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Crofton Global Chem AOP talk March 2015
- 1. Office of Research and Development National Center for Computational Toxicology Global Chem Baltimore March 2015 Kevin M. Crofton Deputy Director National Center for Computational Toxicology Adverse Outcome Pathways: Challenges in Use and Development Source to Outcome Pathways Source Environmental Contaminant Exposure Molecular Initiating Event Cellular Effects Individual Population Community Adverse Outcome Pathways The views expressed in this presentation are those of the presenter and do not necessarily reflect the views or policies of the U.S. EPA
- 2. Office of Research and Development National Center for Computational Toxicology 1 Outline AOPs – What are they good for? Challenges Collaborative Efforts - AOP Wiki How to efficiently build more AOPs AOP integration – Biology is not linear AR Agonism Theca/Granulosa Reduced T & E2 synthesis Hypothalamic Neurons (-) Feedback Hepatocyte Reduced VTG production Ovary Impaired Oocyte Dev. Female Decreased ovulation/spawning Population Declining Trajectory MIE AO
- 3. Office of Research and Development National Center for Computational Toxicology AOPs – What are they good for? 1. Improved predictions of toxicity via decreased uncertainty and increased transparency o Increases level of confidence in the relationship between measured data and adverse outcomes that is critical for risk assessments o Allows use of ‘up-stream’ key events 2. Informs/enhances species to species extrapolation 3. Can be Life-Stage specific 4. Identification of Data Gaps – Construction of an AOP should identify data gaps i.e., critical needs to build a useful model 5. Provide molecular targets for development of in vitro screening assays (e.g., ToxCast, Tox21) and QSARs (e.g., OECD Toolbox) 6. Holy Grail = predictive computational models – If the MIE predicts the Adverse Outcome – then you don’t need to measure the outcome – Must include compensatory mechanics 2
- 4. Office of Research and Development National Center for Computational Toxicology Collaborative Projects https://aopkb.org/ Third party Applications, plugins AOP-KB Hub Shared chemical, biological and toxicological ontologies AOP-KB Intermediate Effects DB Put chemical-related AOP components in a regulatory context AOP Xplorer Visualize attribute networks to discover & explore AOPs in a broader context Effectopedia Detailed development of structured & computational AOPs AOP Wiki Collaborative development of AOP descriptions & evidence Slide from Clemens Wittwehr
- 5. Office of Research and Development National Center for Computational Toxicology 4 AOP Wiki Collaborative development of AOPs • Provides qualitative, text-based descriptions of an AOP in a structured environment • Focus is on documenting the weight of evidence in support of the AOP • Synchronized with the OECD guidance and handbook documents • Interfaces with the AOP Xplorer to visualize AOP information in a network context • Future interface with Effectopedia and Intermediate Effects dB • Crowd-sourcing hypothesis - Online public access to encourage AOP development
- 6. Office of Research and Development National Center for Computational Toxicology Structuring and Storing AOP Information http://aopwiki.org AR Agonism Theca/Granulosa Reduced T & E2 synthesis Hypothalamic Neurons (-) Feedback Hepatocyte Reduced VTG production Ovary Impaired Oocyte Dev. Female Decreased ovulation/spawning Population Declining Trajectory Key event i+1 Key event I Molecular Initiating Event (MIE) Adverse Outcome (AO) 1. Chemical initiators 2. Key event (nodes) MIE & AO are special cases of KEs AOP Components are mapped to specific entities in the Wiki Example Chemicals 1 2 233 3 4 3. KE Relationship (linkage; edge) 4. AOP 2MIE 2AO
- 7. Office of Research and Development National Center for Computational Toxicology AOP Page in Wiki Structured Content Free Text Fields http://aopwiki.org Review Status OECD Project #
- 8. Office of Research and Development National Center for Computational Toxicology How many AOPs do we have and how many do we need? OECD reviewed and approved AOPs – Only one so far – Skin Sensitization AOP Wiki AOPs – 7 “AOPs Ready for Commenting” • The AOPs are open for public comments – 36 “AOPs Under Development” • Available for viewing, but not comments • Note: A number are not active Peer Reviewed Publications – ~ 5 (some overlap with AOP Wiki) 7 Biological Space Coverage for AOPs is limited
- 9. Office of Research and Development National Center for Computational Toxicology Speeding AOP Discovery & Development Formal AOPs Quantitative AOPs Putative AOPs AOP Networks Computationally Predicted AOPs AOPDataNeeds AOPUncertainties
- 10. Office of Research and Development National Center for Computational Toxicology Computational approach for data integration and putative AOP identification DE gene expression data Discretized data Annotated associations Phenotype data Enriched pathways cpAOPnet HTS data Adverse outcome Stressor Slide courtesy of Steve Edwards & Shannon Bell
- 11. Office of Research and Development National Center for Computational Toxicology 10 Computational Modeling – Using ToxCast and ToxRef AOP for Vascular Disruption • AOPs for embryonic vascular disruption developed from biology of vascular development and used ToxCast data to parameterize models • Validated model results with orthogonal organotypic assays and reference teratogens Model Simulations of Dev Vascular Disruption Knudsen et al., unpublished 1 uM 5 uM0 uM 20 uM AOP for Developmental Vascular Disruption Kleinstreuer et al., PLoS Comp Bio, 2013
- 12. Office of Research and Development National Center for Computational Toxicology Thyroperoxidase Inhibition Decrease Serum T4 & T3 Tissue TH Changes Decreased Cognition Decreased T4 & T3 Synthesis TH Responsive Genes Altered Neurophysiology Altered Neuroanatomy OECD Project 1.10: Xenobiotic Induced Inhibition of Thyroperoxidase and Depressed Thyroid Hormone Synthesis and Subsequent Adverse Neurodevelopmental Outcomes in Mammals.
- 13. Office of Research and Development National Center for Computational Toxicology Thyroperoxidase Inhibition Decrease Serum T4 & T3 Tissue TH Changes Decreased Cognition Decreased T4 & T3 Synthesis TH Responsive Genes Altered Neurophysiology Altered Neuroanatomy OECD Project 1.10: Xenobiotic Induced Inhibition of Thyroperoxidase and Depressed Thyroid Hormone Synthesis and Subsequent Adverse Neurodevelopmental Outcomes in Mammals. Activation of Hepatic Nuclear Xenoreceptors Increased hepatic UGT/SULT T4 Biliary Elimination OECD Project 1.9: Upregulation of Thyroid Hormone Catabolism via Activation of Hepatic Nuclear Receptors, and Subsequent Adverse Neurodevelopmental Outcomes in Mammals.
- 14. Office of Research and Development National Center for Computational Toxicology Thyroperoxidase Inhibition Decrease Serum T4 & T3 Tissue TH Changes Decreased Cognition Decreased T4 & T3 Synthesis TH Responsive Genes Altered Neurophysiology Altered Neuroanatomy OECD Project 1.10: Xenobiotic Induced Inhibition of Thyroperoxidase and Depressed Thyroid Hormone Synthesis and Subsequent Adverse Neurodevelopmental Outcomes in Mammals. Activation of Hepatic Nuclear Xenoreceptors Increased hepatic UGT/SULT T4 Biliary Elimination OECD Project 1.9: Upregulation of Thyroid Hormone Catabolism via Activation of Hepatic Nuclear Receptors, and Subsequent Adverse Neurodevelopmental Outcomes in Mammals. New OECD AOP Project: Inhibition of Na+/I- symporter (NIS) decreases TH synthesis leading to learning and memory deficit in children NIS Inhibition Multiple MIEs Same Outcome
- 15. Office of Research and Development National Center for Computational Toxicology Thyroperoxidase NIS Hepatic Nuclear Xenoreceptors Deiodinases Thyroid Receptors Free T3 & T4 TSH Tissue TH Changes Thyroid Hyperplasia Rat Thyroid Tumors Adverse Outcomes T4 & T3 Synthesis Phase 2 Catabolism Cellular Transporters Cellular T4 T3 Conversion Biliary Elimination 4 9 35 6 7 8 Transport Proteins 10 Thyroid Gland Pituitary TSH R TRH R Hypothalamus TR Blood Cellular TR Signaling Altered Development Altered Metabolism 3 2 1 Hypothalamic Pituitary Feedback Bound-TH Integrated Pathways – Multiple MIEs & Species Dependent and Independent AOs Human Developmental Neurotoxicty Amphibian Metamorphosis
- 16. Office of Research and Development National Center for Computational Toxicology AOPWiki Beta version released September 2014. • Developed as a joint project between: – OECD, EU Joint Research Center, Italy, US EPA, US Army Engineering Research and Development Center, Vicksburg MS • Provides a ‘user-friendly’ interface for ‘crowd sourcing the development of AOPs Link - www.aopwiki.org Contacts: Edwards.Stephen@epa.gov Clemens.Wittwehr@ec.europa.eu 15
- 17. Office of Research and Development National Center for Computational Toxicology Thanks for Listening 16