Retardateurs de flamme bromés (métabolites actifs et biomarqueurs d'exposition chez l'homme)

Les retardateurs de flamme bromés sont des agents ignifuges utilisés dans de nombreux produits manufacturés. Les plus courants sont les polybromodiphényl éther (PBDE), le tétrabromo-bisphénol A (TBBPA) et l'hexabromocyclododécane (HBCD). Ces composés considérés comme des polluants organiques persistants (POPs) sont désormais retrouvés dans l'environnement et chez l'Homme, et sont suspectés, ainsi que leurs métabolites, d'être des perturbateurs endocriniens. Des développements analytiques basés sur la spectrométrie de masse ont été engagés afin d'étudier le métabolisme in vitro du TBBPA et des PBDE et rechercher les composés parents et leurs métabolites dans différents prélèvements d'origine humaine. Les métabolites formés chez l'Homme ont ainsi été identifiés comme étant des conjugués pour le TBBPA, et des dérivés hydroxylés, dihydrodiol et conjugués pour les PBDE. La plupart de ces métabolites ont été identifiés et quantifiés dans les fluides biologiques humains, démontrant ainsi l'exposition du foetus et du nouveau-né à ces composés, à des niveaux similaires à ceux retrouvé dans d'autres pays. D'un point de vue qualitatif, la présence de métabolites potentiellement actifs sur des cibles cellulaires a été mise en évidence, ainsi que le passage des résidus vers le lait (TBBPA, HBCD) et/ou au travers de la barrière placentaire (TBBPA et PBDE). Un métabolite spécifique, présent en importantes (octa-BDE hydroxylé) pourrait être un bon biomarqueur d'exposition, et son potentiel toxique devrait par ailleurs être étudiéBrominated Flame Retardants are widely used for the manufacture of fire-proofed industrial products and consumer goods. Major BFRs are polybromodiphenyl ether (PBDE), tetrabromobisphenol A (TBBPA) and hexabromocyclododecane (HBCD). Considered as persistent organic pollutants (POPs), they are detected in various environmental compartments and human samples. Parent compounds as well as several metabolites could act as endocrine disruptors. Methodological developments based on mass spectrometry, in vitro approaches (TBBPA, PBDE) and an extensive review of the available literature have been used to sharpen our current knowledge of the fate of BFR, and to identify both parent compounds and metabolite in human samples. Results obtained in vitro using human primary hepatocyte cultures as well as human cell lines show that human cells biotransform TBBPA into conjugated metabolites and PBDE into hydroxylated, dihydrodiol and conjugated metabolites. Those metabolites were detected in human samples, demonstrating foetal and newborn exposition. BFR and some of their metabolites, including bioactive compounds, are transferred through the placental barrier (TBBPA, PBDE) and/or into milk (TBBPA, HBCD). Even though the monitored concentration levels were found to be low, one of these metabolites, namely (OH-octaBDE) was found to be abundant in almost all serum samples, and appears to be a relevant candidate biomarker of exposureTOULOUSE-ENSAT-Documentation (315552324) / SudocSudocFranceF

Fate and Complex Pathogenic Effects of Dioxins and Polychlorinated Biphenyls in Obese Subjects before and after Drastic Weight Loss

BACKGROUND: In humans, persistent organic pollutants (POPs) are stored primarily in adipose tissue. Their total body burden and their contribution to obesity-associated diseases remain unclear. OBJECTIVES: We characterized POP total body burden and their redistribution in obese individuals before and after drastic weight loss and compared these values with a variety of molecular, biological, and clinical parameters. METHODS: Seventy-one obese subjects were enrolled and underwent bariatric surgery. Blood and adipose tissue samples were obtained at different times from these individuals as well as from 18 lean women. RESULTS: POP content (17 dioxins/furans and 18 polychlorinated biphenyl congeners) in different adipose tissue territories was similar, allowing us to assess total POP body burden from a single biopsy. Total POP body burden was 2 to 3 times higher in obese than in lean individuals. We also found increased expression of some POP target genes in obese adipose tissue. Drastic weight loss led to increased serum POPs and, within 6-12 months, to a significant 15% decrease in total polychlorinated biphenyl body burden. Importantly, serum POP levels were positively correlated with liver toxicity markers and lipid parameters, independently of age and body mass index. CONCLUSIONS: POP content in adipose tissue and serum correlate with biological markers of obesity-related dysfunctions. Drastic weight loss leads to a redistribution of POPs and to a moderate decrease of their total body burden

The NORMAN Suspect List Exchange (NORMAN-SLE): facilitating European and worldwide collaboration on suspect screening in high resolution mass spectrometry

Background The NORMAN Association (https://www.norman-network.com/) initiated the NORMAN Suspect List Exchange (NORMAN-SLE; https://www.norman-network.com/nds/SLE/) in 2015, following the NORMAN collaborative trial on non-target screening of environmental water samples by mass spectrometry. Since then, this exchange of information on chemicals that are expected to occur in the environment, along with the accompanying expert knowledge and references, has become a valuable knowledge base for “suspect screening” lists. The NORMAN-SLE now serves as a FAIR (Findable, Accessible, Interoperable, Reusable) chemical information resource worldwide. Results The NORMAN-SLE contains 99 separate suspect list collections (as of May 2022) from over 70 contributors around the world, totalling over 100,000 unique substances. The substance classes include per- and polyfluoroalkyl substances (PFAS), pharmaceuticals, pesticides, natural toxins, high production volume substances covered under the European REACH regulation (EC: 1272/2008), priority contaminants of emerging concern (CECs) and regulatory lists from NORMAN partners. Several lists focus on transformation products (TPs) and complex features detected in the environment with various levels of provenance and structural information. Each list is available for separate download. The merged, curated collection is also available as the NORMAN Substance Database (NORMAN SusDat). Both the NORMAN-SLE and NORMAN SusDat are integrated within the NORMAN Database System (NDS). The individual NORMAN-SLE lists receive digital object identifiers (DOIs) and traceable versioning via a Zenodo community (https://zenodo.org/communities/norman-sle), with a total of > 40,000 unique views, > 50,000 unique downloads and 40 citations (May 2022). NORMAN-SLE content is progressively integrated into large open chemical databases such as PubChem (https://pubchem.ncbi.nlm.nih.gov/) and the US EPA’s CompTox Chemicals Dashboard (https://comptox.epa.gov/dashboard/), enabling further access to these lists, along with the additional functionality and calculated properties these resources offer. PubChem has also integrated significant annotation content from the NORMAN-SLE, including a classification browser (https://pubchem.ncbi.nlm.nih.gov/classification/#hid=101). Conclusions The NORMAN-SLE offers a specialized service for hosting suspect screening lists of relevance for the environmental community in an open, FAIR manner that allows integration with other major chemical resources. These efforts foster the exchange of information between scientists and regulators, supporting the paradigm shift to the “one substance, one assessment” approach. New submissions are welcome via the contacts provided on the NORMAN-SLE website (https://www.norman-network.com/nds/SLE/)

European interlaboratory comparison investigations (ICI) and external quality assurance schemes (EQUAS) for the analysis of bisphenol A, S and F in human urine: Results from the HBM4EU project

The Human Biomonitoring for Europe initiative (HBM4EU) aims to study the exposure of citizens to chemicals and potentially associated health effects. One objective of this project has been to build a network of laboratories able to answer to the requirements of European human biomonitoring studies. Within the HBM4EU quality assurance and quality control scheme (QA/QC), a number of interlaboratory comparison investigations (ICIs) and external quality assurance schemes (EQUASs) were organized to ensure data consistency, comparability and reliability. Bisphenols are among the prioritized substance groups in HBM4EU, including bisphenol A (BPA), bisphenol S (BPS) and bisphenol F (BPF) in human urine. In four rounds of ICI/EQUAS, two target concentration levels were considered, related to around P25 and P95 of the typical exposure distribution observed in the European general population. Special attention was paid to the conjugated phase II metabolites known to be most dominant in samples of environmentally exposed individuals, through the analysis of both native samples and samples fortified with glucuronide forms. For the low level, the average percentage of satisfactory results across the four rounds was 83% for BPA, 71% for BPS and 62% for BPF. For the high level, the percentages of satisfactory results increased to 93% for BPA, 89% for BPS and 86% for BPF. 24 out of 32 participating laboratories (75%) were approved for the analyses of BPA in the HBM4EU project according to the defined criterion of Z-scores for both low and high concentration levels in at least two ICI/EQUAS rounds. For BPS and BPF, the number of qualified laboratories was 18 out of 27 (67%) and 13 out of 28 (46%), respectively. These results demonstrate a strong analytical capability for BPA and BPS in Europe, while improvements may be needed for BPF.We gratefully acknowledge funding by the European Union's Horizon 2020 research and innovation programme under the grant agreement No. 733032 HBM4EU. The authors would like to thank the HBM4EU Secretariat at the German Environment Agency for administrative support. The authors acknowledge all the participating and expert laboratories (Table A1, SM) that made the HBM4EU QA/QC programme possible as well as the Management and Advisory Boards of HBM4EU.S

Alternative (backdoor) androgen production and masculinization in the human fetus

Funding: The study was supported by the following grants: Chief Scientist Office (Scottish Executive, CZG/4/742) (PAF and PJOS) (http://www.cso.scot.nhs.uk/funding-2/); NHS Grampian Endowments 08/02 (PAF and PJOS) and 15/1/010 (PAF, PF, US, and PJOS) (https://www.nhsgcharities.com/); the Glasgow Children’s Hospital Research Charity Research Fund, YRSS/PHD/2016/05 (NW, MB, PJOS, and PAF) (http://www.glasgowchildrenshospitalcharity.org/research/glasgow-childrens-hospital-charity-research-fund); the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement number 212885 (PAF) (https://ec.europa.eu/research/fp7/index_en.cfm); Medical Research Council Grants MR/L010011/1 (PAF and PJOS) and MR/K501335/1 (MB, PAF, and PJOS) (https://mrc.ukri.org/); and the Kronprinsessan Lovisas Foundation, “Stiftelsen Gunvor och Josef Anérs,” the “Stiftelsen Jane och Dan Olssons,” and the “Stiftelsen Tornspiran” (KS and OS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Proficiency and Interlaboratory Variability in the Determination of Phthalate and DINCH Biomarkers in Human Urine: Results from the HBM4EU Project

A quality assurance/quality control program was implemented in the framework of the EU project HBM4EU to assess and improve the comparability of biomarker analysis and to build a network of competent laboratories. Four rounds of proficiency tests were organized for 15 phthalate and two DINCH urinary biomarkers (0.2-138 ng/mL) over a period of 18 months, with the involvement of 28 laboratories. A substantial improvement in performance was observed after the first round in particular, and by the end of the program, an average satisfactory performance rate of 90% was achieved. The interlaboratory reproducibility as derived from the participants' results varied for the various biomarkers and rounds, with an average of 24% for the biomarkers of eight single-isomer phthalates (e.g., DnBP and DEHP) and 43% for the more challenging biomarkers of the mixed-isomer phthalates (DiNP, DiDP) and DINCH. When the reproducibility was based only on the laboratories that consistently achieved a satisfactory performance, this improved to 17% and 26%, respectively, clearly demonstrating the success of the QA/QC efforts. The program thus aided in building capacity and the establishment of a network of competent laboratories able to generate comparable and accurate HBM data for phthalate and DINCH biomarkers in 14 EU countries. In addition, global comparability was ensured by including external expert laboratories.This study was part of the HBM4EU project receiving funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 733032. Co-funding was received from the Dutch Ministry of Agriculture, Nature and Food Quality (project KB 37-002-014-001/002).S

Human anogenital distance: an update on fetal smoke-exposure and integration of the perinatal literature on sex differences

study question: Do sex and maternal smoking effects on human fetal anogenital distance (AGD) persist in a larger study and how do these data integrate with the wider literature on perinatal human AGD, especially with respect to sex differences? summary answer: Second trimester sex differences in AGD are broadly consistent with neonatal and infant measures of AGD and maternal cigarette smoking is associated with a temporary increase in male AGD in the absence of changes in circulating testosterone. what is known already: AGD is a biomarker of fetal androgen exposure, a reduced AGD in males being associated with cryptorchidism, hypospadias and reduced penile length. Normative fetal AGD data remain partial and windows of sensitivity of human fetal AGD to disruption are not known. study design, size, duration: The effects of fetal sex and maternal cigarette smoking on the second trimester (11 –21 weeks of gestation) human fetal AGD were studied, along with measurement of testosterone and testicular transcripts associated with apoptosis and proliferation. participants/materials, setting methods: AGD, measured from the centre of the anus to the posterior/caudal root of penis/clitoris (AGDapp) was determined in 56 female and 70 male morphologically normal fetuses. These data were integrated with current literature on perinatal AGD in humans. main results and the role of chance: At 11 – 13 weeks of gestation male fetal AGDapp was 61% (P , 0.001) longer than in females, increasing to 70% at 17 – 21 weeks. This sexual dimorphism was independent of growth characteristics (fetal weight, length, gonad weight). We confirmed that at 14 – 16 weeks of gestation male fetal AGDapp was increased 28% (P , 0.05) by in utero cigarette smoke exposure. Testosterone levels were not affected by smoking. To develop normative data, our findings have been integrated with available data from in vivo ultrasound scans and neonatal studies. Inter-study variations in male/female AGD differences lead to the conclusion that normalization and standardization approaches should be developed to enable confidence in comparing data from different perinatal AGD studies. limitations, reasons for caution: Sex differences, and a smoking-dependent increase in male fetal AGD at 14 – 16 weeks, identified in a preliminary study, were confirmed with a larger number of fetuses. However, human fetal AGD should, be re-assessed once much larger numbers of fetuses have been studied and this should be integrated with more detailed analysis of maternal lifestyle. Direct study of human fetal genital tissues is required for further mechanistic insights

Interlaboratory comparison investigations (ICIs) and external quality assurance schemes (EQUASs) for flame retardant analysis in biological matrices: Results from the HBM4EU project

The European Human Biomonitoring Initiative (HBM4EU) is coordinating and advancing human biomonitoring (HBM). For this purpose, a network of laboratories delivering reliable analytical data on human exposure is fundamental. The analytical comparability and accuracy of laboratories analysing flame retardants (FRs) in serum and urine were investigated by a quality assurance/quality control (QA/QC) scheme comprising interlaboratory comparison investigations (ICIs) and external quality assurance schemes (EQUASs). This paper presents the evaluation process and discusses the results of four ICI/EQUAS rounds performed from 2018 to 2020 for the determination of ten halogenated flame retardants (HFRs) represented by three congeners of polybrominated diphenyl ethers (BDE-47, BDE-153 and BDE-209), two isomers of hexabromocyclododecane (α-HBCD and γ-HBCD), two dechloranes (anti-DP and syn-DP), tetrabromobisphenol A (TBBPA), decabromodiphenylethane (DBDPE), and 2,4,6-tribromophenol (2,4,6-TBP) in serum, and four metabolites of organophosphorus flame retardants (OPFRs) in urine, at two concentration levels. The number of satisfactory results reported by laboratories increased during the four rounds. In the case of HFRs, the scope of the participating laboratories varied substantially (from two to ten) and in most cases did not cover the entire target spectrum of chemicals. The highest participation rate was reached for BDE-47 and BDE-153. The majority of participants achieved more than 70% satisfactory results for these two compounds over all rounds. For other HFRs, the percentage of successful laboratories varied from 44 to 100%. The evaluation of TBBPA, DBDPE, and 2,4,6-TBP was not possible because the number of participating laboratories was too small. Only seven laboratories participated in the ICI/EQUAS scheme for OPFR metabolites and five of them were successful for at least two biomarkers. Nevertheless, the evaluation of laboratory performance using Z-scores in the first three rounds required an alternative approach compared to HFRs because of the small number of participants and the high variability of experts' results. The obtained results within the ICI/EQUAS programme showed a significant core network of comparable European laboratories for HBM of BDE-47, BDE-153, BDE-209, α-HBCD, γ-HBCD, anti-DP, and syn-DP. On the other hand, the data revealed a critically low analytical capacity in Europe for HBM of TBBPA, DBDPE, and 2,4,6-TBP as well as for the OPFR biomarkers.We gratefully acknowledge funding by the European Union's Horizon 2020 research and innovation programme under the grant agreement No. 733032.S

Interlaboratory comparison investigations (ICIs) and external quality assurance schemes (EQUASs) for flame retardant analysis in biological matrices: Results from the HBM4EU project

The European Human Biomonitoring Initiative (HBM4EU) is coordinating and advancing human biomonitoring (HBM). For this purpose, a network of laboratories delivering reliable analytical data on human exposure is fundamental. The analytical comparability and accuracy of laboratories analysing flame retardants (FRs) in serum and urine were investigated by a quality assurance/quality control (QA/QC) scheme comprising interlaboratory comparison investigations (ICIs) and external quality assurance schemes (EQUASs). This paper presents the evaluation process and discusses the results of four ICI/EQUAS rounds performed from 2018 to 2020 for the determination of ten halogenated flame retardants (HFRs) represented by three congeners of polybrominated diphenyl ethers (BDE-47, BDE-153 and BDE-209), two isomers of hexabromocyclododecane (α-HBCD and γ-HBCD), two dechloranes (anti-DP and syn-DP), tetrabromobisphenol A (TBBPA), decabromodiphenylethane (DBDPE), and 2,4,6-tribromophenol (2,4,6-TBP) in serum, and four metabolites of organophosphorus flame retardants (OPFRs) in urine, at two concentration levels. The number of satisfactory results reported by laboratories increased during the four rounds. In the case of HFRs, the scope of the participating laboratories varied substantially (from two to ten) and in most cases did not cover the entire target spectrum of chemicals. The highest participation rate was reached for BDE-47 and BDE-153. The majority of participants achieved more than 70% satisfactory results for these two compounds over all rounds. For other HFRs, the percentage of successful laboratories varied from 44 to 100%. The evaluation of TBBPA, DBDPE, and 2,4,6-TBP was not possible because the number of participating laboratories was too small. Only seven laboratories participated in the ICI/EQUAS scheme for OPFR metabolites and five of them were successful for at least two biomarkers. Nevertheless, the evaluation of laboratory performance using Z-scores in the first three rounds required an alternative approach compared to HFRs because of the small number of participants and the high variability of experts' results. The obtained results within the ICI/EQUAS programme showed a significant core network of comparable European laboratories for HBM of BDE-47, BDE-153, BDE-209, α-HBCD, γ-HBCD, anti-DP, and syn-DP. On the other hand, the data revealed a critically low analytical capacity in Europe for HBM of TBBPA, DBDPE, and 2,4,6-TBP as well as for the OPFR biomarkers.We gratefully acknowledge funding by the European Union's Horizon 2020 research and innovation programme under the grant agreement No. 733032.S