Adverse outcome pathways collaboration, Jason O’Brien from the Environment and Climate Change Canada
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On 30 April 2019, the OECD organised a webinar on the Adverse Outcome Pathway (AOP) framework. The AOP framework is a collaborative tool that applies an innovative approach for collecting mechanistic knowledge from various sources that can eventually support chemical safety assessment. The following questions were addressed: What is the AOP framework and why should you care? Why are we developing AOPs? Why collaborations are encouraged and why should scientific societies be brought in? What are the opportunities for collaboration in AOP development?
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Adverse outcome pathways collaboration, Jason O’Brien from the Environment and Climate Change Canada
- 1. AOP Collaboration Jason O’Brien Ecotoxicology and Wildlife Health Division Environment and Climate Change Canada jason.obrien@canada.ca
- 2. AOP framework: Designed with Collaboration in Mind • Collaborative AOP Development • Collaborative Knowledge Dissemination • Collaborative Research Tool
- 3. Often requires a team of collaborators PopulationOrganism Organ System Organ Response Tissue Response Cellular Response Molecular Initiating Event Molecular biologists Physiologists Cellular biologists Ecologists Risk Assessors Rare for a “single person” to produce a full AOP
- 4. Needed: Your Expertise! • Scientific Societies Particularly well suited for AOP development • Comprehensive knowledge on focused areas of biology • Often encompass full range of biological organization required for AOPs • Many benefits: • Support the uptake of new approach methodologies in risk assessment • Efficiently organize science knowledge • Effectively communicate complex biology • Identify knowledge gaps • Direct research to produce the most impact • Create new knowledge!
- 5. Collaborative Development: Wiki-based Modular Development
- 6. Wiki makes co-authorship easy • All aspects of AOP development can be done over the wiki • “Modular” nature of AOPs and Wiki makes co-authorship easy • Divide development tasks • Each co-author adds/edits different components of AOP at same time
- 7. Wiki access requirements READ ACCESS: • All content from aopwiki.org and aopkb.org are freely available worldwide • No user registration required COMMENTOR ACCESS • Ability to comment on all content (KEs, KERs, and AOPs) • User account with verified email address AUTHOR ACCESS • Create and edit KEs, KERs and AOPs • Must request author access: • OPTION 1: Submit an AOP workplan to the OECD (workplans are reviewed twice per year) • OPTION 2: Submit author access request to SAAOP (typically reviewed with a week or two)
- 8. Ways to Contribute • Create a full AOPs • Create partial AOPs • Create single KE /KERs • Borrow and share! • Generate new data •All help share and even generate knowledge
- 9. Full AOP: A Team Effort PopulationOrganism Molecular Initiating Event Cellular Response Tissue Response Organ Response Organ System Molecular biologists Physiologists Cellular biologists Ecologists Risk Assessors
- 10. Collaborate: Partial AOPs Molecular Initiating Event Cellular Response Tissue Response Organ Response Author Group 1 PopulationOrganism Organ System Organ Response Author Group 2 PopulationOrganism Molecular Initiating Event Cellular Response Tissue Response Organ Response Organ System
- 11. Single Elements: Key Event Relationship KEdownKERKEup How Upstream Event is Measured How Downstream Event is Measured Experimental Evidence Linking KEup and KEdown • Causal Evidence • Weight of Evidence Evaluation • Principal Unit of Extrapolation
- 12. Collaborate: Single Elements Molecular Initiating Event Cellular Response All Separate Authors PopulationOrganism Cellular Response Tissue Response Tissue Response Organ Response Organ Response Organ System Organism Organ System PopulationOrganism Molecular Initiating Event Cellular Response Tissue Response Organ Response Organ System
- 13. Borrow and Share AOP components MIE KE3 AOKE1 KE2 MIE2 KE4 AO2
- 14. Collaborate: Networks create new knowledge 5 Separate AOP 8 unique paths (3 new AOPs!)
- 15. >9000 unique paths (from MIE to AO) All contributions help generate NEW knowledge 187 separate “user defined” AOPs NETWORK
- 16. Examples
- 17. Example of Co-operative AOP Authorship: European Food Safety Authority, Parma, Italy European Commission Joint Research Centre University of Lausanne and SCAHT, Switzerland The Danish Environmental Protection Agency, Denmark Department of Biology, University of Konstanz, Germany
- 18. Example KE Sharing and Collaborative KE and KER Development
- 19. NMDARs Inhibition Impairment of learning and memory Neuro- degeneration in hippocampus and cortex Neuroinflammation (M1 neurodegenerative phenotype) NMDARs, Binding of antagonist Calcium influx, Decreased Release of BDNF, Reduced Cell injury /death Increased Protein Alkylation Liver Fibrosis KC activation TGF-b1 expression HSC activation ECM alteration KC activation Cell Injury/ death Induction of secretion of inflammatory cytokines Induction of acute phase response, Propagation of inflammatory response Reactive oxygen species synthesis Cellular toxicity, cell death Tissue injury TH2/M2 response, secretion and activation of interleukins, growth factors Fibroblast proliferation, myofibroblast proliferation Extracellular matrix deposition Fibrosis Retention of or repeated exposure to foreign material leading to continuous inflammation AOP 173 resident cell activation leading to lung fibrosis AOP 38 protein alkylation leading to liver fibrosis AOP 13: Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development leads to neurodegeneration with impairment in learning and memory in aging INFLAMMATION
- 21. Interlinking of 3 AOPs - 3 AOs in 3 organs
- 22. Organizing and disseminating knowledge
- 23. Primary Purpose of AOPs: Efficiently and Effectively Organize Complex Experimental Evidence
- 25. TPO inhibition TH synthesis, decreased T4 in serum, decreased T4 in tissue, decreased T3 in tissue, decreased Metamorphosis, impaired Iodide in thyroid, decreased IYD inhibition NIS inhibition TH in neural tissues, decreased Hippocampal anatomy, altered Hippocampal function, decreased Cognitive function, decreased DIO1 inhibition DIO2 inhibition Anterior SB inflation, impaired Posterior SB inflation, impaired Swimming performance, reduced Hearing, reduced y.o.y survival, reduced Population trajectory, decreased Survival, reduced Organize in a functional easy to interpret framework (machine readable)
- 26. Organize in a functional easy to interpret framework (machine readable) • More accessible to non-experts • Causal relationships clear • Weight of evidence communicated
- 27. AOPs as collaborative Research Tool:
- 28. AOPs as collaborative Research Tool: • Synthesize current knowledge • Weight of evidence assessment • Identify knowledge gaps • Identify areas to focus research efforts • Generate Data that have greatest impact Molecular Initiating Event Cellular Response Tissue Response Organ Response Organ System Organism Population WoE Strong WoE Strong WoE Strong WoE Strong WoE Strong WoE Weak
- 29. AOP framework can “suggest” experimental design Types of causal evidence used in AOPs: • Biological plausibility • Dose, incidence, and temporal relationships • Quantitative understanding
- 30. AOP framework: Designed with Collaboration in Mind • Collaborative AOP Development • Create a full AOPs • Create partial AOPs • Create single KE /KERs • Borrow and share! • Generate new data • Collaborative Research Tool • Synthesize current knowledge • Weight of evidence assessment • Identify knowledge gaps • Identify areas to focus research efforts • Generate Data that have greatest impact • Collaborative Knowledge Dissemination • More accessible to non-experts • Causal relationships clear • Weight of evidence communicated