On 25 January 2022, the OECD held a webinar on Adverse Outcome Pathway (AOP) co-operative activities between Scientific journals and the OECD. This webinar was organised primarily for Scientific Journal editors or publishers who are interested in reviewing/publishing AOPs and collaborating with the OECD in this activity. The objective of the webinar was to present the basis for cooperation between scientific journals and the OECD and discuss the lessons learnt so far. Dan Villeneuve (US EPA) presented the AOP framework and challenges being encountered. Access the webinar replay at: https://oe.cd/testing-assessment-webinars

1. The Framework
Webinar on Adverse Outcome Pathway (AOPs) co-operative activities between Scientific
journals and the OECD, January 25, 2022.
Dan Villeneuve
US EPA, Center for Computational Toxicology and Exposure, Great Lakes Toxicology and
Ecology Division, Duluth, MN, USA.
* The contents of this presentation neither constitute nor necessarily reflect US EPA Policy.

2. Paradigm shift in chemical safety assessment
• Direct observation of concentration at
which adverse effects occur
• Effective but……
• Costly
• Time-consuming
• Animal intensive
• Provide little mechanistic insight
New approach methodologies (NAMs)
• Alternative to intact animal studies
• Focused on interactions with
biological targets or pathways
• Enzyme activities
• Receptor binding
• Gene expression
• Hormone concentrations
• Morphology / behavior
• Require knowledge and evidence-
based inference

3. Medical diagnostic tests
Doctors explain to patients, what the results of
those tests mean relative to health.

4. The scientific enterprise has generated
extensive data/information - continues
• Decades of research and testing data
• Hundreds of articles published daily
• Global scientific output doubles every 9 years
Time-consuming and challenging for subject
matter experts, let alone non-experts to digest.
Highly dispersed, variable relevance
and quality
Journal articles, reports, laboratory
notebooks, agency archives
Institutional and government databases
Is that science informing
decision-making?

5. Adverse Outcome Pathway (AOP) Framework
5
MIE KE1 KE2 AO
Slide adapted from – Elizabeth Huliganga
• Knowledge and evidence
• Organized a particular way
• Key events: measurements
• Key event relationships:
Support inference
• Synthesis and communication of
a body of scientific knowledge

6. 1. AOPs are not stressor-specific – intended to capture
generalizable biological phenomenon
2. AOPs are modular
3. An individual AOP is a pragmatic unit of development
and evaluation – a single series of events linking one
cause to one outcome of concern
4. Greater complexity is captured via networks of AOPs
that share common KEs and/or KERs.
5. AOPs are living documents and are expected to evolve
over time (knowledge synthesis)
Principles of AOP development
Key Events
Upstream
Event
(A)
Downstream
Event
(B)

7. http://aopwiki.org/
OECD AOP Wiki User’s Handbook: https://aopkb.org/common/AOP_Handbook.pdf
AOP Wiki: modular assembly of evolving information
KE Pages
KER Pages
• Title
• Description
• Biological
plausibility
• Empirical support
• Inconsistencies
and uncertainties
• Quantitative
understanding
KE Pages
• Description
• Measurement/
detection
• Domain of
applicability
AOP Page
“Crowd-sourcing”

8. 0
50
100
150
200
250
300
350
400
2018-04
2018-07
2018-10
2019-01
2019-04
2019-07
2019-10
2020-01
2020-04
2020-07
2020-10
2020-12
2021-04
2021-07
2021-10
Count
Survey Date
Total AOPs
TFHA/WNT Endorsed
EAGMST Approved
EAGMST Under Review
Archived
Not Specified
Under Development
800
900
1000
1100
1200
1300
1400
1500
1600
200
220
240
260
280
300
320
340
360
380
Events
or
Relationships
(n)
AOPs
(n)
Survey Date
AOPs Key Events Relationships
Growth of the AOP-KB
• Over 370 AOPs under development in the AOP-Wiki
• Averaging ≈ 50 new AOPs per year
• Only ≈ 19 AOPs have gone through formal review
and endorsement

9. The graphical representation alone is no
more valuable for decision-making than a
sketch on a cocktail napkin….
Can be informative – not likely to hold up
in court
Credible supporting evidence is critical
• Weight of evidence assembly
• Technical peer review

10. GR
Activation
Increase,
cripto-1
Expression
Inhibition
, Activin
Signaling
Inhibition
, fin
regenerat
ion
Reduced
swim
performa
nce
Reduced
survival
Population
trajectory,
decreased
Developing a formal AOP description can be
a daunting amount of work
• Assembling and evaluating evidence
• Extensive peer review and revision (collaborative)
Challenges

11. Stakeholder Roles and Challenges
Authors – develop the content; evaluate judge the level of support
• Lack of funding for knowledge synthesis
• Lack of recognition for contribution to open source AOP-Wiki
“The crowd” – can contribute or comment
• Lack awareness of the ability to comment/discuss
• Hesitance to discuss in a public forum
Reviewers – evaluate the technical quality of the information assembled
• Requires broad range of expertise – cooperative/collaborative review
• More time consuming than typical journal article review
Review managers/editors – organize coordinate the review process; moderate revisions and acceptance
• Challenging to recruit reviewers
• Need a diverse mix of expertise in AOP and subject matter
OECD – Provide the guidance on conducting transparent AOP reviews; organize reviews
• Lack of funding and staff time to organize ad hoc reviews
• Deliberative and slow
Professional Societies – Nexus of expertise and in some cases application / actionable science; publishers
• Varying awareness of AOP framework

12. Up Next….