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Introduction to weight of evidence for adverse outcome pathways


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On Wednesday 15 January 2020 the OECD hosted a second webinar in the series of Adverse Outcome Pathways (AOPs). It focused on the importance of weight of evidence in the process of developing AOPs, the types and lines of evidences assembled, examples demonstrating the lines of evidence and understanding why quantitative AOPs are developed. 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. Bette Meek from the University of Ottawa provided an introduction to weight of evidence for adverse outcome pathways.

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Introduction to weight of evidence for adverse outcome pathways

  1. 1. Introduction to Weight of Evidence for AOPs OECD Webinar January 15th, 2020 Presented by: M.E. Meek, University of Ottawa
  2. 2. Outline • What is WOE analysis for AOPs? • Why is it necessary and important? • What does it entail? 1
  3. 3. What is WOE Analysis for AOPs?
  4. 4. What? • Comprehensive, transparent judgment concerning the extent of the supporting evidence • Based on defined considerations, documented in the Guidance and Handbook for AOP Development • Draws upon considerable previous experience in the assessment of chemicals by regulatory agencies 4
  5. 5. Why is WOE Analysis Necessary/Important?
  6. 6. Why? • To facilitate application of AOPs for different purposes: – e.g., components of priority setting, screening and full hazard/risk assessment: • E.g., organizing data on key events • assessing biological plausibility of associations in epidemiological studies – Environmental monitoring – Developing testing strategies 6
  7. 7. Why (cont’d)? • The “bridge” between research and regulatory application ▫ Knowledge transfer • Provides opportunity to the research/development community – communicating knowledge in a format which supports regulatory application • Provides opportunity to the regulatory community – increasing understanding in development of relevant aspects to tailor research for regulatory application • What studies should I do? 7
  8. 8. What Does WOE Entail?
  9. 9. Background – WOE Analysis for AOPs • Based on modified Bradford Hill (B/H)considerations – Initially introduced to assess causality of associations in epidemiological studies – Subsequently adopted by a wide range of communities – Subset of B/H considerations modified for AOP assessment • based on regulatory experience in assessing chemical specific mechanistic data (mode of action analysis) – Continue to evolve, with additional experience in assessment and application 9
  10. 10. Protein binding DNA binding Receptor/ligand binding Gene activation Protein production Altered signaling Altered physiology Altered tissue development or function Impaired development Impaired reproduction lethality Impaired reproduction/ survival, Population crash Chemical properties MoA AOP Building on Previous Regulatory Experience Chemical specific (toxicokinetics) Chemical agnostic biological pathway (toxicodynamics) 10
  11. 11. Section 1 AOP Description Section 2 KE Descriptions Section 3 – KER Descriptions MIE KEs AO Key Event Relationships/Associations KE Pages KER Pages MIE Page AO Page • Description • Measurement/ detection • Taxonomic applicability • Description • Measurement/ detection • Taxonomic applicability • Evidence for chemical initiation Chemical initiator(s) • Description • Measurement/ detection • Taxonomic applicability • Regulatory relevance Section 5b – MIE, KE, and AO descriptions • Title • Biological plausibility • Empirical support • Quantitative understanding • Uncertainties and inconsistencies Section 4 – Overall Assessment of the AOP AOP Wiki & Handbook Consideration Defining Questions High Moderate Low Biological Plausibility of KERs (S. 6) Support for Essentiality of KEs (S.7) Empirical Support for KERs (S.6.) Annex 1
  12. 12. • Biological Plausibility – KERs – Extent of knowledge of the biology of the pathway – Knowledge of the structural-functional relationships • Essentiality – KEs within AOP – Necessity of Key Events – Experimental support normally from specialized studies to block or modify key events, stop/recovery studies • Empirical Support – KERs – Pattern of Quantitative Associations among Key Events often considered through application of stressors Weight/Extent of the Evidence - AOPs More important Less important H M L H M L H M L 12
  13. 13. Communicating WOE/Confidence and Quantitation of KERs – AOP 3 H H H H H HH M H M H H HMM B.P. & Empirical Support - KERS Essentiality of KEs - AOP Quantitation of KERs 13
  14. 14. Fit for purpose for different applications is dictated by level of confidence in supporting information. Data needed for development Cost and time required for development Prediction/extrapolation uncertainties Component of Quantitative hazard assessment (high tier, high impact) Component of Qualitative hazard assessment (low tier, low impact) Component of screening and prioritization Component of Informed approaches to testing and assessment Weight of Evidence - Bridging Development and Application
  15. 15. Weight of Evidence – the Take Away • Making AOPs relevant to application, drawing on regulatory experience • Bridging the interface between the research and regulatory communities – Focussing/informing on the types of studies that address weight of evidence elements essential for regulatory application • Providing robust and transparent documentation of the extent of the evidence supporting AOPs/components to facilitate application 15H M L jlv1m9d1g32-en