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.

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.

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.

Cross-sectional associations between exposure to per- and polyfluoroalkyl substances and body mass index among European teenagers in the HBM4EU aligned studies.

Per- and polyfluoroalkyl substances (PFAS) are widespread pollutants that may impact youth adiposity patterns. We investigated cross-sectional associations between PFAS and body mass index (BMI) in teenagers/adolescents across nine European countries within the Human Biomonitoring for Europe (HBM4EU) initiative. We used data from 1957 teenagers (12-18 yrs) that were part of the HBM4EU aligned studies, consisting of nine HBM studies (NEBII, Norway; Riksmaten Adolescents 2016-17, Sweden; PCB cohort (follow-up), Slovakia; SLO CRP, Slovenia; CROME, Greece; BEA, Spain; ESTEBAN, France; FLEHS IV, Belgium; GerES V-sub, Germany). Twelve PFAS were measured in blood, whilst weight and height were measured by field nurse/physician or self-reported in questionnaires. We assessed associations between PFAS and age- and sex-adjusted BMI z-scores using linear and logistic regression adjusted for potential confounders. Random-effects meta-analysis and mixed effects models were used to pool studies. We assessed mixture effects using molar sums of exposure biomarkers with toxicological/structural similarities and quantile g-computation. In all studies, the highest concentrations of PFAS were PFOS (medians ranging from 1.34 to 2.79 µg/L). There was a tendency for negative associations with BMI z-scores for all PFAS (except for PFHxS and PFHpS), which was borderline significant for the molar sum of [PFOA and PFNA] and significant for single PFOA [ß-coefficient (95% CI) per interquartile range fold change = -0.06 (-0.17, 0.00) and -0.08 (-0.15, -0.01), respectively]. Mixture assessment indicated similar negative associations of the total mixture of [PFOA, PFNA, PFHxS and PFOS] with BMI z-score, but not all compounds showed associations in the same direction: whilst [PFOA, PFNA and PFOS] were negatively associated, [PFHxS] associated positively with BMI z-score. Our results indicated a tendency for associations of relatively low PFAS concentrations with lower BMI in European teenagers. More prospective research is needed to investigate this potential relationship and its implications for health later in life.

AOP-helpFinder webserver: a tool for comprehensive analysis of the literature to support adverse outcome pathways development.

MOTIVATION: Adverse outcome pathways (AOPs) are a conceptual framework developed to support the use of alternative toxicology approaches in the risk assessment. AOPs are structured linear organizations of existing knowledge illustrating causal pathways from the initial molecular perturbation triggered by various stressors, through key events (KEs) at different levels of biology, to the ultimate health or ecotoxicological adverse outcome. RESULTS: Artificial intelligence can be used to systematically explore available toxicological data that can be parsed in the scientific literature. Recently, a tool called AOP-helpFinder was developed to identify associations between stressors and KEs supporting thus documentation of AOPs. To facilitate the utilization of this advanced bioinformatics tool by the scientific and the regulatory community, a webserver was created. The proposed AOP-helpFinder webserver uses better performing version of the tool which reduces the need for manual curation of the obtained results. As an example, the server was successfully applied to explore relationships of a set of endocrine disruptors with metabolic-related events. The AOP-helpFinder webserver assists in a rapid evaluation of existing knowledge stored in the PubMed database, a global resource of scientific information, to build AOPs and Adverse Outcome Networks supporting the chemical risk assessment. AVAILABILITY AND IMPLEMENTATION: AOP-helpFinder is available at http://aop-helpfinder.u-paris-sciences.fr/index.php. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The Exposome and Toxicology: A Win-Win Collaboration.

The development of the exposome concept has been one of the hallmarks of environmental and health research for the last decade. The exposome encompasses the life course environmental exposures including lifestyle factors from the prenatal period onwards. It has inspired many research programs and is expected to influence environmental and health research, practices, and policies. Yet, the links bridging toxicology and the exposome concept have not been well developed. In this review, we describe how the exposome framework can interface with and influence the field of toxicology, as well as how the field of toxicology can help advance the exposome field by providing the needed mechanistic understanding of the exposome impacts on health. Indeed, exposome-informed toxicology is expected to emphasize several orientations including (1) developing approaches integrating multiple stressors, in particular chemical mixtures, as well as the interaction of chemicals with other stressors, (2) using mechanistic frameworks such as the adverse outcome pathways to link the different stressors with toxicity outcomes, (3) characterizing the mechanistic basis of long-term effects by distinguishing different patterns of exposures and further exploring the environment-DNA interface through genetic and epigenetic studies, and (4) improving the links between environmental and human health, in particular through a stronger connection between alterations in our ecosystems and human toxicology. The exposome concept provides the linkage between the complex environment and contemporary mechanistic toxicology. What toxicology can bring to exposome characterization is a needed framework for mechanistic understanding and regulatory outcomes in risk assessment.

Getting out of crises: Environmental, social-ecological and evolutionary research is needed to avoid future risks of pandemics.

The implementation of One Health/EcoHealth/Planetary Health approaches has been identified as key (i) to address the strong interconnections between risk for pandemics, climate change and biodiversity loss and (ii) to develop and implement solutions to these interlinked crises. As a response to the multiple calls from scientists on that subject, we have here proposed seven long-term research questions regarding COVID-19 and emerging infectious diseases (EIDs) that are based on effective integration of environmental, ecological, evolutionary, and social sciences to better anticipate and mitigate EIDs. Research needs cover the social ecology of infectious disease agents, their evolution, the determinants of susceptibility of humans and animals to infections, and the human and ecological factors accelerating infectious disease emergence. For comprehensive investigation, they include the development of nature-based solutions to interlinked global planetary crises, addressing ethical and philosophical questions regarding the relationship of humans to nature and regarding transformative changes to safeguard the environment and human health. In support of this research, we propose the implementation of innovative multidisciplinary facilities embedded in social ecosystems locally: ecological health observatories and living laboratories. This work was carried out in the frame of the European Community project HERA (www.HERAresearchEU.eu), which aims to set priorities for an environment, climate and health research agenda in the European Union by adopting a systemic approach in the face of global environmental change.

NPAHs and OPAHs in the atmosphere of two central European cities: Seasonality, urban-to-background gradients, cancer risks and gas-to-particle partitioning.

Derivatives of polycyclic aromatic hydrocarbons (PAHs) such as nitrated- and oxygenated-PAHs (NPAHs and OPAHs) could be even more toxic and harmful for the environment and humans than PAHs. We assessed the spatial and seasonal variations of NPAHs and OPAHs atmospheric levels, their cancer risks and their gas-to-particle partitioning. To this end, about 250 samples of fine particulate matter (PM2.5) and 50 gaseous samples were collected in 2017 in central Europe in the cities of Brno and Ljubljana (two traffic and two urban background sites) as well as one rural site. The average particulate concentrations were ranging from below limit of quantification to 593 pg m-3 for Σ9NPAHs and from 1.64 to 4330 pg m-3 for Σ11OPAHs, with significantly higher concentrations in winter compared to summer. In winter, the particulate levels of NPAHs and OPAHs were higher at the traffic site compared to the urban background site in Brno while the opposite was found in Ljubljana. NPAHs and OPAHs particulate levels were influenced by the meteorological parameters and co-varied with several air pollutants. The significance of secondary formation on the occurrence of some NPAHs and OPAHs is indicated. In winter, 27-47% of samples collected at all sites were above the acceptable lifetime carcinogenic risk. The gas-particle partitioning of NPAHs and OPAHs was influenced by their physico-chemical properties, the season and the site-specific aerosol composition. Three NPAHs and five OPAHs had higher particulate mass fractions at the traffic site, suggesting they could be primarily emitted as particles from vehicle traffic and subsequently partitioning to the gas phase along air transport. This study underlines the importance of inclusion of the gas phase in addition to the particulate phase when assessing the atmospheric fate of polycyclic aromatic compounds and also when assessing the related health risk.

The association between environmental exposures to chlordanes, adiposity and diabetes-related features: a systematic review and meta-analysis.

Chlordane compounds (CHLs) are components of technical chlordane listed in the Stockholm convention on persistent organic pollutants identified as endocrine disrupting chemicals (EDCs) and may interfere with hormone biosynthesis, metabolism or action resulting in an unbalanced hormonal function. There is increasing scientific evidence showing EDCs as risk factors in the pathogenesis and development of obesity and obesity-related metabolic syndromes such as type 2 diabetes, but there is no systematized information on the effect of CHLs in humans. Our aim is to identify the epidemiological data on the association between CHLs with adiposity and diabetes using a systematic approach to identify the available data and summarizing the results through meta-analysis. We searched PubMed and Web of Science from inception up to 15 February 2021, to retrieve original data on the association between chlordanes, and adiposity or diabetes. For adiposity, regression coefficients and Pearson or Spearman correlation coefficients were extracted and converted into standardized regression coefficients. Data were combined using fixed effects meta-analyses to compute summary regression coefficients and corresponding 95% confidence intervals (95% CI). For the association between chlordanes and diabetes, Odds ratios (ORs) were extracted and the DerSimonian and Laird method was used to compute summary estimates and respective 95% CI. For both, adjusted estimates were preferred, whenever available. Among 31 eligible studies, mostly using a cross-sectional approach, the meta-analysis for adiposity was possible only for oxychlordane and transchlordane, none of them were significantly associated with adiposity [(ß = 0.04, 95% CI 0.00; 0.07, I2 = 89.7%)] and (ß = 0.02, 95% CI - 0.01; 0.06), respectively. For diabetes, the estimates were positive for all compounds but statistically significant for oxychlordane [OR = 1.96 (95% CI 1.19; 3.23)]; for trans-nonachlor [OR = 2.43 (95% CI 1.64; 3.62)] and for heptachlor epoxide [OR = 1.88 (95% CI 1.42; 2.49)]. Our results support that among adults, the odds of having diabetes significantly increase with increasing levels of chlordanes. The data did not allow to reach a clear conclusion regarding the association with adiposity.

Neurodevelopmental exposome: The effect of in utero co-exposure to heavy metals and phthalates on child neurodevelopment.

In this study, the exposome paradigm has been applied on a mother-child cohort adopting an optimised untargeted metabolomics approach for human urine followed by advanced bioinformatics analysis. Exposome-wide association algorithms were used to draw links between in utero co-exposure to metals and phthalates, metabolic pathways deregulation, and clinically observed phenotypes of neurodevelopmental disorders such as problems in linguistic, motor development and cognitive capacity. Children (n = 148) were tested at the first and second year of their life using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). Their mothers had been exposed to metals and phthalates during the pregnancy, according to human biomonitoring results from previously performed studies. Untargeted metabolomics analysis of biobanked urine samples from the mothers was performed using a combination of the high throughput analytical methods liquid chromatography-high resolution mass spectrometry (LC-HRMS) and nuclear magnetic resonance (NMR). Most perturbed metabolic pathways from co-exposure heavy metals and phthalates were pathways related to the tricarboxylic acid cycle (TCA cycle) and oxidative phosphorylation, indicating the possibility of disruption of mitochondrial respiration. Overproduction of reactive oxygen species (ROS); the presence of glutathione peroxidase 3 (GPx3) during pregnancy and presence of glutathione peroxidase 1 (GPx1) in the umbilical cord were linked to verbal development problems. Another finding of the study is that in real life, adverse outcomes occur as a combination of environmental and social factors, all of them acting synergistically towards the deployment of an observed phenotype. Finally, the two-steps association process (exposure to pathways and pathways to adverse outcomes) was able to (a) provide associations that are not evident by directly associating exposure to outcomes and (b) provides additional insides on the mechanisms of environmental disease.

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.

Neighbourhood and path-based greenspace in three European countries: associations with objective physical activity.

BACKGROUND: Greenspace has been associated with health benefits in many contexts. An important pathway may be through outdoor physical activity. We use a novel approach to examine the link between greenspace microenvironments and outdoor physical activity levels in the HEALS study conducted in Edinburgh (UK), the Netherlands, and Athens and Thessaloniki (Greece). METHODS: Using physical activity tracker recordings, 118 HEALS participants with young children were classified with regard to daily minutes of moderate to vigorous physical activity (MVPA); 60 were classified with regard to the metabolic equivalent task (MET)-minutes for each of the 1014 active trips they made. Greenspace indicators were generated for Normalised Difference Vegetation Index (NDVI), tree cover density (TCD), and green land use (GLU). We employed linear mixed-effects models to analyse (1) daily MVPA in relation to greenspace within 300 m and 1000 m of residential addresses and (2) trip MET-minutes in relation to average greenspace within a 50 m buffer of walking/cycling routes. Models were adjusted for activity, walkability, bluespace, age, sex, car ownership, dog ownership, season, weekday/weekend day, and local meteorology. RESULTS: There was no clear association between MVPA-minutes and any residential greenspace measure. For example, in fully adjusted models, a 10 percentage point increase in NDVI within 300 m of home was associated with a daily increase of 1.14 (95% CI - 0.41 to 2.70) minutes of MVPA. However, we did find evidence to indicate greenspace markers were positively linked to intensity and duration of activity: in fully adjusted models, 10 percentage point increases in trip NDVI, TCD, and GLU were associated with increases of 10.4 (95% CI: 4.43 to 16.4), 10.6 (95% CI: 4.96 to 16.3), and 3.36 (95% CI: 0.00 to 6.72) MET-minutes, respectively. The magnitude of associations with greenspace tended to be greater for cycling. CONCLUSIONS: More strenuous or longer walking and cycling trips occurred in environments with more greenspace, but levels of residential greenspace did not have a clear link with outdoor MVPA. To build on our research, we suggest future work examine larger, more diverse populations and investigate the influence of greenspace for trip purpose and route preference.

Multi-omics analysis reveals that co-exposure to phthalates and metals disturbs urea cycle and choline metabolism.

This study aimed to evaluate the response of HepaRG cells after co-exposure to phthalates and heavy metals, using a high-dimensional biology paradigm (HDB). Liver is the main metabolism site for the majority of xenobiotics. For this reason, the HepaRG cell line was used as an in vitro model, and cells were exposed to two characteristic mixtures of phthalates and heavy metals containing phthalates (DEHP, DiNP, BBzP) and metals (lead, methylmercury, total mercury) in a concentration-dependent manner. The applied chemical mixtures were selected as the most abundant pollutants in the REPRO_PL and PHIME cohorts, which were studied using the exposome-wide approach in the frame of the EU project HEALS. These studies investigated the environmental causation of neurodevelopmental disorders in neonates and across Europe. The INTEGRA computational platform was used for the calculation of the effective concentrations of the chemicals in the liver through extrapolation from human biomonitoring data and this dose (and a ten-times higher one) was applied to the hepatocyte model. Multi-omics analysis was performed to reveal the genes, proteins, and metabolites affected by the exposure to these chemical mixtures. By extension, we could detect the perturbed metabolic pathways. The generated data were analyzed using advanced bioinformatic tools following the HEALS connectivity paradigm for multi-omics pathway analysis. Co-mapped transcriptomics and proteomics data showed that co-exposure to phthalates and heavy metals leads to perturbations of the urea cycle due to differential expression levels of arginase-1 and -2, argininosuccinate synthase, carbamoyl-phosphate synthase, ornithine carbamoyltransferase, and argininosuccinate lyase. Joint pathway analysis of proteomics and metabolomics data revealed that the detected proteins and metabolites, choline phosphate cytidylyltransferase A, phospholipase D3, group XIIA secretory phospholipase A2, α-phosphatidylcholine, and the a 1,2-diacyl-sn-glycero-3-phosphocholine, are responsible for the homeostasis of the metabolic pathways phosphatidylcholine biosynthesis I, and phospholipases metabolism. The urea, phosphatidylcholine biosynthesis I and phospholipase metabolic pathways are of particular interest since they have been identified also in human samples from the REPRO_PL and PHIME cohorts using untargeted metabolomics analysis and have been associated with impaired psychomotor development in children at the age of two. In conclusion, this study provides the mechanistic evidence that co-exposure to phthalates and metals disturb biochemical processes related to mitochondrial respiration during critical developmental stages, which are clinically linked to neurodevelopmental perturbations.

The COVID-19 pandemic and global environmental change: Emerging research needs.

The outbreak of COVID-19 raised numerous questions on the interactions between the occurrence of new infections, the environment, climate and health. The European Union requested the H2020 HERA project which aims at setting priorities in research on environment, climate and health, to identify relevant research needs regarding Covid-19. The emergence and spread of SARS-CoV-2 appears to be related to urbanization, habitat destruction, live animal trade, intensive livestock farming and global travel. The contribution of climate and air pollution requires additional studies. Importantly, the severity of COVID-19 depends on the interactions between the viral infection, ageing and chronic diseases such as metabolic, respiratory and cardiovascular diseases and obesity which are themselves influenced by environmental stressors. The mechanisms of these interactions deserve additional scrutiny. Both the pandemic and the social response to the disease have elicited an array of behavioural and societal changes that may remain long after the pandemic and that may have long term health effects including on mental health. Recovery plans are currently being discussed or implemented and the environmental and health impacts of those plans are not clearly foreseen. Clearly, COVID-19 will have a long-lasting impact on the environmental health field and will open new research perspectives and policy needs.

Suspect and non-targeted screening of chemicals of emerging concern for human biomonitoring, environmental health studies and support to risk assessment: From promises to challenges and harmonisation issues.

Large-scale suspect and non-targeted screening approaches based on high-resolution mass spectrometry (HRMS) are today available for chemical profiling and holistic characterisation of biological samples. These advanced techniques allow the simultaneous detection of a large number of chemical features, including markers of human chemical exposure. Such markers are of interest for biomonitoring, environmental health studies and support to risk assessment. Furthermore, these screening approaches have the promising capability to detect chemicals of emerging concern (CECs), document the extent of human chemical exposure, generate new research hypotheses and provide early warning support to policy. Whilst of growing importance in the environment and food safety areas, respectively, CECs remain poorly addressed in the field of human biomonitoring. This shortfall is due to several scientific and methodological reasons, including a global lack of harmonisation. In this context, the main aim of this paper is to present an overview of the basic principles, promises and challenges of suspect and non-targeted screening approaches applied to human samples as this specific field introduce major specificities compared to other fields. Focused on liquid chromatography coupled to HRMS-based data acquisition methods, this overview addresses all steps of these new analytical workflows. Beyond this general picture, the main activities carried out on this topic within the particular framework of the European Human Biomonitoring initiative (project HBM4EU, 2017-2021) are described, with an emphasis on harmonisation measures.

Integrative Strategy of Testing Systems for Identification of Endocrine Disruptors Inducing Metabolic Disorders-An Introduction to the OBERON Project.

Exposure to chemical substances that can produce endocrine disrupting effects represents one of the most critical public health threats nowadays. In line with the regulatory framework implemented within the European Union (EU) to reduce the levels of endocrine disruptors (EDs) for consumers, new and effective methods for ED testing are needed. The OBERON project will build an integrated testing strategy (ITS) to detect ED-related metabolic disorders by developing, improving and validating a battery of test systems. It will be based on the concept of an integrated approach for testing and assessment (IATA). OBERON will combine (1) experimental methods (in vitro, e.g., using 2D and 3D human-derived cells and tissues, and in vivo, i.e., using zebrafish at different stages), (2) high throughput omics technologies, (3) epidemiology and human biomonitoring studies and (4) advanced computational models (in silico and systems biology) on functional endpoints related to metabolism. Such interdisciplinary framework will help in deciphering EDs based on a mechanistic understanding of toxicity by providing and making available more effective alternative test methods relevant for human health that are in line with regulatory needs. Data generated in OBERON will also allow the development of novel adverse outcome pathways (AOPs). The assays will be pre-validated in order to select the test systems that will show acceptable performance in terms of relevance for the second step of the validation process, i.e., the inter-laboratory validation as ring tests. Therefore, the aim of the OBERON project is to support the organization for economic co-operation and development (OECD) conceptual framework for testing and assessment of single and/or mixture of EDs by developing specific assays not covered by the current tests, and to propose an IATA for ED-related metabolic disorder detection, which will be submitted to the Joint Research Center (JRC) and OECD community.

Health impact assessment by the implementation of Madrid City air-quality plan in 2020.

OBJECTIVES: Air pollutant concentrations in many urban areas are still above the legal and recommended limits that are set to protect the citizens' health. Madrid is one of the cities where traffic causes high NO2 levels. In this context, Madrid City Council launched the Air Quality and Climate Change Plan for the city of Madrid (Plan A), a local strategy approved by the previous government in 2017. The aim of this study was to conduct a quantitative health impact assessment to evaluate the number of premature deaths that could potentially be prevented by the implementation of Plan A in Madrid in 2020, at both citywide and within-city level. The main purpose was to support decision-making processes in order to maximize the positive health impacts from the implementation of Plan A measures. METHODS: The Regional Statistical Office provided information on population and daily mortality in Madrid. For exposure assessment, we estimated PM2.5, NO2 and O3 concentration levels for Madrid city in 2012 (baseline air-quality scenario) and 2020 (projected air-quality scenario based on the implementation of Plan A), by means of an Eulerian chemical-transport model with a spatial resolution of 1 km × 1 km and 30 vertical levels. We used the concentration-response functions proposed by two relevant WHO projects to calculate the number of attributable annual deaths corresponding to all non-accidental causes (ICD-10: A00-R99) among all-ages and the adult population (>30 years old) for each district and for Madrid city overall. This health impact assessment was conducted dependant on health-data availability. RESULTS: In 2020, the implementation of Plan A would imply a reduction in the Madrid citywide annual mean PM2.5 concentration of 0.6 µg/m3 and 4.0 µg/m3 for NO2. In contrast, an increase of 1 µg/m3 for O3 would be expected. The annual number of all-cause deaths from long-term exposure (95% CI) that could be postponed in the adult population by the expected air-pollutant concentration reduction was 88 (57-117) for PM2.5 and 519 (295-750) for NO2; short-term exposure accounted for 20 (7-32) for PM2.5 and 79 (47-111) for NO2 in the total population. According to the spatial distribution of air pollutants, the highest mortality change estimations were for the city centre - including Madrid Central and mainly within the M-30 ring road -, as compared to peripheral districts. The positive health impacts from the reductions in PM2.5 and NO2 far exceeded the adverse mortality effects expected from the increase in O3. CONCLUSIONS: Effective implementation of Plan A measures in Madrid city would bring about an appreciable decline in traffic-related air-pollutant concentrations and, in turn, would lead to significant health-related benefits.

The exposome - a new approach for risk assessment.

Complementing the human genome with an exposome reflects the increasingly obvious impact of environmental exposure, which far exceeds the role of genetics, on human health. Considering the complexity of exposures and, in addition, the reactions of the body to exposures - i.e., the exposome - reverses classical exposure science where the precise measurement of single or few exposures is associated with specific health or environmental effects. The complete description of an individual's exposome is impossible; even less so is that of a population. We can, however, cast a wider net by foregoing some rigor in assessment and compensating with the statistical power of rich datasets. The advent of omics technologies enables a relatively cheap, high-content description of the biological effects of substances, especially in tissues and biofluids. They can be combined with many other rich data-streams, creating big data of exposure and effect. Computational methods increasingly allow data integration, discerning the signal from the noise and formulating hypotheses of exposure-effect relationships. These can be followed up in a targeted way. With a better exposure element in the risk equation, exposomics - new kid on the block of risk assessment - promises to identify novel exposure (interactions) and health/environment effect associations. This may also create opportunities to prioritize the more relevant chemicals for risk assessment, thereby lowering the burden on hazard assessment in an expo-sure-driven approach. Technological developments and synergies between approaches, quality assurance (ultimately as Good Exposome Practices), and the integration of mechanistic thinking will advance this approach.

Urban greenspace and the indoor environment: Pathways to health via indoor particulate matter, noise, and road noise annoyance.

BACKGROUND/AIM: The exposome includes urban greenspace, which may affect health via a complex set of pathways, including reducing exposure to particulate matter (PM) and noise. We assessed these pathways using indoor exposure monitoring data from the HEALS study in four European urban areas (Edinburgh, UK; Utrecht, Netherlands; Athens and Thessaloniki, Greece). METHODS: We quantified three metrics of residential greenspace at 50 m and 100 m buffers: Normalised Difference Vegetation Index (NDVI), annual tree cover density, and surrounding green land use. NDVI values were generated for both summer and the season during which the monitoring took place. Indoor PM2.5 and noise levels were measured by Dylos and Netatmo sensors, respectively, and subjective noise annoyance was collected by questionnaire on an 11-point scale. We used random-effects generalised least squares regression models to assess associations between greenspace and indoor PM2.5 and noise, and an ordinal logistic regression to model the relationship between greenspace and road noise annoyance. RESULTS: We identified a significant inverse relationship between summer NDVI and indoor PM2.5 (-1.27 µg/m3 per 0.1 unit increase [95% CI -2.38 to -0.15]) using a 100 m residential buffer. Reduced (i.e., <1.0) odds ratios (OR) of road noise annoyance were associated with increasing summer (OR = 0.55 [0.31 to 0.98]) and season-specific (OR = 0.55 [0.32 to 0.94]) NDVI levels, and tree cover density (OR = 0.54 [0.31 to 0.93] per 10 percentage point increase), also at a 100 m buffer. In contrast to these findings, we did not identify any significant associations between greenspace and indoor noise in fully adjusted models. CONCLUSIONS: We identified reduced indoor levels of PM2.5 and noise annoyance, but not overall noise, with increasing outdoor levels of certain greenspace indicators. To corroborate our findings, future research should examine the effect of enhanced temporal resolution of greenspace metrics during different seasons, characterise the configuration and composition of green areas, and explore mechanisms through mediation modelling.

Association between the exposure to phthalates and adiposity: A meta-analysis in children and adults.

BACKGROUND: Exposure to environmental chemicals has become one of the major concerns in the past decades. Phthalates are a family of synthetic organic chemicals used in the manufacture of plastics, solvents, and personal care products. These compounds are considered as endocrine-disrupting compounds (EDCs) since they may interfere with the endocrine system and disrupt its physiologic function. AIM: The purpose of this work is to synthesize results from published literature on the association between the exposure to phthalates and adiposity in adults and children. METHODS: We searched PubMed from inception up to 01 August 2019, to retrieve original papers reporting data on the association between EDCs and adiposity, using the following search expression: (("Endocrine disruptor" OR Endocrine disruptor[mh] OR phthalate) AND (Obesity OR Overweight OR BMI OR "Body fat" OR Adipose tissue[mh] OR Body size[mh] OR "body size" OR "body weight" OR Anthropometry OR "anthropometric measures")) AND (humans[mh]). The study variables and characteristics were collected during data extraction, namely the study design, sample, exposure, outcome, descriptive and association measures. Study quality was assessed using the STROBE template for observational studies. Although studies examined several adiposity measures, Body Mass Index (BMI) and Waist Circumference (WC) were the most commonly used, therefore, we used the beta coefficients regarding BMI and WC, and odds ratios when BMI outcome was categorical to perform the meta-analysis. Data from the studies were combined using fixed effects meta-analyses to compute summary regression coefficients or odds ratios and corresponding 95% confidence intervals (95% CI). Heterogeneity between studies was assessed by the I2 statistic. RESULTS: In the systematic review we found 29 publications addressing the association between phthalate compounds and adiposity. The vast majority of the included studies reported associations that were not statistically significant. For most of the phthalate compounds there were few studies providing compatible measures and therefore it was not possible to combine the results in a meta-analysis. Both for BMI and WC, the meta-analysis for MiBP, MCPP and MbzP showed negative associations and null association for MBP in children, although none of them was significant. For MEP, positive but not significant associations were found both in children and adults. Conversely, for MEHP a negative association was found also in children and adults although it did not reach statistical significance. Only for MECPP a significant association was found for obesity in adults (OR = 1.67 (95% CI 1.30; 2.16). CONCLUSION: In general, a positive association between phthalates and adiposity measures was found, especially in adults. However, most of the results did not reach statistical significance and the inconsistencies found between studies did not allow to reach a definitive conclusion. Additionally, we cannot exclude a possible effect of publication bias.