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Structure identification by Mass Spectrometry Non-Targeted Analysis using the US EPA’s CompTox Chemistry Dashboard

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Identification of unknowns in mass spectrometry based non-targeted analyses (NTA) requires the integration of complementary pieces of data to arrive at a confident, consensus structure. Researchers use chemical reference databases, spectral matching, fragment prediction tools, retention time prediction tools, and a variety of other data to arrive at tentative, probable, and confirmed, if possible, identifications. With the diverse, robust data contained within the US EPA’s CompTox Chemistry Dashboard (https://comptox.epa.gov), the goal of this research is to identify and implement a harmonized identification tool and workflow using previously generated chemistry data. Data has been compiled from product use, functional use prediction models, environmental media occurrence prediction models, and PubMed references, among other sources. We will report on our development of a visualization tool whereby users can visualize the relative contribution of identification-based metrics on a list of candidate structures and observe the greatest likelihood of occurrence. These data and visualization tools support NTA identification via the Dashboard and demonstrate an open, accessible tool for all users of HRMS data. This abstract does not necessarily represent the views or policies of the U.S. Environmental Protection Agency.

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Structure identification by Mass Spectrometry Non-Targeted Analysis using the US EPA’s CompTox Chemistry Dashboard

  1. 1. Structure identification by Mass Spectrometry Non-Targeted Analysis using the US EPA’s CompTox Chemistry Dashboard Antony Williams1, Andrew D. McEachran2, Chris Grulke1, Seth Newton3, Kristin Isaacs3, Katherine Phillips3, Nancy Baker1 and Jon R. Sobus3 1) National Center for Computational Toxicology, U.S. Environmental Protection Agency, RTP, NC 2) Oak Ridge Institute of Science and Education (ORISE) Research Participant, Research Triangle Park, NC 3) National Exposure Research Laboratory, U.S. Environmental Protection Agency, RTP, NC March 2018 ACS Spring Meeting, New Orleans http://www.orcid.org/0000-0002-2668-4821 The views expressed in this presentation are those of the author and do not necessarily reflect the views or policies of the U.S. EPA
  2. 2. Abstract • Structure identification by Mass Spectrometry Non-Targeted Analysis using the US EPA’s CompTox Chemistry Dashboard • • Antony J. Williams, Andrew D. McEachran, Chris Grulke, Seth Newton, Kristin Isaacs, Katherine Phillips, Nancy Baker and Jon Sobus • • Identification of unknowns in mass spectrometry based non-targeted analyses (NTA) requires the integration of complementary pieces of data to arrive at a confident, consensus structure. Researchers use chemical reference databases, spectral matching, fragment prediction tools, retention time prediction tools, and a variety of other data to arrive at tentative, probable, and confirmed, if possible, identifications. With the diverse, robust data contained within the US EPA’s CompTox Chemistry Dashboard (https://comptox.epa.gov), the goal of this research is to identify and implement a harmonized identification tool and workflow using previously generated chemistry data. Data has been compiled from product use, functional use prediction models, environmental media occurrence prediction models, and PubMed references, among other sources. We will report on our development of a visualization tool whereby users can visualize the relative contribution of identification-based metrics on a list of candidate structures and observe the greatest likelihood of occurrence. These data and visualization tools support NTA identification via the Dashboard and demonstrate an open, accessible tool for all users of HRMS data. This abstract does not necessarily represent the views or policies of the U.S. Environmental Protection Agency. 1
  3. 3. The CompTox Chemistry Dashboard • A publicly accessible website delivering access: – ~760,000 chemicals with related property data – Experimental and predicted physicochemical property data – Experimental Human and Ecological hazard data – Integration to “biological assay data” for 1000s of chemicals – Information regarding consumer products containing chemicals – Links to other agency websites and public data resources – “Literature” searches for chemicals using public resources – “Batch searching” for thousands of chemicals – Real time prediction of physchem and toxicity endpoints – DOWNLOADABLE Open Data for reuse and repurposing 2
  4. 4. CompTox Chemistry Dashboard https://comptox.epa.gov/dashboard 3
  5. 5. 1 of ~761,000 Chemical Pages 4
  6. 6. Advanced Searches 5
  7. 7. Batch Searches 6
  8. 8. What’s under the Data Tabs? Focus on Hydraulic Fracturing Chemicals 7
  9. 9. Surfacing Lists of Chemicals • Specific subsets of chemicals, “lists”, can be displayed on the dashboard • If there are chemicals that map together then these link to existing: – Property data – Hazard data – Exposure data – In vitro bioassay data – Documents and Literature 8
  10. 10. Detailed Chemical Pages 9
  11. 11. Access to Chemical Hazard Data 10
  12. 12. In Vitro Bioassay Screening ToxCast and Tox21 11
  13. 13. Sources of Exposure to Chemicals 12
  14. 14. Identifiers to Support Searches 13
  15. 15. Literature Searches and Links 14
  16. 16. External Links to Data and Services 15
  17. 17. Integrated Linkouts 16
  18. 18. Integrated Linkouts Comparative Toxicogenomics DB 17
  19. 19. Batch Access to Dashboard Data 18
  20. 20. Batch Search Through Dashboard 19
  21. 21. Batch Search Through Dashboard 20
  22. 22. Batch Access to Dashboard Data 21
  23. 23. Many Hydraulic Fracturing Chemicals are “Complex” 22
  24. 24. UVCB Chemicals 23
  25. 25. Di-sec-butylphenol 24 CAS Representation Dashboard Representation
  26. 26. “Markush Structures” https://en.wikipedia.org/wiki/Markush_structure 25
  27. 27. Suspect Screening and Non-Targeted Analysis Workflow 26 DSSTox Chemical Database “Molecular Features” Extracted Samples Raw Samples Raw Features Matched Formulas Mapped Structures Prioritized Structures (using ToxPi) Confirmed Structures (using ToxCast standards) Processed Features Prioritized Features Predicted Formulas Candidate Structures Sorted Structures Predicted Retention Times Predicted/Observed Functional Use Top Candidate Structure(s) Suspect Screening Non-Targeted Analysis Predicted Concentrations Predicted/Observed Media Occurrence Predicted Mass Spectra Methodological Concordance Red = Analytical Chemistry Blue = Data Processing & Analysis Green = Informatics & Web Services Purple = Mathematical & QSPR Modeling Color Key Content from J. Sobus, US-EPA-NERL
  28. 28. The Dashboard to Support MS-Analysis 27 MS-Ready Structures Underpin Analysis
  29. 29. Specific Data-Mappings “MS-Ready Structures” 28
  30. 30. MS-Ready Mappings • Input Formula: C10H16N2O8 • EXACT Formula Search: 3 Chemicals 29
  31. 31. MS-Ready Mappings • Same Input Formula: C10H16N2O8 • MS Ready Formula Search: 88 Chemicals 30
  32. 32. Complexity to Simplicity 88 Chemicals – 7 in EPAHFR 31
  33. 33. Complexity to Simplicity 88 Chemicals – 7 in the list 32
  34. 34. Searching batches Formula (or mass) searching 33
  35. 35. Future Work • CFM-ID – Viewing and Downloading pre-predicted spectra – Search spectra against the database • Ranking 34
  36. 36. Conclusions 35
  37. 37. Acknowledgments • Hydraulic Fracturing Drinking Water Study Team • The CompTox Chemistry Dashboard team • Todd Martin (TEST Predictions), US-EPA-NRMRL • NERL colleagues: – Jon Sobus, Elin Ulrich, Mark Strynar, Seth Newton (NTA Analysis) – Katherine Phillips, Kathie Dionisio, Kristin Isaacs (Consumer Products Database) • Emma Schymanski – Luxembourg Center for Systems Biomedicine (MS-ready/NTA) 36
  38. 38. Contact Antony Williams US EPA Office of Research and Development National Center for Computational Toxicology (NCCT) Williams.Antony@epa.gov ORCID: https://orcid.org/0000-0002-2668-4821 37

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