EU Aligned Studies. Participating subjects were school-aged children belonging to the Northern Adriatic cohort II (NAC-II), Italy, Odense Child Cohort (OCC), Denmark, and PCB cohort, Slovakia. In each cohort, children's neurodevelopment was assessed through the Full-Scale Intelligence Quotient score (FSIQ) of the Wechsler Intelligence Scale of Children test using three different editions. The children's urine samples, collected for one point in time concurrently with the neurodevelopmental evaluation, were analyzed for several phthalates/HEXAMOLL® DINCH biomarkers. The relation between phthalates/HEXAMOLL® DINCH and FSIQ was explored by applying separate multiple linear regressions in each cohort. The means and standard deviations of FSIQ were 109 ± 11 (NAC-II), 98 ± 12 (OCC), and 81 ± 15 (PCB cohort). In NAC-II, direct associations between FSIQ and DEHP's biomarkers were found: 5OH-MEHP+5oxo-MEHP (ß = 2.56; 95% CI 0.58-4.55; N = 270), 5OH-MEHP+5cx-MEPP (ß = 2.48; 95% CI 0.47-4.49; N = 270) and 5OH-MEHP (ß = 2.58; 95% CI 0.65-4.51; N = 270). On the contrary, in the OCC the relation between DEHP's biomarkers and FSIQ tended to be inverse but imprecise (p-value ≥ 0.10). No associations were found in the PCB cohort. FSIQ was not associated with HEXAMOLL® DINCH in any cohort. In conclusion, these results do not provide evidence of an association between concurrent phthalate/DINCHHEXAMOLLR DINCH exposure and IQ in children.

The European Human Biomonitoring Initiative (HBM4EU): Human biomonitoring guidance values (HBM-GVs) for the aprotic solvents N-methyl-2-pyrrolidone (NMP) and N-ethyl-2-pyrrolidone (NEP).

Toxicologically and/or epidemiologically derived guidance values referring to the internal exposure of humans are a prerequisite for an easy to use health-based interpretation of human biomonitoring (HBM) results. The European Joint Programme HBM4EU derives such values, named human biomonitoring guidance values (HBM-GVs), for priority substances which could be of regulatory relevance for policy makers and have been identified by experts of the participating countries, ministries, agencies and stakeholders at EU and national level. NMP and NEP are such substances for which unresolved policy relevant issues should be clarified by targeted research. Since widespread exposure of the general population in Germany to NMP and NEP was shown for the age groups 3-17 years and 20-29 years, further investigations on exposure to NMP and NEP in other European countries are warranted. The HBM-GVs derived for both solvents focus on developmental toxicity as decisive endpoint. They amount for the sum of the two specific urinary NMP metabolites 5-HNMP and 2-HMSI and likewise of the two specific urinary NEP metabolites 5-HNEP and 2-HESI to 10 mg/L for children and 15 mg/L for adolescents/adults. The values were determined following a consultation process on the value proposals within HBM4EU. A health-based risk assessment was performed using the newly derived HBM-GVGenPop and exposure data from two recent studies from Germany. The risk assessment revealed that even when considering the combined exposure to both substances by applying the Hazard Index approach, the measured concentrations are below the HBM-GVGenPop in all cases investigated (i.e., children, adolescents and young adults).

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.

Chemical prioritisation strategy in the European Human Biomonitoring Initiative (HBM4EU) - Development and results.

The European Human Biomonitoring Initiative (HBM4EU1) has established a European Union-wide human biomonitoring (HBM) programme to generate knowledge on human internal exposure to chemical pollutants and their potential health impacts in Europe, in order to support policy makers' efforts to ensure chemical safety and improve health in Europe. A prioritisation strategy was necessary to determine and meet the most important needs of both policy makers and risk assessors, as well as common national needs of participating countries and a broad range of stakeholders. This strategy consisted of three mains steps: 1) mapping of knowledge gaps identified by policy makers, 2) prioritisation of substances using a scoring system, and 3) generation of a list of priority substances reflective of the scoring, as well as of public policy priorities and available resources. For the first step, relevant ministries and agencies at EU and national levels, as well as members of the Stakeholder Forum each nominated up to 5 substances/substance groups of concern for policy-makers. These nominations were collated into a preliminary list of 48 substances/substance groups, which was subsequently shortened to a list of 23 after considering the total number of nominations each substance/substance group received and the nature of the nominating entities. For the second step, a panel of 11 experts in epidemiology, toxicology, exposure sciences, and occupational and environmental health scored each of the substances/substance groups using prioritisation criteria including hazardous properties, exposure characteristics, and societal concern. The scores were used to rank the 23 substances/substance groups. In addition, substances were categorised according to the level of current knowledge about their hazards, extent of human exposure (through the availability of HBM data), regulatory status and availability of analytical methods for biomarker measurement. Finally, in addition to the ranking and categorisation of the substances, the resources available for the project and the alignment with the policy priorities at European level were considered to produce a final priority list of 9 substances/substance groups for research activities and surveys within the framework of the HBM4EU project.

Human biomonitoring initiative (HBM4EU): Human biomonitoring guidance values (HBM-GVs) derived for bisphenol A.

The "European Human Biomonitoring Initiative" (HBM4EU) derives human biomonitoring guidance values (HBM-GVs) for the general population (HBM-GVGenPop) and/or for occupationally exposed adults (HBM-GVWorker) for several priority substances and substance groups as identified by policy makers, scientists and stakeholders at EU and national level, including bisphenol A (BPA). Human exposure to BPA is widespread and of particular concern because of its known endocrine-disrupting properties. Unlike the conjugated forms of BPA circulating in the body, free BPA is known to interact with the nuclear estrogen receptors. Because free BPA is considered to be more toxicologically active than the conjugated forms (e.g. BPA-glucuronide (BPA-G) and BPA-sulfate (BPA-S)), its measurement in blood provides the superior surrogate of the biologically effective dose. However, considering the difficulty of implementing blood sampling in large HBM cohorts, as well as the current analytical capacities complying with the quality assurance (QA)/quality control (QC) schemes, total BPA in urine (i.e. the sum of free and conjugated forms of BPA measured after an hydrolysis of phase II metabolites) was retained as the relevant exposure biomarker for BPA. HBM-GVGenPop for total BPA in urine of 230 µg/L and 135 µg/L for adults and children, respectively, were developed on the basis of toxicological data. To derive these values, the concentrations of urinary total BPA consistent with a steady-state exposure to the temporary Tolerable Daily Intake (t-TDI) of 4 µg/kg bw/day set in 2015 by the European Food Safety Authority (EFSA) were estimated. The BPA human physiologically-based pharmacokinetic (PBPK) model developed by Karrer et al. (2018) was used, assuming an oral exposure to BPA at the t-TDI level averaged over 24 h. Dermal uptake of BPA is suspected to contribute substantially to the total BPA body burden, which in comparison with the oral route, is generating a higher ratio of free BPA to total BPA in blood. Therefore, an alternative approach for calculating the HBM-GVGenPop according to the estimated relative contributions of both the oral and dermal routes to the global BPA exposure is also discussed. Regarding BPA exposure at the workplace, the steady-state concentration of urinary total BPA was estimated after a dermal uptake of BPA that would generate the same concentration of free BPA in plasma (considered as the bioactive form) as would a 24 h-averaged intake to the European Chemicals Agency (ECHA)'s oral DNEL of 8 µg BPA/kg bw/day set for workers. The predicted concentration of urinary total BPA at steady-state is equivalent to, or exceeds the 95th percentile of total BPA in urine measured in different European HBM studies conducted in the general population. Thus, no HBM-GVWorker was proposed, as the high background level of BPA coming from environmental exposure - mostly through food intake - is making the discrimination with the occupational exposure to BPA difficult.

The European Human Biomonitoring Initiative (HBM4EU): Human biomonitoring guidance values for selected phthalates and a substitute plasticizer.

Ubiquitous use of plasticizers has led to a widespread internal exposure of the European population. Until today, metabolites are detected in almost every urine sample analysed. This raised the urgent need for a toxicological interpretation of the internal exposure levels. The European Human Biomonitoring Initiative (HBM4EU) contributes substantially to the knowledge on the actual exposure of European citizens to chemicals prioritised within HBM4EU, on their potential impact on health and on the interpretation of these data to improve policy making. On that account, human biomonitoring guidance values (HBM-GVs) are derived for the general population and the occupationally exposed population agreed at HBM4EU consortium level. These values can be used to assess phthalate exposure levels measured in HBM studies in a health risk assessment context. HBM-GVs were derived for five phthalates (DEHP, DnBP, DiBP, BBzP and DPHP) and for the non-phthalate substitute Hexamoll® DINCH. For the adult general population, the HBM-GVs for the specific metabolite(s) of the respective parent compounds in urine are the following: 0.5 mg/L for the sum of 5-oxo-MEHP and 5-OH-MEHP; 0.19 mg/L for MnBP, 0.23 mg/L for MiBP; 3 mg/L for MBzP; 0.5 mg/L for the sum of oxo-MPHP and OH-MPHP and 4.5 mg/L for the sum of OH-MINCH and cx-MINCH. The present paper further specifies HBM-GVs for children and for workers.

Scoping Review-The Association between Asthma and Environmental Chemicals.

Asthma is one of the most common chronic diseases worldwide affecting all age groups from children to the elderly. In addition to other factors such as smoking, air pollution and atopy, some environmental chemicals are shown or suspected to increase the risk of asthma, exacerbate asthma symptoms and cause other respiratory symptoms. In this scoping review, we report environmental chemicals, prioritized for investigation in the European Human Biomonitoring Initiative (HBM4EU), which are associated or possibly associated with asthma. The substance groups considered to cause asthma through specific sensitization include: diisocyanates, hexavalent chromium Cr(VI) and possibly p-phenylenediamine (p-PDA). In epidemiological studies, polyaromatic hydrocarbons (PAHs) and organophosphate insecticides are associated with asthma, and phthalates, per- and polyfluoroalkyl substances (PFASs), pyrethroid insecticides, mercury, cadmium, arsenic and lead are only potentially associated with asthma. As a conclusion, exposure to PAHs and some pesticides are associated with increased risk of asthma. Diisocyanates and Cr(VI) cause asthma with specific sensitization. For many environmental chemicals, current studies have provided contradicting results in relation to increased risk of asthma. Therefore, more research about exposure to environmental chemicals and risk of asthma is needed.

Human biomonitoring initiative (HBM4EU): Human biomonitoring guidance values (HBM-GVs) derived for cadmium and its compounds.

AIMS: The methodology agreed within the framework of the HBM4EU project is used in this work to derive HBM-GVs for the general population (HBM-GVGenPop) and for workers (HBM-GVWorker) exposed to cadmium (Cd) and its compounds. METHODS: For Cd, a significant number of epidemiological studies with dose-response relationships are available, in particular for kidney effects. These effects are described in terms of a relation between urinary Cd (U-Cd) or blood Cd (B-Cd) levels and low molecular weight proteinuria (LMWP) markers like beta-2-microglobulin (ß2M) and retinol-binding protein (RBP). In order to derive HBM-GVs for the general population and workers, an assessment of data from evaluations conducted by national or international organisations was undertaken. In this work, it appeared relevant to select renal effects as the critical effect for the both groups, however, differences between general population (including sensitive people) and workers (considered as an homogenous population of adults who should not be exposed to Cd if they suffer from renal diseases) required the selection of different key studies (i.e. conducted in general population for HBM-GVGenPop and at workplace for HBM-GVWorker). RESULTS AND CONCLUSIONS: For U-Cd, a HBM-GVGenPop of 1 µg/g creatinine (creat) is recommended for adults older than 50 years, based on a robust meta-analysis performed by EFSA (EFSA, 2009a). To take into account the accumulation of Cd in the human body throughout life, threshold or 'alert' values according to age were estimated for U-Cd. At workplace, a HBM-GVWorker of 2 µg/g creat is derived from the study of Chaumont et al., (2011) for U-Cd, and in addition to this recommendation a HBM-GVworker for B-Cd of 5 µg/L is also proposed. The HBM-GVWorker for U-Cd is similar to the biological limit value (BLV) set by the new amendment of the European Carcinogens and Mutagens Directive in June 2019 (2 µg/g creat for U-Cd).

Environmental Substances Associated with Osteoporosis-A Scoping Review.

INTRODUCTION: Osteoporosis is a disease having adverse effects on bone health and causing fragility fractures. Osteoporosis affects approximately 200 million people worldwide, and nearly 9 million fractures occur annually. Evidence exists that, in addition to traditional risk factors, certain environmental substances may increase the risk of osteoporosis. METHODS: The European Human Biomonitoring Initiative (HBM4EU) is a joint program coordinating and advancing human biomonitoring in Europe. HBM4EU investigates citizens' exposure to several environmental substances and their plausible health effects aiming to contribute to policymaking. In HBM4EU, 18 priority substances or substance groups were selected. For each, a scoping document was prepared summarizing existing knowledge and health effects. This scoping review is based on these chemical-specific scoping documents and complementary literature review. RESULTS: A possible link between osteoporosis and the body burden of heavy metals, such as cadmium (Cd) and lead (Pb), and industrial chemicals such as phthalates and per- and poly-fluoroalkyl substances (PFASs) was identified. CONCLUSIONS: Evidence shows that environmental substances may be related to osteoporosis as an adverse health effect. Nevertheless, more epidemiological research on the relationship between health effects and exposure to these chemicals is needed. Study results are incoherent, and pervasive epidemiological studies regarding the chemical exposure are lacking.

Human biomonitoring initiative (HBM4EU) - Strategy to derive human biomonitoring guidance values (HBM-GVs) for health risk assessment.

The European Joint Program "HBM4EU" is a joint effort of 30 countries and the European Environment Agency, co-funded under the European Commission's Horizon 2020 program, for advancing and implementing human biomonitoring (HBM) on a European scale and for providing scientific evidence for chemical policy making. One important outcome will be a Europe-wide improvement and harmonization of health risk assessment following the coordinated derivation or update of health-related guidance values referring to the internal body burden. These guidance values - named HBM guidance values or HBM-GVs - can directly be compared with HBM data. They are derived within HBM4EU for priority substances identified by the HBM4EU chemicals prioritization strategy based on existing needs to answer policy relevant questions as raised by national and EU policy makers. HBM-GVs refer to both the general population and occupationally exposed adults. Reports including the detailed reasoning for the values' proposals are subjected to a consultation process within all partner countries of the consortium to reach a broad scientific consensus on the derivation approach and on the derived values. The final HBM-GVs should be applied first within the HBM4EU project, but may also be useful for regulators and risk assessors outside this project. The subsequent adoption of derived HBM-GVs at EU-level needs to be discussed and decided within the responsible EU bodies. Nevertheless, the establishment of HBM-GVs as part of HBM4EU is already a step forward in strengthening HBM-based policy efforts for public and occupational health. The strategy for deriving HBM-GVs which is based on already existing approaches from the German HBM Commission, the French Agency for Food, Environmental and Occupational Health & Safety (ANSES) as well as from the US-based scientific consultant Summit Toxicology, the allocation of a level of confidence to the derived values, and the consultation process within the project are comprehensively described to enlighten the work accomplished under the HBM4EU initiative.

Per- and polyfluoroalkyl substances in blood plasma - Results of the German Environmental Survey for children and adolescents 2014-2017 (GerES V).

The 5th cycle of the German Environmental Survey (GerES V) investigated the internal human exposure of children and adolescents aged 3-17 years in Germany to per- and polyfluoroalkyl substances (PFAS). The fieldwork of the population-representative GerES V was performed from 2014 to 2017. In total, 1109 blood plasma samples were analysed for 12 PFAS including perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and perfluorohexane sulfonic acid (PFHxS). PFOS was quantified in all and PFOA in almost all samples, demonstrating ubiquitous exposure. The highest geometric mean concentrations measured were 2.49 ng/mL for PFOS, followed by PFOA (1.12 ng/mL) and PFHxS (0.36 ng/mL), while concentrations of other PFAS were found in much lower concentrations. The 95th percentile levels of PFOS and PFOA were 6.00 and 3.24 ng/mL, respectively. The results document a still considerable exposure of the young generation to the phased out chemicals PFOS and PFOA. The observed exposure levels vary substantially between individuals and might be due to different multiple sources. The relative contribution of various exposure parameters such as diet or the specific use of consumer products need to be further explored. Although additional investigations on the time trend of human exposure are warranted, GerES V underlines the need for an effective and sustainable regulation of PFAS as a whole.