[ICNTS25] (Chemical) Data Handling in a Modern NTS World

Prof. Dr. Emma L. Schymanski (plus many, many colleagues and collaborators!) Environmental Cheminformatics Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg [email protected] / https://gitlab.com/uniluxembourg/lcsb/eci https://wwwen.uni.lu/lcsb/research/environmental_cheminformatics/ (Chemical) Data Handling in a Modern NTS World Slides available at DOI: 10.5281/zenodo.17320946 International Conference on Non-Target Screening (ICNTS25): Erding, Germany, 13-16 October 2025 The Exposome meets the Metabolome 2 Mod. from Vermeulen, Schymanski et al. (2020). Science. DOI: 10.1126/science.aay3164, Miller & Jones (2014) DOI: 10.1093/toxsci/kft251. “The cumulative measure of environmental influences and associated biological responses throughout the lifespan, including exposures from the environment, diet, behaviour and endogenous processes” (Miller & Jones, 2014) 4 Source: Begoña Talavera Andújar, PhD Thesis. https://hdl.handle.net/10993/61575. Measuring the Exposome – Multiple Chemical Classes! 5 Source: Begoña Talavera Andújar, PhD Thesis. https://hdl.handle.net/10993/61575. Measuring the Exposome – Multiple Chemical Classes! 6 Concentration Drug metabolites Environmental chemicals MmM µM nM pM fM Endogenous metabolites Drugs Food and Plant chemicals Human metabolome and exposome Limited dynamic range LC-ESI-HRMS Source: Begoña Talavera Andújar, PhD Thesis. https://hdl.handle.net/10993/61575. Measuring the Exposome – Wide Range of Concentrations Grand Challenge: HR-MS “Chemical Space” is too Big! 290 million 122 million 129 million Candidates with high information content Candidates with low information content 1.2 million …and prohibitive run times! 7 122 million The Vast Chemical Space of Exposomics … Numbers updated 9 Oct. 2025. Mod. from Escher et al (2020). Science. DOI: 10.1126/science.aay6636 Image: ESO/IDA/Danish 1.5 m http://www.eso.org/public/images/potw1015a/ 122 million The Vast Chemical Space of Exposomics … Numbers updated 9 Oct. 2025. Mod. from Escher et al (2020). Science. DOI: 10.1126/science.aay6636 Image: ESO/IDA/Danish 1.5 m http://www.eso.org/public/images/potw1015a/ https://pubchem.ncbi.nlm.nih.gov/ Gathering Expert Knowledge: NORMAN-SLE https://www.norman-network.com/nds/SLE/ 16 Mohammed Taha et al. (2022) DOI: 10.1186/s12302-022-00680-6 Gathering Expert Knowledge: NORMAN-SLE https://www.norman-network.com/nds/SLE/ 17 Mohammed Taha et al. (2022) DOI: 10.1186/s12302-022-00680-6 Mohammed Taha et al. (2022) DOI: 10.1186/s12302-022-00680-6 18 122 million < 0.01% of PubChem The Vast Chemical Space of Exposomics … 566,122 133,573 suspects Non-target Screening Suspect Screening Target Analysis Numbers updated 9 Oct. 2025. Mod. from Escher et al (2020). Science. DOI: 10.1126/science.aay6636 Image: ESO/IDA/Danish 1.5 m http://www.eso.org/public/images/potw1015a/ Creating Informative Subsets of 20 Elapavalore et al. (2025) DOI: 10.1021/acs.estlett.4c01003 Schymanski et al. (2021) DOI: 10.1186/s13321-021-00489-0 Creating Informative Subsets of ~500,000 entries “small” Elapavalore et al. (2025) DOI: 10.1021/acs.estlett.4c01003 Schymanski et al. (2021) DOI: 10.1186/s13321-021-00489-0 21 for Exposomics 22 http://pubchemlite.lcsb.uni.lu/ caffeine Database: for Exposomics 23 https://pubchemlite.lcsb.uni.lu/e/compound/2519 caffeine Database: for Exposomics 24 https://pubchemlite.lcsb.uni.lu/e/compound/2519 caffeine Database: for Exposomics 25 https://pubchemlite.lcsb.uni.lu/e/compound/2519 caffeine …and now in 2025: Fluorinated ions are everywhere… Tisler et al. (2025) DOI: 10.1021/acs.est.5c06876 32 Elapavalore et al. (2025) DOI: 10.1021/acs.estlett.4c01003 & Schymanski et al. (2021) DOI: 10.1186/s13321-021-00489-0 33 : Fewer and more relevant candidates – with context is a Dynamic Collection … •… built every week, updated online every month •… re-evaluated with every build for continuous quality control •… growing as knowledge grows! DOI: 10.5281/ zenodo.5995885 34 http://pubchemlite.lcsb.uni.lu/ Variation of Content Over Time (2022-2024) •Variation of content over time Elapavalore et al. (2025) DOI: 10.1021/acs.estlett.4c01003 35 Key Facts About •All TPs in the NORMAN-SLE are in •Most “suspect classes” are in Elapavalore et al. (2025) DOI: 10.1021/acs.estlett.4c01003 & https://fairtps.lcsb.uni.lu/stats/ 36 Key Facts About •All TPs in the NORMAN-SLE are in •Most “suspect classes” are in •Scoring terms “MetFrag Score, MoNA Exact Similarity, PubMed Count, Patent Count & Annotation Count” yield: o81 % of correct candidates in first place o98.4 % of correct candidates in Top 3 Elapavalore et al. (2025) DOI: 10.1021/acs.estlett.4c01003 37 => High throughput identification (quickly!) Small molecule omics: Rapidly growing fields 38 Talavera Andújar & Schymanski, under review, Exposome. Mod. from Begoña Talavera Andújar, https://hdl.handle.net/10993/61575. Time (years) 1998 -Definition of metabolome (S.G. Oliver et al.) 2005 -First definition of exposome (C. Wild) -Formation of MSI -Commercial Orbitrap -NORMAN network started -METLIN 2007 -HMDB -MSI publish minimum reporting standards 2010 -MetFrag -MassBank 2012 -MetaboAnalyst -CASMI starts 2004 -Metabolomics Society constituted -PubChem 2013 -HELIX -HERCULES 2014 -Exposome redefined (Miller and Jones) -Schymanski et al. confidence levels 2015 -MS-DIAL -NORMAN-SLE 2017 -CompTox Dashboard -ChemRICH -mQACC founded 2022 -PARC start -MMDB -EIRENE 2019 -Blood Exposome Database 2020 -ReDU 2021 -patRoon -PubChemLite for Exposomics -Exposome journal Era of AI… 2024 -PARC QA/QC guidelines -mQACC guidelines 2016 -HBMEU4 -GNPS 2023 -NORMAN guidance on non-target screening -ms2query ? -Harmonized QC criteria for metabolomics and exposomics -Exposomics Society Community efforts! 2025 -NEXUS network 2018 -Metabolomics QC samples guidelines (Broadhurst et al.) YOUR Contributions are Adding Stars into Space 39 Source: Talavera Andújar & Schymanski, under review, Exposome. https://gitlab.com/uniluxembourg/lcsb/eci/exposomics-plots . Triglycerides Nucleotides EU Pesticides PFOS and related substances Talavera Andújar et al. (2024). Environment International DOI: 10.1016/j.envint.2024.109151 40 Exposomics Workflows – Best of Many Worlds! “Translating” Software Outputs Isn’t Always Easy … B) Level 2 Level 1 Level 5 Level 4 Level 3 Unknown Unequivocal Molecular Formula Tentative structure candidates Probable structure a) By library spectral match b) By diagnostic evidence Confirmed structure by reference standard Increasing confidence Identification Confidence MS-DIAL patRoon >= 3 ion fragments matching Dot product 70-100 Fragment presence 50-100 Minimum data requirements-Software based >= 3 ion fragments matching Dot product 50-70 Fragment presence 50-100 MoNAScore > 0.9 One candidate only MoNAScore 0.7-0.9 2a 3a Talavera Andújar & Schymanski, under review, Exposome. Mod. from Begoña Talavera Andújar, https://hdl.handle.net/10993/61575. 41 Browsing Dead-End (and other) Predicted TPs 48 https://gcitps.lcsb.uni.lu/ & Palm et al. (2025) Presentation at SETAC Europe, 13 May 2025. DOI: 10.5281/zenodo.15574837 Predicting Dead-end Transformation Products 49 Source: Emma Palm. Palm et al. (2025) Presentation at SETAC Europe, 13 May 2025. DOI: 10.5281/zenodo.15574837. Number of precursors: 170 Browsing Dead-End (and other) Predicted TPs 50 Source: Emma Palm. Palm et al. (2025) Presentation at SETAC Europe, 13 May 2025 . DOI: 10.5281/zenodo.15574837 Predicting Dead-end Transformation Products 51 Source: Emma Palm. Palm et al. (2025) Presentation at SETAC Europe, 13 May 2025. DOI: 10.5281/zenodo.15574837 Number of precursors: 13 Predicting Dead-end Transformation Products 52 Source: Emma Palm. Palm et al. (2025) Presentation at SETAC Europe, 13 May 2025. DOI: 10.5281/zenodo.15574837 Number of precursors: 13 FAIR-TPs 53 Mayahi, Palm & Schymanski (in prep.). https://fairtps.lcsb.uni.lu/stats/ & https://fairtps.lcsb.uni.lu/about/ NTS @ ECI, LCSB, Uni.lu PubChemLite to explore chemical space Cheminformatics developments Chemical space challenge Analytical method design Exploring transformations Disease impacts Slide inspired by B. Talavera 54 Email: emma.schymans[email protected] in:emma-schymanski / @[email protected] https://wwwen.uni.lu/lcsb/research/environmental_ cheminformatics/ https://gitlab.com/uniluxembourg/lcsb/eci/ https://pubchemlite.lcsb.uni.lu/ Merci/Danke schön/Thank you! H2020: 101036756 55 Analytical Frontiers Computational Tools TPs & PMTs NTS & Hazard Assessment NTS & Managing Chemicals Please join us in Ascona for Nontarget2026! When: April 12-17, 2026 Abstract submission: Nov. 30th, 2025 More details: https://www.eawag.ch/nontarget2026