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.

1. Introduction to Weight of Evidence for AOPs
OECD Webinar
January 15th, 2020
Presented by:
M.E. Meek, University of Ottawa
bmeek@uottawa.ca

2. Outline
• What is WOE analysis for AOPs?
• Why is it necessary and important?
• What does it entail?
1

3. What is WOE Analysis for AOPs?

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. Why is WOE Analysis Necessary/Important?

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. 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. What Does WOE Entail?

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. 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. 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. • 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. 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. 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. 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 Lhttps://doi.org/10.1787/5
jlv1m9d1g32-en
https://aopwiki.org/