The role of analytical chemistry in exposure science: Focus on the aquatic environment

Exposure science, in its broadest sense, studies the interactions between stressors (chemical, biological, and physical agents) and receptors (e.g. humans and other living organisms, and non-living items like buildings), together with the associated pathways and processes potentially leading to negative effects on human health and the environment. The aquatic environment may contain thousands of compounds, many of them still unknown, that can pose a risk to ecosystems and human health. Due to the unquestionable importance of the aquatic environment, one of the main challenges in the field of exposure science is the comprehensive characterization and evaluation of complex environmental mixtures beyond the classical/priority contaminants to new emerging contaminants. The role of advanced analytical chemistry to identify and quantify potential chemical risks, that might cause adverse effects to the aquatic environment, is essential. In this paper, we present the strategies and tools that analytical chemistry has nowadays, focused on chromatography hyphenated to (high-resolution) mass spectrometry because of its relevance in this field. Key issues, such as the application of effect direct analysis to reduce the complexity of the sample, the investigation of the huge number of transformation/degradation products that may be present in the aquatic environment, the analysis of urban wastewater as a source of valuable information on our lifestyle and substances we consumed and/or are exposed to, or the monitoring of drinking water, are discussed in this article. The trends and perspectives for the next few years are also highlighted, when it is expected that new developments and tools will allow a better knowledge of chemical composition in the aquatic environment. This will help regulatory authorities to protect water bodies and to advance towards improved regulations that enable practical and efficient abatements for environmental and public health protection

Atlas of the clinical genetics of human dilated cardiomyopathy

[Abstract] Aim. Numerous genes are known to cause dilated cardiomyopathy (DCM). However, until now technological limitations have hindered elucidation of the contribution of all clinically relevant disease genes to DCM phenotypes in larger cohorts. We now utilized next-generation sequencing to overcome these limitations and screened all DCM disease genes in a large cohort. Methods and results. In this multi-centre, multi-national study, we have enrolled 639 patients with sporadic or familial DCM. To all samples, we applied a standardized protocol for ultra-high coverage next-generation sequencing of 84 genes, leading to 99.1% coverage of the target region with at least 50-fold and a mean read depth of 2415. In this well characterized cohort, we find the highest number of known cardiomyopathy mutations in plakophilin-2, myosin-binding protein C-3, and desmoplakin. When we include yet unknown but predicted disease variants, we find titin, plakophilin-2, myosin-binding protein-C 3, desmoplakin, ryanodine receptor 2, desmocollin-2, desmoglein-2, and SCN5A variants among the most commonly mutated genes. The overlap between DCM, hypertrophic cardiomyopathy (HCM), and channelopathy causing mutations is considerably high. Of note, we find that >38% of patients have compound or combined mutations and 12.8% have three or even more mutations. When comparing patients recruited in the eight participating European countries we find remarkably little differences in mutation frequencies and affected genes. Conclusion. This is to our knowledge, the first study that comprehensively investigated the genetics of DCM in a large-scale cohort and across a broad gene panel of the known DCM genes. Our results underline the high analytical quality and feasibility of Next-Generation Sequencing in clinical genetic diagnostics and provide a sound database of the genetic causes of DCM.Hôpitaux de Paris; PHRC AOM0414

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/)

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/)

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

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.The NORMAN-SLE project has received funding from the NORMAN Association via its joint proposal of activities. HMT and ELS are supported by the Luxembourg National Research Fund (FNR) for project A18/BM/12341006. ELS, PC, SEH, HPHA, ZW acknowledge funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 101036756, project ZeroPM: Zero pollution of persistent, mobile substances. The work of EEB, TC, QL, BAS, PAT, and JZ was supported by the National Center for Biotechnology Information of the National Library of Medicine (NLM), National Institutes of Health (NIH). JOB is the recipient of an NHMRC Emerging Leadership Fellowship (EL1 2009209). KVT and JOB acknowledge the support of the Australian Research Council (DP190102476). The Queensland Alliance for Environmental Health Sciences, The University of Queensland, gratefully acknowledges the financial support of the Queensland Department of Health. NR is supported by a Miguel Servet contract (CP19/00060) from the Instituto de Salud Carlos III, co-financed by the European Union through Fondo Europeo de Desarrollo Regional (FEDER). MM and TR gratefully acknowledge financial support by the German Ministry for Education and Research (BMBF, Bonn) through the project “Persistente mobile organische Chemikalien in der aquatischen Umwelt (PROTECT)” (FKz: 02WRS1495 A/B/E). LiB acknowledges funding through a Research Foundation Flanders (FWO) fellowship (11G1821N). JAP and JMcL acknowledge financial support from the NIH for CCSCompendium (S50 CCSCOMPEND) via grants NIH NIGMS R01GM092218 and NIH NCI 1R03CA222452-01, as well as the Vanderbilt Chemical Biology Interface training program (5T32GM065086-16), plus use of resources of the Center for Innovative Technology (CIT) at Vanderbilt University. TJ was (partly) supported by the Dutch Research Council (NWO), project number 15747. UFZ (TS, MaK, WB) received funding from SOLUTIONS project (European Union’s Seventh Framework Programme for research, technological development and demonstration under Grant Agreement No. 603437). TS, MaK, WB, JPA, RCHV, JJV, JeM and MHL acknowledge HBM4EU (European Union’s Horizon 2020 research and innovation programme under the grant agreement no. 733032). TS acknowledges funding from NFDI4Chem—Chemistry Consortium in the NFDI (supported by the DFG under project number 441958208). TS, MaK, WB and EMLJ acknowledge NaToxAq (European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie Grant Agreement No. 722493). S36 and S63 (HPHA, SEH, MN, IS) were funded by the German Federal Ministry for the Environment, Nature Conservation and Nuclear Safety (BMU) Project No. (FKZ) 3716 67 416 0, updates to S36 (HPHA, SEH, MN, IS) by the German Federal Ministry for the Environment, Nature Conservation, Nuclear Safety and Consumer Protection (BMUV) Project No. (FKZ) 3719 65 408 0. MiK acknowledges financial support from the EU Cohesion Funds within the project Monitoring and assessment of water body status (No. 310011A366 Phase III). The work related to S60 and S82 was funded by the Swiss Federal Office for the Environment (FOEN), KK and JH acknowledge the input of Kathrin Fenner’s group (Eawag) in compiling transformation products from European pesticides registration dossiers. DSW and YDF were supported by the Canadian Institutes of Health Research and Genome Canada. The work related to S49, S48 and S77 was funded by the MAVA foundation; for S77 also the Valery Foundation (KG, JaM, BG). DML acknowledges National Science Foundation Grant RUI-1306074. YL acknowledges the National Natural Science Foundation of China (Grant No. 22193051 and 21906177), and the Chinese Postdoctoral Science Foundation (Grant No. 2019M650863). WLC acknowledges research project 108C002871 supported by the Environmental Protection Administration, Executive Yuan, R.O.C. Taiwan (Taiwan EPA). JG acknowledges funding from the Swiss Federal Office for the Environment. AJW was funded by the U.S. Environmental Protection Agency. LuB, AC and FH acknowledge the financial support of the Generalitat Valenciana (Research Group of Excellence, Prometeo 2019/040). KN (S89) acknowledges the PhD fellowship through Marie Skłodowska-Curie grant agreement No. 859891 (MSCA-ETN). Exposome-Explorer (S34) was funded by the European Commission projects EXPOsOMICS FP7-KBBE-2012 [308610]; NutriTech FP7-KBBE-2011-5 [289511]; Joint Programming Initiative FOODBALL 2014–17. CP acknowledges grant RYC2020-028901-I funded by MCIN/AEI/1.0.13039/501100011033 and “ESF investing in your future”, and August T Larsson Guest Researcher Programme from the Swedish University of Agricultural Sciences. The work of ML, MaSe, SG, TL and WS creating and filling the STOFF-IDENT database (S2) mostly sponsored by the German Federal Ministry of Education and Research within the RiSKWa program (funding codes 02WRS1273 and 02WRS1354). XT acknowledges The National Food Institute, Technical University of Denmark. MaSch acknowledges funding by the RECETOX research infrastructure (the Czech Ministry of Education, Youth and Sports, LM2018121), the CETOCOEN PLUS project (CZ.02.1.01/0.0/0.0/15_003/0000469), and the CETOCOEN EXCELLENCE Teaming 2 project supported by the Czech ministry of Education, Youth and Sports (No CZ.02.1.01/0.0/0.0/17_043/0009632).Peer reviewe

Växt-toxikologiskt test med flytbladsväxten Lemna minor.

Flytbladsväxten Lemna minor är bl.a genom sin stora geografiska spridning och enkla odlingsform mycket väl lämpad som akvatisk testorganism. Den har länge använts vid fysiologiska experiment, utförandena har dock varit mindre lämpade för rutinmässig toxikologisk testning. IVL har därför i detta syfte tagit fram en lämplig metod. Mediets kväve och fosfor-halter har minimerats och pH hållits någorlunda konstant med buffert. Parametrar som noteras är bladtillväxthastighet, rotlängd, slutbiomassa samt bladvikten. Testtiden har minimerats till < 7dygn.Flytbladsväxten Lemna minor är bl.a genom sin stora geografiska spridning och enkla odlingsform mycket väl lämpad som akvatisk testorganism. Den har länge använts vid fysiologiska experiment, utförandena har dock varit mindre lämpade för rutinmässig toxikologisk testning. IVL har därför i detta syfte tagit fram en lämplig metod. Mediets kväve och fosfor-halter har minimerats och pH hållits någorlunda konstant med buffert. Parametrar som noteras är bladtillväxthastighet, rotlängd, slutbiomassa samt bladvikten. Testtiden har minimerats till < 7dygn

Nordisk ringtest av akut respektive långtidstoxicitet på hinnkräftan Daphnia magna.

IVL har deltagit i en Nordisk ringtest där akut- respektive långtidstoxicitet på hinnkräftan Daphnia magna testats. Utförandena har i stort följt metoder rekommenderade av ISO-1979 och OECD-1980. Testsubstanser har varit kaliumdikromat, zinksulfat, tetrapropylenbensensulfonat, pentaklorfenol samt pp-DDT. För långtidstoxiska effekter testades endast kaliumdikromat och pentaklorfenol. Resultaten vid akuttesten visar god reproducerbarhet mellan replikaten med undantag för pp-DDT, som visade sig mycket svår att 'läsa av'. Även vid långtids-testerna var överensstämmelsen mellan relikaten goda.IVL har deltagit i en Nordisk ringtest där akut- respektive långtidstoxicitet på hinnkräftan Daphnia magna testats. Utförandena har i stort följt metoder rekommenderade av ISO-1979 och OECD-1980. Testsubstanser har varit kaliumdikromat, zinksulfat, tetrapropylenbensensulfonat, pentaklorfenol samt pp-DDT. För långtidstoxiska effekter testades endast kaliumdikromat och pentaklorfenol. Resultaten vid akuttesten visar god reproducerbarhet mellan replikaten med undantag för pp-DDT, som visade sig mycket svår att 'läsa av'. Även vid långtids-testerna var överensstämmelsen mellan relikaten goda

Akut- och långtidtoxicitet av avloppsvatten från en textilindustri på hinnkräftan Daphnia Magna.

Inom projektet 'karaktärisering av industriella utsläpp' bestämdes det att en jämförande undersökning av toxtester för evertebrater och fisk skulle göras. För detta syfte testades ett textilindustriavloppsvatten med ett flertal toxicitetstester. Denna rapport redovisar resultat från test med hinnkräftan Daphnia magna.Inom projektet 'karaktärisering av industriella utsläpp' bestämdes det att en jämförande undersökning av toxtester för evertebrater och fisk skulle göras. För detta syfte testades ett textilindustriavloppsvatten med ett flertal toxicitetstester. Denna rapport redovisar resultat från test med hinnkräftan Daphnia magna

Hur nyttja data från produktregistret för identifiering av kandidater till monitoringprogrammet : En förstudie

Miljöövervakning är en viktig del i arbetet för att nå det svenska miljökvalitetsmålet ”giftfri miljö”. Inom miljöövervakningen studeras resthalter av ett flertal ämnen i exempelvis luftdeposition, biota, reningsverk, jord och vatten. Fördelning i miljön styrs förutom av inneboende kemikalieegenskaper, såsom tex. vattenlöslighet och persistens, även av kemikaliehanteringen. Kemikalieinspektionens register över svenska kemiska produkter (produktregistret) är en viktig källa till kemikaliehantering (72 000 produkter, 14 500 olika ämnen). Denna studie har haft till syfte att belysa om hanteringsdata i produktregistret kan användas för att identifiera högemitterande kemikalier samt till vilka recipienter dessa emitteras. Arbetet har lags upp som en förstudie där olika metoder har prövats. Inledningsvis analyserades och strukturerades funktioner och användningsområden (”branscher”) i produktregistret med hjälp av multivariat dataanalys. Framtagna modeller gav en god överblick av produktregistret och kan även användas för att screena efter prioriterade ämnen. En översiktlig genomgång av tillgängliga miljöövervakningsuppgifter kopplades till profiler i produktregistret. Utifrån detta valdes 12 kemikalier ut (Triclosan, dietylhexylftalat, dibutylftalat, kromsalter, glyfosat, tributylfosfat, tributyltennoxid, nonylfenol, limonen, hexabromocyclododecan och pentabromodifenyler) som modellsubstanser för fortsatta studier. Substanserna representerar olika användningsområden och ett brett spektra kemisk-fysikaliska egenskaper. En styrka i produktregistermaterialet är att data finns lagrat för ett antal år tillbaks i tiden. Tidstrender i kvantitet och användningsmönster kan användas som tidiga varningstecken på ökad spriding. För att få ett mått på en kemikalies hanteringsdrivna emissionsbenägenhet utarbetades ett ”spridningsindex” utifrån hanteringsdata. Principen för indexet är att för ett ämne räkna fram ett emissionsbidrag för alla kemiska produkter där ämnet förekommer. Dessa kvantitetsviktas och summeras till ett övergripande spridningsindex. Emissionen har differentierats till olika miljöer här kallad primärrecipienter. Dessa är ytvatten, jord, luft, reningsverk samt människa. Ämneshalter i inkommande avloppsvatten samt i slam i reningsverk användes för validering av spridningsindex för primärrecipienten ”reningsverk”. Resultatet visar att tidstrender baserade på spridningsindex verkar överensstämma med uppmätta trender i slam. Ingen koppling erhölls mellan spridningsindex och uppmätta halter av olika ämnen i inkommande avloppsvatten. Spridningsindex användes även i kombination med multimedia fugacitetsberäkningar för att uppskatta den vidare spridningen till mera perifera närmiljöer, här kallad sekundärrecipienter. Fugacitetsberäkningarna utfördes för DEHP, dibutylftalat, triclosan, och HBCD och byggde på en modell som skattar den procentuella fördelningen mellan luft, vatten, jord och sediment. Den beräknade fördelningen i sekundärrecipienter jämfördes med motsvarande fördelning som den ser ut i miljöövervakningsdata. Resultatet visade på en god överensstämmelse. Som kontroll gjordes även beräkningar där emissionsfördelningen antogs vara lika stor till resp. primärrecipient. Dessa visade på en sämre överensstämmelse vilket indikerar att användning av spridningsindex ökar prognosförmågan. En vidare utveckling av emission-uppskattningar kan ge unika möjligheter att nyttja hanteringsdata i produktregistret vid miljöövervakning Validering av emissionsuppskattningarna med hjälp av tillgängliga miljöövervakningsdata visade på svårigheter att hitta lämpligt data. Mycket data berör ämnen som inte återfinns i registret så som avvecklade ämnen och nedbrytningsprodukter. Ett annat problem var att tillgänglig dokumentation sällan räckte för att kunna definiera vilken typ av recipient som de representerar. Förstudien identifierade ett antal rekommendationer: (1) Multivariattekniken kan förbättras (2) Vidareutveckla rutiner tidstrendanalys i produktregistret (3) Förändra typ av data som anmäls till registret (4) Optimera gjorda emissionuppskattningar (5) Omarbeta spridningsindex så att de närmar sig en verklig kvantitet (6) Utveckla multimedia fugacitetsmodellen m.a.p. svensk geografi samt joniserbara ämnen/metaller (7) Standardisering av analyser och sammanställning av miljöövervakningsdata (8) För att skapa en heltäckande bild av kemikalieflödet i samhället borde kopplingarna med läkemedel, kosmetika och varor bättre styrkas