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Funding Information: This work was supported by the European Union's Horizon 2020 research and innovation program projects HBM4EU [grant number 733032 ]. Authors acknowledge the editorial assistance of Richard Davies. Publisher Copyright: © 2023 The Author(s) Human biomonitoring (HBM) studies have highlighted widespread daily exposure to environmental chemicals. Some of these are suspected to contribute to adverse health outcomes such as reproductive, neurological, and metabolic disorders, among other developmental and chronic impairments. One of the objectives of the H2020 European Human Biomonitoring Initiative (HBM4EU) was the development of informative effect biomarkers for application in a more systematic and harmonized way in large-scale European HBM studies. The inclusion of effect biomarkers would complement exposure data with mechanistically-based information on early and late adverse effects. For this purpose, a stepwise strategy was developed to identify and implement a panel of validated effect biomarkers in European HBM studies. This work offers an overview of the complete procedure followed, from comprehensive literature search strategies, selection of criteria for effect biomarkers and their classification and prioritization, based on toxicological data and adverse outcomes, to pilot studies for their analytical, physiological, and epidemiological validation. We present the example of one study that demonstrated the mediating role of the effect biomarker status of brain-derived neurotrophic factor BDNF in the longitudinal association between infant bisphenol A (BPA) exposure and behavioral function in adolescence. A panel of effect biomarkers has been implemented in the HBM4EU Aligned Studies as main outcomes, including traditional oxidative stress, reproductive, and thyroid hormone biomarkers. Novel biomarkers of effect, such as DNA methylation status of BDNF and kisspeptin (KISS) genes were also evaluated as molecular markers of neurological and reproductive health, respectively. A panel of effect biomarkers has also been applied in HBM4EU occupational studies, such as micronucleus analysis in lymphocytes and reticulocytes, whole blood comet assay, and malondialdehyde, 8-oxo-2′-deoxyguanosine and untargeted metabolomic profile in urine, to investigate, for example, biological changes in response to hexavalent chromium Cr(VI) exposure. The use of effect biomarkers in HBM4EU has demonstrated their ability to detect early biological effects of chemical exposure and to identify subgroups that are at higher risk. The roadmap developed in HBM4EU confirms the utility of effect biomarkers, and support one of the main objectives of HBM research, which is to link exposure biomarkers to mechanistically validated effect and susceptibility biomarkers in order to better understand the public health implications of human exposure to environmental chemicals. publishersversion published

Funding: This project received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 733032 HBM4EU, and co-funding from the authors’ organisations. The results presented here are based on a huge body of work performed as part of Task 5.3 of the HBM4EU in 2017–2022. First and foremost, we would like to acknowledge all our Task 5.3 colleagues for their valuable contribution to the project work, including the individual RAs and EBoD calculations. In addition, we would like to thank all our other HBM4EU colleagues, the HBM4EU-aligned study data owners, and the other stakeholders who provided support for and feedback on our work during its course. 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. publishersversion published

Funding Information: The authors would like to thank everybody who contributed to the HBM4EU Aligned Studies: the participating children, teenagers, adults and their families, the fieldworkers that collected the samples and database managers that made the information available to HBM4EU, the HBM4EU project partners, especially those from WP7 for developing all materials supporting the fieldwork, WP9 for organizing the QA/QC scheme under HBM4EU and all laboratories who performed the analytical measurements. We would like to acknowledge Sun Kyoung Jung from the National Institute of Environmental Research of South-Korea for providing the KoNEHS Cycle III results (crt adjusted). HBM4EU is co-financed under Horizon 2020 (grant agreement No 733032). The authors thank all principal investigators of the contributing studies for their participation and contribution to the HBM4EU Aligned Studies and the national program owners for their financial support. Further details on funding for all the participating studies can be found in the Supplemental Material, Table S12. 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. publishersversion published

Exposure to per- and polyfluoroalkyl substances (PFAS), a widely-used class of persistentchemicals, has been linked to an array of adverse health outcomes. While most individuals inEurope are exposed to background-levels of PFAS, some populations living near contaminatedsites (‘PFAS hotspots’) are exposed at moderate, high or extremely high levels. Several PFAShotspots have been identified in various regions in the EU, and new PFAS hotspots continue to bediscovered. There is a large public health concern within several of these PFAS hotspots. In orderto address the health concern of citizens living in the neighbourhood of PFAS hotspots, humanbiomonitoring in hotspot regions have been conducted, or are ongoing or planned.Within the HBM4EU project, the need for a network of experts addressing PFAS exposure inhotspots in EU has been recognised. The collaboration within the network resulted in four main outcomes, reported in this document: An inventory of human biomonitoring studies in PFAS hotspots in Europe was created: overview the exposure levels, type and source of the contamination, exposuredeterminants, health research and policy impact of PFAS contamination at various hotspotsacross Europe A workshop on PFAS hotspots was organized (2 May 2022). During this half-day workshop, the knowledge and challenges related to PFAS hotspots across Europe werepresented and discussed with European, regional and local risk managers of contaminated sites, environmental health care workers, scientists, and regulatory authorities involved inchemical risk assessment. A guidance document on identification and monitoring, human biomonitoring, andrisk communication in PFAS hotspots has been drafted via collaboration within thenetwork. The guidance aims to be useful for policy makers and scientists confronted withnew PFAS hotpots (guidance document: see chapter 5 of this report).Recommendations for further research and policy recommendations. Recommendations for further research and policy recommendations &nbsp

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.

Co-authors: Glória Isidro, Henriqueta Louro, Maria João Silva (INSA) The current deliverable describes the process of revision of the first list of indicators (published in June 2017 as D6.1.) and presents the indicator leaflets ((see attachment 1) that link key results of HBM4EU to the objectives of the project as laid down in the description of action. These indicator leaflets already contain a lot of results on the revised list of indicators, and give very valuable information on the progress of HBM4EU in relation to the specific goals of the project. Combining the information from these leaflets in the frame of expected impacts will allow us to put forward conclusions towards impact and sustainability of HBM4EU. As such, this restructured list answers to the main comments on the first list of indicators from the task 6.5 partners, the Management Board, the Governing Board and the EU Policy Board, in concretu to: • Drastically reduce the number of indicators from 48 indicators (including 9 internal indicators) on the first list to 28 indicators on the revised list without losing essential information. Moreover by bundling related indicators we now have 22 indicator leaflets (and 1 overview leaflet); • Make the relationship between the indicators and the goals of HBM4EU more clear by structuring the list of indicators according to the overarching objectives and specific goals; • Use the indicators to say something about the impact of the HBM4EU project: the indicator leaflets were used to give input for the impact section of the periodic technical reporting 2018 to describe the progress made for the 5 expected impacts of HBM4EU. This exercise will be continued and ameliorated in the 2019 periodic technical reporting as more indicator leaflets will be available compared to 2018; • Link the indicators with the work on sustainability of HBM in Europe: the indicators were presented at the sustainability workshop in Paris. Participants indicated that they think the leaflets will be useful for institutional discussions, national hub meetings, meetings with policy makers and other meetings and that they would like to use them as soon as they are available. The added value of having indicators of success, is to monitor the implementation and achieved impact of HBM4EU. This will allow for a more efficient tracking of achieved goals. This deliverable will help to further optimize and revise the first set of indicators to monitor the implementation of the HBM4EU and the achieved impact. The indicators of success are written in a clear language, they are concise and capture the main achievements in the list of indicators that has been agreed amongst the partners. Therefore, they can be easily used by all partners across the consortium, the EU Policy Board and our HBM4EU ambassador Thomas Jackl. HORIZON2020 Programme Contract No. 733032 HBM4EU info:eu-repo/semantics/publishedVersion