1. Office of Research and Development National Center for Computational Toxicology May 18, 2011 RASS December 11, 2013 Elaine Cohen Hubal Chemical Safety for Sustainability Research Program Providing the Missing Link: The Exposure Ontology ExO Disclaimer. Although this work was reviewed by EPA and approved for presentation, it may not necessarily reflect official Agency policy.

2. Office of Research and Development National Center for Computational Toxicology What Is Exposure Science? The bridge between the sources of chemical, physical and biological agents and human health –Provides crucial information to estimate real-life risks to health and to identify the most effective ways to prevent and reduce these risks. 1 www.isesweb.org

3. Office of Research and Development National Center for Computational Toxicology Exposure for Risk Evaluation: Approaches Questionnaire based metrics (epidemiology) Surrogate exposure metrics (ambient measures) Exposure measurement (direct or point-of-contact) Biomonitoring (NHANES) Modeled estimates (indirect or scenario evaluation) 2 2 SOURCE / STRESSOR FORMATION TRANSPORT/ TRANSFORMATION ENVIRONMENTAL CHARACTERIZATION EXPOSURE DOSE Individual Community Population ADVERSE OUTCOME EXPOSURE MODELS PBPK MODELS TRANSPORT, TRANSFORMATION, and FATE PROCESS MODELS ACTIVITY PATTERN

4. Office of Research and Development National Center for Computational Toxicology 3 Stressor Biological Receptor Outcome Perturbation Population Individual Tissue Cell Biological Molecules Environmental Source Ambient Exposure Environmental Source Personal Exposure Internal Exposure (Tissue Dose) Dose to Cell Dose of Stressor Molecules Disease Incidence/Prevalence Disease State (Changes to Health Status) Dynamic Tissue Changes (Tissue Injury) Dynamic Cell Changes (Alteration in Cell Division, Cell Death) Dynamic Changes in Intracellular Processes Cohen Hubal, JESEE, 2008 Systems Biology: Exposure at All Levels of Biological Organization

5. Office of Research and Development National Center for Computational Toxicology Susceptibility (Genetic Variants / Epigentic Modifications) Improved Measures of Individual Etiological Processes and Individual Exposures Key Perturbations Key Targets Personal Risk Profile Extrapolation for Risk Assessment Biomarkers Indicators Metrics Public Health Policy Prevention Education Personal Risk Management Information Biological Insight (Toxicity Pathways) Environmental Factors (Exposure) Cohen Hubal, et al. JTEH, 2010 Exposure for Translation

6. Office of Research and Development National Center for Computational Toxicology 5 Knowledge Systems – Enabling Hypothesis Development Computational Techniques – Two Branches A combination of discovery and engineering (mechanistic)-based modeling approaches required for hypothesis development and testing Knowledge-discovery –Data-collection, mining, and analysis –Required to extract information from extant data on critical exposure determinants, link exposure information with toxicity data, and identify limitations and gaps in exposure data. Mechanistic (dynamic) simulation –Mathematical modeling at various levels of detail –Required to model the human-environment system and to test our understanding of this system.

7. Office of Research and Development National Center for Computational Toxicology 6 Exposure-Hazard Knowledge System Translation of HTP hazard information requires holistic risk assessment knowledge system –Include ontologies, databases, linkages –Facilitate computerized collection, organization, and retrieval of exposure, hazard, and susceptibility information –Define relationships, allow automated reasoning, facilitate meta analyses Standardized exposure ontologies required to –Develop biologically-relevant exposure metrics –Design and interpret in vitro toxicity tests –Incorporate information on susceptibility and background exposures to assess individual and population-level risks

8. Office of Research and Development National Center for Computational Toxicology 7 Schematic of ontologies, databases and ontology/database linkages needed for the efficient development of a Foods-for-Health Knowledge System MC Lange, et al. (2007) A multi-ontology framework to guide agriculture and food towards diet and health. J Sci Food and Ag 87(8)1427-34.

9. Office of Research and Development National Center for Computational Toxicology 8 Exposure Data Sources http://actor.epa.gov Peter Egeghy, NERL

10. Office of Research and Development National Center for Computational Toxicology Exposure Data Landscape 9 Network of exposure taxonomy used in ACToR; Egeghy et al, 2011

11. Office of Research and Development National Center for Computational Toxicology Exposure Data Landscape 10 Number of unique chemicals by data type in ACToR; Egeghy et al, 2011

12. Office of Research and Development National Center for Computational Toxicology 11 Exposure Data Collection and Access: ACToR, Aggregated Computational Toxicology Resource Tabular Data, Links to Web Resources Chemical ID, Structure Chemical Internet Searches ACToR API ToxRefDB http://actor.epa.gov/ ToxCastDB ExpoCastDB In Vivo Study Data - OPP ToxCast Data – NCCT, ORD, Collaborators Exposure Data – NERL, NCCT ACToR Core DSSTox Chemical ID & Structure QC, Inventory Tracking

13. Office of Research and Development National Center for Computational Toxicology Exposure Data Collection and Access : ExpoCastDB Goals Consolidate observational human exposure data, improve access and provide links to health related data House measurements from human exposure studies Encourage standardized reporting of observational exposure information Provide separate interface with inner workings of ACToR Facilitate linkages with toxicity data, environmental fate data, chemical manufacture information Provide basic user functions Visualization (e.g., scatterplots, probability plots, goodness-of-fit) Obtain summary statistics and estimate distributional parameters Download customized datasets http://actor.epa.gov/

14. Office of Research and Development National Center for Computational Toxicology 13 Generic_chemical table in ACToR 1 Measure (Chemical) Laboratory method N 1 Sample N N N 1 N N Subject N N Exposure Taxonomy (Assay_ category_ CV table in ACToR) N N Location Location_CV (cont vocab.) Study Sources N N N N N N N N N 1 N 1 N N N 1 N N N N N N Study_CV cont. vocab 1 N N N N Medium ( serum, air, soil, etc.) Technique / sampling method Exposure Data Collection and Access: ExpoCastDB Four initial studies from National Exposure Research Laboratory Full raw data sets available for download Browse data capability Descriptive statistics capabilities

15. Office of Research and Development National Center for Computational Toxicology 14 ExO: An Ontology for Exposure Science

16. Office of Research and Development National Center for Computational Toxicology 15 Background: Significant progress has been made in collecting and improving access to genomic, toxicology, and health data These information resources lack exposure data required to –translate molecular insights –elucidate environmental contributions to diseases –assess human health risks at the individual and population levels Aim: Facilitate centralization and integration of exposure data to inform understanding of environmental health Bridge gap between exposure science and other environmental health disciplines Vehicle: Carolyn Mattingly, Mount Desert Island Biological Laboratory LRI seed funding, followed by NIEHS RO1 Exposure Data Collection and Access: Design and Evaluation of the Exposure Ontology, ExO

17. Office of Research and Development National Center for Computational Toxicology Ontologies An ontology is a formal representation of knowledge within a domain and typically consists of classes, the properties of those classes, and the relationships between these Many fields are developing ontologies to –Organizing and analyzing large amounts of complex information from multiple scientific disciplines –Provide unprecedented perspective –Enable more informed hypothesis development 16 (http://www.obofoundry.org/) (Gruber, Int. J. Human-Computer Studies, 1995)

18. Office of Research and Development National Center for Computational Toxicology Design and Evaluation of the Exposure Ontology: ExO Develop an exposure ontology consistent with those being used in toxicology and other health sciences Facilitate centralization and integration of exposure data to inform understanding of environmental health Bridge gap between exposure science and other environmental health disciplines –Initially focus development on human exposure to chemicals –Ultimately, provide domains that can be extended to encompass exposure data for the full range of receptors and stressors 17

19. Office of Research and Development National Center for Computational Toxicology Exposure Ontology Working Group Working Group MemberInstitutionRole/expertise Carolyn Mattingly, PhD Mount Desert Island Biological Laboratory Facilitator/curated database development Judith Blake, PhD.The Jackson Laboratory Facilitator/ontology development Michael Callahan, PhM.MDB, Inc. Core Member/ exposure assessment Elaine Cohen Hubal, PhDUS EPA; NCCT Core Member/ exposure research Robin Dodson, ScD.Silent Spring Institute (SSI)Member/exposure research Peter Egeghy, PhD.US EPA, NERLMember/exposure research Jane Hoppin, ScD.NIEHS Member/epidemiology Thomas McKone, PhD. Lawrence Berkeley National Laboratory (LBNL) Core Member/ exposure research Ruthann Rudel, MS.Silent Spring Institute (SSI)Member/exposure research 18

20. Office of Research and Development National Center for Computational Toxicology Initial pilot curation to identify major concepts Expand test data set to evaluate extensibility of conceptual model and cross -reference existing ontologies Model relationships among data concepts Iterate data model refinement and curation Disseminate exposure ontology for public feedback Disseminate exposure ontology for public feedback Full working group evaluation of draft ontology Phase I Phase IIPhase IIIPhase IV Phases of Exposure Ontology Development

21. Office of Research and Development National Center for Computational Toxicology Definitions of Central Concepts Exposure Stressor - An agent, stimulus, activity, or event that causes stress or tension on an organism and interacts with an exposure receptor during an exposure event. Exposure Receptor - An entity (e.g., a human, human population, or a human organ) that interacts with an exposure stressor during an exposure event. Exposure Event - An interaction between an exposure stressor and an exposure receptor. Exposure Outcome - Entity that results from the interaction between an exposure receptor and an exposure stressor during an exposure event. 20 Mattingly et al, submitted

22. Office of Research and Development National Center for Computational Toxicology Exposure Event Exposure Outcome Exposure Stressor Exposure Receptor Biolog. Agent Chem. Agent Biomech. Agent Phys. Agent Psychosoc. Agent Public Policy Inter- vention Biolog. Response Anthro- sphere Disease Symptom Molecular Response Location Temporal Pattern Intensity Route Assay Medium Method Location Human Pop. Location Genetic Background Lifestage Health Status Socioeconomic Status Occupation Source Location Process Transport Path Individual Relational View of Selected ExO Domains Mattingly et al, submitted

23. Office of Research and Development National Center for Computational Toxicology Exposure Outcome Phenotype (e.g., OMIM, MeSH) Exposure Outcome Phenotype (e.g., OMIM, MeSH) Chemical (e.g., MeSH) Chemical (e.g., MeSH) Biological System (e.g., Functional model of anatomy) Biological System (e.g., Functional model of anatomy) Assessed by Pathways, Networks Reactions (e.g., KEGG, Reactome) Pathways, Networks Reactions (e.g., KEGG, Reactome) Occur within Genes Gene Products Biological Process Molecular Function Cellular Component (e.g., Gene Ontology Biological Process Molecular Function Cellular Component (e.g., Gene Ontology Interact via Encode Annotated with Exposure Stressor (e.g., ExO) Exposure Stressor (e.g., ExO) Exposure Receptor (e.g., ExO) Exposure Receptor (e.g., ExO) Is a Interacts with Exposure Event (e.g., ExO, ExpoCastDB) Exposure Event (e.g., ExO, ExpoCastDB) Via an Results in an Interacts with (e.g., CTD) Interacts with (e.g., CTD) Is a Mattingly et al, submitted High-level schematic of Exposure Ontology (ExO) integration within a broader biological context.

24. Office of Research and Development National Center for Computational Toxicology Next Steps Open source approach With input from the scientific community, further specify branches Leverage existing ontologies (e.g., CHEBI and MeSH for “Chemical agent” Stressors; DO, OMIM and MeSH for “Disease” Outcomes). Cross-referencing will underscore where ExO fits into a broader knowledge space and where it may add value to existing ontologies. 23

25. Office of Research and Development National Center for Computational Toxicology 24 pathway data Diseases Genes Chemicals chemical-disease relationships chemical-disease relationships chemical-gene interactions chemical-gene interactions gene-disease relationships gene-disease relationships functional annotations Exposure Data (curated and public sources) Beyond EPA: Pilot Curation of Exposure Data into CTD Carolyn Mattingly

26. Office of Research and Development National Center for Computational Toxicology 25 Acknowledgements ExO– Carolyn Mattingly, Tom McKone, Judy Blake, Mike Callahan ExpoCastDB -- Richard Judson, Peter Egeghy, Sumit Gangwal