EU-wide exposure data of 11 chemical substance groups from the HBM4EU Aligned Studies (2014–2021)

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.publishersversionpublishe

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)

HBM4EU is co-financed under Horizon 2020 (grant agreement No 733032).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 from 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, and 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 the 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 policymakers for the implementation of targeted measures.info:eu-repo/semantics/publishedVersio

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

Βιολογική ανάλυση πολλαπλών διαστάσεων για την αποτίμηση της επίδρασης της έκθεσης σε βαρέα μέταλλα, πλαστικοποιητές και φυτοφάρμακα στην παιδική νευροανάπτυξη

Humans are exposed to environmental chemicals in their everyday life and and this exposure can impact the development of various chronic diseases. Characterisation, monitoring and regulation of the ever-increasing space of environmental chemicals for their potential adverse health effects is both necessary and challenging. In simpler terms, comprehensively understanding the exposure and health effects of chemicals is vital for overall well-being. Consequently, there has been a rising focus on comprehensively characterising the human exposome in conjunction with the genome, proteome, and metabolome to gain deeper insights into the environmental factors critical for human health and disease. This thesis is dedicated to establishing a thorough, interdisciplinary framework for comprehensively understanding the effects of various environmental stressors on chronic non-communicable diseases, including neurodevelopmental disorders. It emphasises the importance of utilising systems biology approaches to characterise the internal exposome. These comprehensive approaches were applied to three birth cohorts to explore the impacts of prenatal exposure to real-life mixtures of metals, phthalates/DINCH, organophosphates, and organochlorines on fetal and infancy development, particularly concerning developmental neurotoxicity. The chemicals of interest were chosen based on the scientific and regulatory interest they have gathered owing to their potential adverse effects on early childhood development, facilitated by their ability to traverse the placental barrier. First, the optimised untargeted LC-MS and NMR metabolomics protocols for human and in vitro samples preparation and data acquisition in the case of exposome studies, accounting for the use of different instruments (Orbitrap and Q-TOF) are described. A full description of the robust, comprehensive bioinformatics workflow developed for the data pre-processing and processing of untargeted MS and NMR metabolomics data leveraging R packages is followed. Next in line is the presentation of the workflow for the integration of multiple omics data, including transcriptomics, proteomics, and metabolomics, based on R packages and online tools, followed by the exposome data analysis, which aims to draw links between human biomonitoring, sociodemographic and lifestyle data, metabolic pathways, and clinically observed phenotypes, by implemented advanced mathematical methods, including the Bayesian kernel machine regression (BKMR) and Environment-wide association studies (EWAS).The pipelines, as mentioned above, were applied in three different birth cohorts: PHIME (SLO, n=180), REPRO_PL (PL, n=148), and EXHES Tarragona (SP, n=35) cohorts. These studies were part of the Health and Environment-wide Associations based on Large Population Surveys (HEALS; http:/heals-eu.eu/) project, whose main objective was to develop an integrated methodology that will support the comprehensive study of the exposure-health associations by organising the environmental, socioeconomic, exposure, biomarker, and health effect data, and providing all the necessary analytical and computational sequences. In summary, exposure to mixtures of metals, phthalates/DINCH, and pesticide metabolites was linked with lower cognitive, language, and motor development scores during the first two years of life. Furthemore, the BKMR analysis results highlighted the significant impact of mono-(2-ethylhexyl) phthalate (MEHP) from a combination of various metals, phthalates/DINCH, organophosphates, and organochlorines on birth height, with a PIP (Posterior Inclusion Probability) value of 0.86. In addition, findings from the EWAS analysis indicated the influence of prenatal exposure to organophosphates (IMPY) and organochlorine pesticides, such as DDD, β-HCH, DDT, and pirimiphos-methyl, on birth height. Moreover, correlations were found between several factors, including birth weight, height, gestational age, preterm delivery, socioeconomic status, and paternal education. Additionally, the study identified intriguing relationships between exposure or neurodevelopmental parameters and the metabolism of amino acids and lipids, encompassing various metabolic pathways. These findings highlight the complex connections between chemical exposures and various aspects of child development. A comprehensive multi-omics analysis was conducted using the HepaRG cell line exposed to mixtures of phthalates (DEHP, DiNP, and BBzP) and heavy metals (Pb, Cd, and Hg) based on human biomonitoring data from PHIME and REPRO_PL studies, to obtain a deeper understanding of the mechanism behind the adverse effects of prenatal exposure to metals and phthalates. The INTEGRA computational platform was used to calculate the effective concentrations of the chemicals in the liver through extrapolation from human biomonitoring data. This dose (and a ten-times higher one) was applied to the hepatocyte model. The study revealed significant differential expressions in 29 genes, 230 proteins, and 157 metabolites. These differentially expressed biomarkers were linked to several metabolic pathways associated with neurodevelopment, including the TCA cycle, arginine metabolism, and glycolysis, among others, providing valuable insights into the potential mechanisms underlying the impact of these mixtures on developmental processes. Overal, the thesis findings strongly suggest that the combined exposure to metals, phthalates, organophosphates, and organochlorines can disturb the Tricarboxylic Acid (TCA) cycle, leading to disruptions in mitochondrial function and subsequent implications for developmental neurotoxicity. The disturbances in the TCA cycle arising from co-exposure to metals and phthalates can be attributed to two interrelated processes. Firstly, the concurrent exposure to metals and phthalates results in changes in glutamine levels, subsequently affecting glutamate expression, ornithine levels, and arginine production. Arginine's role in urea cycle catabolism and nitric oxide (NO) production is then impacted, influencing oxygen delivery and adenosine triphosphate (ATP) production within the TCA cycle. Alternatively, exposure to specific substances like DEHP, DiNP, BBzP, Pb, Cd, and Hg can reduce lactate levels, resulting in diminished pyruvate levels. Pyruvate's role as a precursor for Acetyl-CoA is affected, leading to decreased Acetyl-CoA within the mitochondria. Several identified genes and metabolites, including CPS1, HSD17B6, ADH1A, lactate, arginine, glutamate, glutamine, ATP, and Acetyl-CoA, could potentially be biomarkers of effect in this context. In conclusion, integrating methods devised for characterising the external exposome into the presented workflow based on a high-dimensional biology paradigm is crucial in establishing a comprehensive approach for unravelling the intricate connections between the exposome and human health. This comprehensive understanding will serve as a foundation for informing effective strategies for disease prevention, accurate risk assessment, and the development of personalised interventions.Οι άνθρωποι εκτίθενται σε περιβαλλοντικές χημικές ουσίες καθημερινά. H έκθεση αυτή μπορεί να επηρεάσει την ανάπτυξη διαφόρων χρόνιων νοσημάτων. O χαρακτηρισμός, η παρακολούθηση και η νομοθετική ρύθμιση της χρήσης των συνεχώς αυξανόμενων επικίνδυνων χημικών από τη βιομηχανία αποτελεί επιτακτική ανάγκη και παράλληλα πρόκληση. Έτσι, λοιπόν, μεγάλο μέρος της επιστημονικής κοινότητας, καθώς και οι θεσμοί, έχουν εστιάσει στη μελέτη του εκθεσιώματος. Ο όρος εκθεσίωμα (exposome) αναφέρεται σε όλους τους παράγοντες, ενδογενείς και εξωγενείς που επηρεάζουν την έκφραση των γονιδίων από τη στιγμή της σύλληψής μας. Η παρούσα διατριβή έχει ως στόχο τη δημιουργία μιας ολοκληρωμένης μεθοδολογίας για την κατανόηση των επιπτώσεων της έκθεσης σε μείγμα διάφορων περιβαλλοντικών παραγόντων σε χρόνιες μη μεταδιδόμενες ασθένειες, συμπεριλαμβανομένων των νευροαναπτυξιακών διαταραχών, καθώς αναγνωρίζεται η ανάγκη για την εφαρμογή προσεγγίσεων συστημικής βιολογίας στον χαρακτηρισμό του εσωτερικού εκθεσιώματος (internal exposome). Η μεθοδολογία που αναπτύχθηκε εφαρμόστηκε σε τρεις κοορτές με σκοπό την εξερεύνηση των επιπτώσεων της προγεννητικής έκθεσης σε μείγματα μετάλλων, φθαλικών, οργανοφωσφορικών και οργανοχλωρικών ενώσεων στην εμβρυϊκή και βρεφική ανάπτυξη, ιδιαίτερα όσον αφορά τη παιδική νευροανάπτυξη. Τα χημικά που συμπεριλήφθησαν επιλέχθηκαν βάσει του επιστημονικού και θεσμικού ενδιαφέροντος που έχουν συγκεντρώσει λόγω των πιθανών αρνητικών επιδράσεών τους στην παιδική νευροανάπτυξη, εξαιτίας της ικανότητάς τους να διαπερνούν τον πλακούντα. Αρχικά, περιγράφονται τα βελτιστοποιημένα πρωτόκολλα για τη μη-στοχευμένη μεταβολομική ανάλυση ανθρώπινων και κυτταρικών (in vitro) δειγμάτων με τη χρήση υγρής χρωματογραφίας συζευγμένης με φασματομετρία μαζών (LC-MS) και του πυρηνικού µαγνητικού συντονισµού (NMR). Ακολουθεί μια πλήρης περιγραφή της αναπτυγμένης ροής εργασιών για την προ-επεξεργασία και επεξεργασία των δεδομένων μη στοχευμένης μεταβολομικής ανάλυσης με τη χρήση των πακέτων της γλώσσας προγραμματισμού R. Στη συνέχεια, παρουσιάζεται τη ροή εργασίας για την ενσωμάτωση πολλαπλών ομικών δεδομένων (multi-omics), συμπεριλαμβανομένων των μεταγραφομικών, πρωτεομικών και μεταβολομικών δεδομένων, βασισμένη, επίσης, σε πακέτα R και ανοικτών διαδικτυακών εργαλείων. Ακολουθεί η περιγραφή της ροής εργασιών για την ανάλυση των δεδομένων εκθεσιώματος, η οποία έχει ως στόχο να συνδέσει την ανθρώπινη βιοπαρακολούθηση, τα κοινωνικοοικονομικά δεδομένα και αυτά του τρόπου ζωής, τα μεταβολικά μονοπάτια, και τα κλινικά δεδομένα χρησιμοποιώντας προηγμένες μαθηματικές μεθόδους, συμπεριλαμβανομένoυ του μοντέλου παλινδρόμησης BKMR (Bayesian kernel machine regression) και της μεθόδου EWAS (Environment-Wide Association Study). Τα προαναφερθέντα πρωτόκολλα και οι μεθοδολογίες εφαρμόστηκαν σε τρεις διαφορετικές κοορτές, PHIME (SLO, n=180), REPRO_PL (PL, n=148) και EXHES Tarragona (SP, n=35). Αυτές οι μελέτες ήταν μέρος του ευρωπαϊκού προγράμματος HEALS (http:/heals-eu.eu/), το οποίο είχε ως κύριο στόχο την ανάπτυξη μιας ολοκληρωμένης μεθοδολογίας που θα υποστήριζει την ολοκληρωμένη μελέτη των συνδέσεων έκθεσης-υγείας. Συνοψίζοντας, βρέθηκε ότι η έκθεση σε μείγματα μετάλλων, φθαλικών/DINCH και φυτοφαρμάκων βρέθηκε να σχετίζεται σημαντικά με μειωμένη γνωστική, γλωσσική και κινητική ανάπτυξη κατά τα πρώτα δύο χρόνια της ζωής. Επιπρόσθετα, τα αποτελέσματα της ανάλυσης BKMR υπογράμμισαν τη σημαντική επίδραση του μονο- (2-αιθυλεξυλ) φθαλικού (MEHP) στο ύψος της γέννησης, με τιμή PIP (Posterior Inclusion Probability) 0.86. Τα ευρήματα από την ανάλυση EWAS έδειξαν ότι και η προγεννητική έκθεση σε οργανοφωσφορικά (IMPY) και οργανοχλωρικά φυτοφαρμάκα, όπως τα DDD, β-HCH, και DDT, επιδρά σημαντικά στο ύψος γέννησης. Επιπλέον, παρατηρήθηκαν συσχετίσεις μεταξύ πολλών παραγόντων, συμπεριλαμβανομένου του βάρους, του ύψους γέννησης, της εγκυμοσύνης, της πρόωρης γέννησης, της κοινωνικοοικονομικής κατάστασης και εκπαιδευτικής βαθμίδας των γονέων. Επιπλέον, η μελέτη εντόπισε ενδιαφέρουσες σχέσεις μεταξύ της έκθεσης ή/και των παραμέτρων νευροαναπτυξιακής αξιολόγησης και των μεταβολικών μονοπατιών που σχετίζονται με τον μεταβολισμό των αμινξέων και των λιπιδίων.Αυτά τα ευρήματα υπογραμμίζουν τις σύνθετες συνδέσεις μεταξύ της έκθεσης σε βαρέα μέταλλα, πλαστικοποιητές και φυτοφάρμακα και των διαφόρων πτυχών της νευροανάπτυξης του παιδιού. Διεξήχθη μια ολοκληρωμένη ανάλυση πολλαπλών ομικών αναλύσεων χρησιμοποιώντας την κυτταρική σειρά HepaRG με στόχο τη βαθύτερη κατανόηση του μηχανισμού που δρα πίσω από τις αρνητικές επιδράσεις της προγεννητικής έκθεσης σε βαρέα μέταλλα (Pb, Cd και Hg) και φθαλικές ενώσεις (DEHP, DiNP και BBzP). Οι τιμές έκθεσης βασίστηκαν στα δεδομένα ανθρώπινης βιοπαρακολούθησης των PHIME και REPRO_PL. Η υπολογιστική πλατφόρμα INTEGRA χρησιμοποιήθηκε για τον υπολογισμό των συγκεντρώσεων των χημικών στο ήπαρ. Η μελέτη αποκάλυψε σημαντικές διαφορικές εκφράσεις σε 29 γονίδια, 230 πρωτεΐνες και 157 μεταβολίτες. Αυτοί οι διαφορετικά εκφραζόμενοι βιοδείκτες συσχετίστηκαν με πολλές μεταβολικές διαδρομές που σχετίζονται με τη νευροανάπτυξη, συμπεριλαμβανομένου του κύκλου τρικαρβοξυλικού οξέος, του μεταβολισμού της αργινίνης και της γλυκόλυσης, μεταξύ άλλων, παρέχοντας πολύτιμες ενδείξεις για τους δυνητικούς μηχανισμούς. Τα ευρήματα της διατριβής υποδηλώνουν ισχυρά ότι η συνδυασμένη έκθεση σε μέταλλα, φθαλικές, οργανοφωσφορικές και οργανοχλωρικές ενώσεις μπορεί να διαταράξει τον κύκλο του τρικαρβοξυλικού οξέος (TCA), οδηγώντας σε διαταραχές στη λειτουργία των μιτοχονδρίων, με συνέπειες στη νευρανάπτυξη τα πρώτα χρόνια ζωής. Οι διαταραχές στον κύκλο TCA που προκύπτουν από τη συνέκθεση σε μέταλλα και φθαλικά μπορούν να αποδοθούν σε δύο αλληλένδετες διαδικασίες. Καταρχήν, η συνέκθεση σε βαρέα μέταλλα και φθαλικά οδηγεί σε αλλαγές στα επίπεδα γλουταμίνης, επηρεάζοντας στη συνέχεια την έκφραση του γλουταμικού οξέος, τα επίπεδα ορνιθίνης και την παραγωγή αργινίνης. Ο ρόλος της αργινίνης στον καταβολισμό του κύκλου της ουρίας και στην παραγωγή οξειδίου του αζώτου (NO) επηρεάζεται, διαταράσσοντας στην παροχή οξυγόνου και την παραγωγή αδενοσίνης τριφωσφορικού οξέος (ATP) εντός του κύκλου TCA. Εναλλακτικά, η έκθεση σε συγκεκριμένες ουσίες όπως DEHP, DiNP, BBzP, Pb, Cd και Hg μπορεί να οδηγήσει σε μειωμένα επίπεδα γαλακτικού οξέος, με αποτέλεσμα τη μείωση των επιπέδων πυρουβικού οξέος. Ο ρόλος του πυρουβικού οξέος ως προδρόμου του ακετυλ-CoA επηρεάζεται, οδηγώντας σε μείωση του ακετυλ-CoA εντός των μιτοχονδρίων. Αρκετά εντοπισμένα γονίδια και μεταβολίτες, συμπεριλαμβανομένων των CPS1, HSD17B6, ADH1A, γαλακτικού οξέος, αργινίνης, γλουταμίνης, ATP και ακετυλ-CoA, θα μπορούσαν πιθανώς να λειτουργήσουν ως βιοδείκτες της επίδρασης της συνέκθεσης στα μέταλλα, και στους πλαστικοποιητές. Συμπερασματικά, η ενσωμάτωση των μεθόδων που έχουν σχεδιαστεί για τη χαρακτηρισμό του εξωτερικού εκθεσιώματος (external exposome) στην παρουσιασμένη ροή εργασιών, που βασίστηκε στη βιολογική ανάλυση πολλαπλών διαστάσεων, είναι κρίσιμη για τη θέσπιση μιας ολοκληρωμένης προσέγγισης απαραίτητης για τον πλήρη αποσαφηνισμό των πολύπλοκων συνδέσεων μεταξύ της συνέκθεσης σε χημικά και της ανθρώπινης υγείας. Αυτή η κατανόηση θα χρησιμεύσει ως θεμέλιο για την ακριβή αξιολόγηση του κινδύνου εμφάνισης χρόνιων νόσων, τη θέσπιση αποτελεσματικών στρατηγικών για την πρόληψή τους και την ανάπτυξη ατομικών παρεμβάσεων

Harmonized quality assurance/quality control provisions to assess completeness and robustness of MS1 data preprocessing for LC-HRMS-based suspect screening and non-targeted analysis

International audienceNon-targeted and suspect screening analysis using liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS) holds great promise to comprehensively characterize complex chemical mixtures. Data preprocessing is a crucial part of the process, however, some limitations are observed: (i) peak-picking and feature extraction might be incomplete, especially for low abundant compounds, and (ii) limited reproducibility has been observed between laboratories and software for detected features and their relative quantification. We first conducted a critical review of existing solutions that could improve the reproducibility of preprocessing for LC-HRMS. Solutions include providing repositories and reporting guidelines, open and modular processing workflows, public benchmark datasets, tools to optimize the data preprocessing and to filter out false positive detections. We then propose harmonized quality assurance/quality control guidelines that would allow to assess the sensitivity of feature detection, reproducibility, integration accuracy, precision, accuracy, and consistency of data preprocessing for human biomonitoring, food and environmental communities

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

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