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.

Human risk associated with exposure to mixtures of antiandrogenic chemicals evaluated using in vitro hazard and human biomonitoring data.

BACKGROUND: Scientific evidence for underestimated toxicity from unintentional exposure to chemical mixtures is mounting. Yet, harmonized approaches on how to assess the actual risk of mixtures is lacking. As part of the European Joint programme 'Human Biomonitoring for Europe' we explored a novel methodology for mixture risk assessment of chemicals affecting male reproductive function. METHODOLOGY: We explored a methodology for chemical mixture risk assessment based on human in vitro data combined with human exposure data, thereby circumventing the drawbacks of using hazard data from rodents and estimated exposure intake levels. Human androgen receptor (hAR) antagonism was selected as the most important molecular initiating event linked to adverse outcomes on male reproductive health. RESULTS: Our work identified 231 chemicals able to interfere with hAR activity. Among these were 61 finally identified as having both reliable hAR antagonist and human biomonitoring data. Calculation of risk quotients indicated that PCBs (118, 138, 157), phthalates (BBP, DBP, DIBP), benzophenone-3, PFOS, methylparaben, triclosan, some pesticides (i.e cypermethrin, ß-endosulfan, methylparathion, p,p-DDE), and a PAH metabolite (1-hydroxypyrene) contributed to the mixture effect. The major chemical mixture drivers were PCB 118, BBP, PFOS, DBP, and the UV filter benzophenone-3, together contributing with 75% of the total mixture effect that was primarily driven by high exposure values. CONCLUSIONS: This viable way forward for mixture risk assessment of chemicals has the advantages of (1) being a more comprehensive mixture risk assessment also covering data-poor chemicals, and (2) including human data only. However, the approach is subjected to uncertainties in terms of in vitro to in vivo extrapolation, it is not ready for decision making, and needs further development. Still, the results indicate a concern for adverse effects on reproductive function in highly exposed boys, especially when considering additional exposure to data-poor chemicals and chemicals acting by other mechanisms of action.

HBM4EU results support the Chemicals' Strategy for Sustainability and the Zero-Pollution Action Plan.

One of the major goals of the European Human Biomonitoring Initiative (HBM4EU) was to bridge the gap between science and policy by consulting both policy makers and national scientists and generating evidence of the actual exposure of residents to chemicals and whether that exposure would be suggest a potential health risk. Residents' perspectives on chemical exposure and risk were also investigated. HBM4EU's research was designed to answer specific short-term and long-term policy questions at national and European levels, and for its results to directly support regulatory action on chemicals. A strategy was established to prioritise chemicals for analysis in human matrices, with a total of 18 substances/substance groups chosen to be investigated throughout the five-and a -half-year project. HBM4EU produced new evidence of human exposure levels, developed reference values for exposure, investigated determinants of exposure and derived health-based guidance values for those substances. In addition, HBM4EU promoted the use of human biomonitoring data in chemical risk assessment and developed innovative tools and methods linking chemicals to possible health impacts, such as effect biomarkers. Furthermore, HBM4EU advanced understand of effects from combined exposures and methods to identify emerging chemicals. With the aim of supporting policy implementation, science-to-policy workshops were organised, providing opportunities for joint reflection and dialogue on research results. I, and indicators were developed to assess temporal and spatial patterns in the exposure of European population. A sustainable human biomonitoring monitoring framework, producing comparable quality assured data would allow: the evaluation of time trends; the exploration of spatial trends: the evaluation of the influence of socio-economic conditions on chemical exposure. Therefore, such a framework should be included in the European Chemicals' Strategy for Sustainability and the data would support the Zero Pollution Action Plan.

From science to policy: How European HBM indicators help to answer policy questions related to phthalates and DINCH exposure.

Within the European Human Biomonitoring (HBM) Initiative HBM4EU we derived HBM indicators that were designed to help answering key policy questions and support chemical policies. The result indicators convey information on chemicals exposure of different age groups, sexes, geographical regions and time points by comparing median exposure values. If differences are observed for one group or the other, policy measures or risk management options can be implemented. Impact indicators support health risk assessment by comparing exposure values with health-based guidance values, such as human biomonitoring guidance values (HBM-GVs). In general, the indicators should be designed to translate complex scientific information into short and clear messages and make it accessible to policy makers but also to a broader audience such as stakeholders (e.g. NGO's), other scientists and the general public. Based on harmonized data from the HBM4EU Aligned Studies (2014-2021), the usefulness of our indicators was demonstrated for the age group children (6-11 years), using two case examples: one phthalate (Diisobutyl phthalate: DiBP) and one non-phthalate substitute (Di-isononyl cyclohexane-1,2- dicarboxylate: DINCH). For the comparison of age groups, these were compared to data for teenagers (12-18 years), and time periods were compared using data from the DEMOCOPHES project (2011-2012). Our result indicators proved to be suitable for demonstrating the effectiveness of policy measures for DiBP and the need of continuous monitoring for DINCH. They showed similar exposure for boys and girls, indicating that there is no need for gender focused interventions and/or no indication of sex-specific exposure patterns. They created a basis for a targeted approach by highlighting relevant geographical differences in internal exposure. An adequate data basis is essential for revealing differences for all indicators. This was particularly evident in our studies on the indicators on age differences. The impact indicator revealed that health risks based on exposure to DiBP cannot be excluded. This is an indication or flag for risk managers and policy makers that exposure to DiBP still is a relevant health issue. HBM indicators derived within HBM4EU are a valuable and important complement to existing indicator lists in the context of environment and health. Their applicability, current shortcomings and solution strategies are outlined.

HBM4EU feasibility studies: Lessons learned in combining health and human biomonitoring studies.

BACKGROUND: The European Human Biomonitoring Initiative (HBM4EU) is a joint program evaluating humans' exposure to several environmental substances and their potential health effects. One of the main objectives of HBM4EU is to make use of human biomonitoring (HBM) to assess human exposure to chemicals in Europe to better understand the associated health impacts and to improve chemical risk assessment. In parallel to HBM studies, health examination surveys (HESs), nutrition/dietary surveys, and disease specific health surveys are conducted in many European countries. In HESs, information collected by questionnaire(s) is supplemented with physical examinations and analysis of clinical and biological biomarkers in biological samples. HBM and health examination survey (HES) use similar data collection methods and infrastructures hence the feasibility of combining these two is explored in this paper. METHODS: Within HBM4EU, three feasibility studies (in Finland, Germany, and UK/England) were conducted to evaluate opportunities and obstacles of combining HBM and health studies. In this paper we report lessons learned from these feasibility studies. RESULTS: The Finnish feasibility study called KouBio-KUOPIO study was a new initiative without links to existing studies. The German feasibility study added a HBM module to the first follow-up examination of the LIFE-Adult-Study, a population-based cohort study. The UK feasibility integrates a sustainable HBM module into the Health Survey for England (HSfE), an annual health examination survey. Benefits of combining HBM and HESs include the use of shared infrastructures. Furthermore, participants can receive additional health information from HES, and participation rates tend to be higher due to the potential to obtain personal health information. Preparatory phases including obtaining ethical approval can be time-consuming and complicated. Recruitment of participants and low participation rates are common concerns in survey research and therefore designing user-friendly questionnaires with low participant burden is important. Unexpected events such as the COVID-19 pandemic can cause substantial challenges and delays for such studies. Furthermore, experiences from several countries demonstrated that long-term funding for combined studies can be difficult to obtain. CONCLUSIONS: In the future, incorporating HBM modules into existing HESs can provide a feasible and cost-effective method to conduct HBM studies and obtain a wide range of relevant data to support public health policies and research.

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).

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.

Learning from previous work and finding synergies in the domains of public and environmental health: EU-funded projects BRIDGE Health and HBM4EU.

BACKGROUND: During the last decade, the European Union initiated several projects in the domains of public and environmental health. Within this framework, BRIDGE Health (Bridging Information and Data Generation for Evidence-based Health policy and Research) and HBM4EU (European human biomonitoring initiative) have been implemented. Whereas, the focus of BRIDGE Health was towards a sustainable and integrated health information system (HIS), the aim of HBM4EU is to improve evidence of the internal exposure of European citizens to environmental chemicals by human biomonitoring (HBM) and the impact of internal exposure on health. As both, environmental and public health determinants are important for health promotion, disease prevention and policy, BRIDGE Health and HBM4EU have overlapping aims and outcomes. In order to improve health information regarding public health and environmental health issues, best use and exchange of respective networks and project results is necessary. METHODS: Both projects have implemented health information (HI) and HBM tasks in order to provide adequate environmental and public health information of the European population. Synergies of the projects were identified in the working progress and because of overlapping networks and experts a focused analysis of both projects was envisaged. This paper elaborates on the aims and outcomes of both projects and the benefit of merging and channelling research results for the use of better health information and policy making that may be of relevance for any other project in these research fields. RESULTS: The need for focused exchanges and collaborations between the projects were identified and benefits of exchanges were highlighted for the specific areas of indicator development, linkage of data repositories and the combination of HBM studies and health examination surveys (HES). Further recommendations for a European wide harmonisation among different tasks in the fields of public health and environmental health are being developed. CONCLUSIONS: Lessons learned from HBM4EU and BRIDGE Health show that continuous efforts must be undertaken, also by succeeding projects, to guarantee the exchange between public health and environmental health issues. Networks covering both are essential to provide better evidence of knowledge. The experiences from BRIDGE Health and HBM4EU give a valuable input for any future activity in these domains. Avoiding overlaps and streamlining further exchange of public health and environmental health contributes to best use of research results and allows to develop new strategies and tools for improvement of health information and thus enhances people's health and well-being.

Development of Policy Relevant Human Biomonitoring Indicators for Chemical Exposure in the European Population.

The European Union's 7th Environmental Action Programme (EAP) aims to assess and minimize environmental health risks from the use of hazardous chemicals by 2020. From this angle, policy questions like whether an implemented policy to reduce chemical exposure has had an effect over time, whether the health of people in specific regions or subpopulations is at risk, or whether the body burden of chemical substances (the internal exposure) varies with, for example, time, country, sex, age, or socio-economic status, need to be answered. Indicators can help to synthesize complex scientific information into a few key descriptors with the purpose of providing an answer to a non-expert audience. Human biomonitoring (HBM) indicators at the European Union (EU) level are unfortunately lacking. Within the Horizon2020 European Human Biomonitoring project HBM4EU, an approach to develop European HBM indicators was worked out. To learn from and ensure interoperability with other European indicators, 15 experts from the HBM4EU project (German Umweltbundesamt (UBA), Flemish research institute VITO, University of Antwerp, European Environment Agency (EEA)), and the World Health Organization (WHO), European Core Health Indicator initiative (ECHI), Eurostat, Swiss ETH Zurich and the Czech environmental institute CENIA, and contributed to a workshop, held in June 2017 at the EEA in Copenhagen. First, selection criteria were defined to evaluate when and if results of internal chemical exposure measured by HBM, need to be translated into a European HBM-based indicator. Two main aspects are the HBM indicator's relevance for policy, society, health, and the quality of the biomarker data (availability, comparability, ease of interpretation). Secondly, an approach for the calculation of the indicators was designed. Two types of indicators were proposed: 'sum indicators of internal exposure' derived directly from HBM biomarker concentrations and 'indicators for health risk', comparing HBM concentrations to HBM health-based guidance values (HBM HBGVs). In the latter case, both the percentage of the studied population exceeding the HBM HBGVs (PE) and the extent of exceedance (EE), calculated as the population's exposure level divided by the HBM HBGV, can be calculated. These indicators were applied to two examples of hazardous chemicals: bisphenol A (BPA) and per- and polyfluoroalkyl substances (PFASs), which both have high policy and societal relevance and for which high quality published data were available (DEMOCOPHES, Swedish monitoring campaign). European HBM indicators help to summarize internal exposure to chemical substances among the European population and communicate to what degree environmental policies are successful in keeping internal exposures sufficiently low. The main aim of HBM indicators is to allow follow-up of chemical safety in Europe.

Environmental health surveillance in a future European health information system.

BACKGROUND: To date Health information (HI) in the European Union does not comprise indicators or other information related to impacts of hazardous chemicals in consumer products, food, drinking water or air on the health status of the population. Therefore, we inventorised and evaluated the potential of environmental health surveillance and research data sources in the European population to provide HBM-based indicators of internal human exposure and health impact of relevant chemicals. METHODS: We established an up-dated inventory of European cross-sectional Human Biomonitoring (HBM) surveys and of birth cohorts, and compared chemicals and chemical groups addressed by HBM with indicators and health end points collected via European Core Health Indicators (ECHI), in birth registries, as well as in environmental and food data bases and health registries to see on how data collection could be aligned. Finally, we investigated study designs of HBM survey and health examination surveys for potential synergies. RESULTS: The inventory covers a total of 11 European cross-sectional national programmes and a large number of birth cohorts and includes information on study population, age groups, covered substances, sampled matrices, and frequency. The comparison of data collections shows that there are many overlaps between environmental chemicals with environmental and health reporting. HBM data could be linked with ECHI indicators for work-related risks, body mass index (BMI), and low birth weight, with perinatal disease, neurologic disorders, and some chronic diseases, or with data bases for e.g. indoor air, food, or consumer products. Existing initiatives to link data collections at European Environment Agency (EEA) and Joint Research Center (JRC) or at World Health Organization (WHO) are good options to further develop linkage of HBM with exposures sources and health end points. CONCLUSIONS: There is potential to use HBM based information in a number of public health policies, and this would help to align reporting to international commitments. Environmental health surveillance based on HBM and HBM-based indicators, is an excellent tool to inform public health policies about risks from environmental chemicals, and the EU health information system would benefit from additional HBM-based indicators for monitoring exposure burden from environmental chemicals. Considerable efforts are needed to align and establish routine data collections and to develop a surveillance system and indicators which may inform public health policies.

[Integration of sex/gender into environmental health research. Results of the interdisciplinary research network Sex/Gender-Environment-Health (GeUmGe-NET)]. / Integration von Geschlecht in die Forschung zu umweltbezogener Gesundheit. Ergebnisse des interdisziplinären Forschungsnetzwerks Geschlecht ­ Umwelt ­ Gesundheit (GeUmGe-NET).

The comprehensive consideration of sex/gender in health research is essential to increase relevance and validity of research results. Contrary to other areas of health research, there is no systematic summary of the current state of research on the significance of sex/gender in environmental health. Within the interdisciplinary research network Sex/Gender-Environment-Health (GeUmGe-NET) the current state of integration of sex/gender aspects or, respectively, gender theoretical concepts into research was systematically assessed within selected topics of the research areas environmental toxicology, environmental medicine, environmental epidemiology and public health research on environment and health. Knowledge gaps and research needs were identified in all research areas. Furthermore, the potential for methodological advancements by using gender theoretical concepts was depicted. A dialogue between biomedical research, public health research, and gender studies was started with the research network GeUmGe-NET. This dialogue has to be continued particularly regarding a common testing of methodological innovations in data collection and data analysis. Insights of this interdisciplinary research are relevant for practice areas such as environmental health protection, health promotion, environmental justice, and environmental health monitoring.