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TRANSCRIPT
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Introduction to the AOPframework concept and online course
Catherine Willett Coordinator, Human Toxicology Project Director, Science PolicyHSUS/HSI [email protected]
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Whyo Need for more efficient tools for chemcial risk
assessmento Need to better use our existing and future data and
knowledgeWhat
o The Adverse Outcome Pathway frameworko Purpose, definition
Howo Relational “knowledgebase”o Guidanceo Evaluationo Training and free course
Outline
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Issue #1: too many chemicals, current system inadequate
o e.g. tens of thousands of chemicals await assessment
o e.g. 95% clinical failure rate for new drugs in spite of increased spending
o Faster, more relevant approaches needed across sectors
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Issue #2: The need to better leverage our existing knowledge
Too much data!o Decades of research and testing datao Global scientific output doubles every 9 years
Where is the data?!o Journal articles, reports, laboratory notebooks, agency archives, o Institutional and government databases
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Better access, better organization leads to better understanding
o PDFso Fragmentedo Siloedo Proprietary
o Searchableo Machine-readableo Linkedo Facilitating collaborationo Avoiding duplication
(adapted from D. Villeneuve)
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A practical solution for a practical problem:o How to use molecular understanding to make better
decisions about chemical safetyo Provides a framework for collecting, organizing and
evaluating biological information
?
Adverse Outcome Pathway framework: linking molecular initiation to adverse outcomes
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A sequence of events o beginning with initial interactions of a stressor with a biomolecule in a
target cell or tissue (the molecular initiating event), o progressing through a dependent series of intermediate events (key
events) o culminating with an adverse outcome*
*if compensatory mechanisms are overwhelmed
Protein bindingDNA binding
Receptor/ligand binding
Gene activationProtein
productionAltered signaling
Altered physiologyAltered tissue
development or function
Impaired development
Impaired reproduction
lethality
Impaired reproduction/
survival,Population crash
Chemical properties
AOPs: Linking molecular information to adverse outcomes
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AOPs: Provides scaffold for organizing, evaluating and understanding data
Mechanistic Toxicology Data(‘omics, biomarkers)
Clinical, EpidemiologyEco Field Studies
Molecular data Regulatory Endpoints
High Throughput Guideline Studies
Protein bindingDNA binding
Receptor/ligand binding
Gene activationProtein
productionAltered signaling
Altered physiologyAltered tissue
development or function
Impaired development
Impaired reproduction
lethality
Impaired reproduction/
survival,Population crash
Chemical properties
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Essential elements of an AOP
Protein bindingDNA binding
Receptor/ligand binding
Gene activationProtein
productionAltered signaling
Altered physiologyAltered tissue
development or function
Impaired development
Impaired reproduction
lethality
Impaired reproduction/
survival,Population crash
Chemical properties
o Key Events (KEs) – nodes
• Change in biological or physiological state
• Measurable and essential for progression
o Molecular Initiating Event (MIE): specialized KE that represents the initial point of stressor interaction with the organism
o Adverse Outcome (AO): specialized KE of regulatory significance
o Key Event Relationships (KERs)
o Connection between two key events
o Critical for assembling evidence in support of the AO
o Facilitates inference or extrapolation
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Building an AOP
Protein bindingDNA binding
Receptor/ligand binding
Gene activationProtein
productionAltered signaling
Altered physiologyAltered tissue
development or function
Impaired development
Impaired reproduction
lethality
Impaired reproduction/
survival,Population crash
Chemical properties
o Start anywhere
• but one AOP = one MIE leading to one AO as a pragmatic unit
o Gather all existing knowledge
• Not every detail, but critical steps or check-points
• Collaboration is encouraged
o Evaluate and document the information
• Refer to extensive OECD guidance
o Translate and capture information as a pathway in the AOP Wiki
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AOPs are modularo Key events and relationships can be shared by multiple AOPs
AOPs are living documentso AOP descriptions can be expected to evolve over timeo As descriptions are updated and expanded – all AOP descriptions they
link to update automatically
AOP networks will emerge and are the basis for prediction
Fundamental principles of AOP development
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AOP Knowledgebase: an international partnership
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o Captures and organizes all information and supporting documentation for AOP elements
o Supported by extensive guidance, tutorials and an online course
o Is designed to enable rigorous evaluation and scientific review
Publically accessible since 2014www.aopwiki.org
AOP Wiki: information storage, linkage and evaluation
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AOP Wiki 2.2 released Jan 28, 2018
AOP WIKI: Home page
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AOP WIKI: search “liver fibrosis”
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AOP 38 Summary
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AOP WIKI: KER and AOP confidence evaluation
Biological Plausibility: between KE upstream and KE downstream?
High (strong):Extensiveunderstanding of KER
Moderate: KER is plausible
Low (weak): some empirical support
Essentiality: are downstream KEs prevented if upstream KE’s blocked?
High (strong): direct evidence from experimental studies
Moderate: indirect evidence
Low (weak)No or contradictory evidence
Empirical Evidence: amount, quality, consistent, inconsistent?
High (strong): extensiveevidence for temporal, dose-response
Moderate: multiple reports of consistentevidence, some inconsistent
Low (weak): limited or no studies and/or significant inconsistencies
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List of AOPs
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OECD AOP Development Programme
Extended Advisory Group for Molecular Screening & Toxicogenomics (EAGMST)o Guidance, users Handbook
o Review
o Training
Task force on Hazard Assessment (TFHA)o Guidance for use of AOPs in
regulatory decision making
o Integrated Approaches to Testing and Assessment (IATA)
Society for the Advancement of AOPSo Not officially part of the OECD programme
o Any person active in developing an AOP in the wiki can join
o Is another way to enter the AOP wiki
o Provides “gardening” and other support functions
o www.saaop.org
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OECD AOP Development Programme
AOP Wiki Access: three levels
1. Read access: anyone can access the wiki, search and read entries
2. Commenter access: a self-created account is needed to leave commentso Create an account on the wiki
3. Author access: to write and edit AOPso must be requested through the wiki
o You should have a familiarity with the wiki and desire to build an AOP
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Work Process for Development and Review of AOPs through OECD
Enter AOP Wiki through SAAOP
Enter AOP Wiki through EAGMST
SAAOP gardeners check format and compliance with OECD guidance
Content and structural review by EAGMST
Technical review by scientific expert group
Process review by OECD National Coordinators (WNT)
Publication on website in OECD Series on Adverse Outcome Pathways
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OECD Guidance for developing AOPs
Guidance Document for Developing and Assessing AOPs (2017)Series on Testing & Assessment No. 233
OECD User’s Handbook Supplement to the Guidance Document for Developing and Assessing AOPs (2017) Series on Testing & Assessment No. 233 Series on Adverse Outcome Pathways No. 1
Section of AOP Wiki Section of Handbook
AOP Description Section 1
KE descriptions (unique pages) Section 2
KER descriptions (unique pages)KER evaluation
Section 3
Overall AOP assessment Section 4
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AOP Online Training CourseThree volume course:1. Introduction and Overview2. AOP Wiki Training with quizes3. Self exam
Download:https://humantoxicologyproject.org/about-pathways-2/aop-online-course/Run:https://aopwiki.org/
Please run, download and share!
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Current state of the AOP Wiki
23 June 2017 D. Villeneuve
The more participation, the better it will be!