Can AOPs Save the World?
Kristie Sullivan, MPH
VP for Research Policy

What is an Adverse Outcome Pathway?
• First described by US EPA ecotoxicologists in 2010
• OECD AOP Programme formed• Crowd-sourced database called AOP Wiki
• Trainings conducted at dozens of fora
• Review and publication process established• Since 2010, there have been 4000 publications• SAAOP formed to host AOP Wiki and facilitate training• Lush black box prize awarded in 2015
• All major regulatory agencies incorporating AOP concepts

AOP: A knowledge bridgeRegulatory
Toxicology(or, safetyevaluations)Organizational Framework for Information
Combines information from multiple fields of inquiry to illuminate
knowledge of biological pathways, highlight species differences orsimilarities, identify research needs, and support regulatory decisions.
MolecularInteractions

Organelle/CellularEffects• Receptor
interaction• Covalentbinding• Gene activation• Oxidative stress• Immune cellactivation

OrganEffects

IndividualEffects

Population
Effects• Tissueproliferation• Alteredfunction• Altered
reproduction• Disease• Lethality• Population
reduction• Extinction

Effort to catalog AOPs is bringing toxicity information into a usable, accessible format

Regulatory Context for Nonanimal Test Methods
Link molecular events to events of regulatory interest, provide
mechanistic support for computational tools, ID assay development
needs, & inform IATA
MolecularInteractions

Organelle/CellularEffects

Organ
Effects

Individual
Effects

High-throughput assays
In vitro 2D cell lines / iPS / primary cells
In vitro 3D reconstructed tissues
Microphysiological systems

Computational Modeling

PopulationEffects

OECD’s AOP Programme: A success story• 8 Published AOPs
• Global AOP Network• 230 AOPs
• 1125 Key Events• >1300 KE Relationships• >380 Stressors• ~3500 Pathways

https://aopkb.oecd.org
https://aopwiki.org

AOP ELEMENTS: THYROID AOP NETWORK
IYD
inhibition

NIS
inhibition

TPO
inhibition

TH inneuraltissues,
decreased

Hippocampal
anatomy,alteredT4 inserum,
decreased

T4 intissue,
decreased

Cognitivefunction,decreased

Iodide inthyroid,decreasedTH
synthesis,
decreased

Metamorphosis,
impaired

Survival,
reducedT3 intissue,
decreased

DIO1
inhibition

DIO2
inhibition

Molecular
Initiating EventHippocampal
function,decreased

Key Events

Anterior SBinflation,
impairedHearing,
reduced

PosteriorSB
inflation,
impaired

Swimmingperformance,
reducedKey Event Relationships

y.o.ysurvival,
reducedPopulation
trajectory,
decreased

Adverse
Outcome (s)AOP Wiki endpoint coverage
8070
60
50
40
30
20
100
Ecotoxicity

Reprotoxicity

Lethality

Neurotoxicity

Carcinogenicity

Endocrine Disr.

DevelopmentalToxicity

Hepatotoxicity

IATA is the New OECD Test Guideline
DefinedApproaches

In vivo Test Guidelines
In vitro Test Guidelines

AOP

Non-standard tests(Q)SARs
Categorisation/Read-acrossWeight of Evidence

Exposure
ADME
Slide: Nicole Kleinstreuer, NICEATM

ChemicalIATA

http://www.oecd.org/chemicalsafety/risk-assessment/iataintegrated-approaches-to-testing-and-assessment.htm

What about medical research?
• Atherosclerosis as a Model Workshop, April 2018 (NIEHS)• Using AOP framework to combine chemical and non-chemical stressors
related to biological pathways for atherosclerosis• Parkinsonism• Adverse outcome pathways: Application to enhance mechanistic
understanding of neurotoxicity (Bal-Price and Meek 2017,
doi: [10.1016/j.pharmthera.2017.05.006]• Suggest mechanism-based reclassification of disease• Alzheimer’s, Asthma, and others• Recommendations toward a human pathway-based approach to diseaseresearch (Marshall et al 2018, doi: [10.1016/j.drudis.2018.05.038]• BioMed21: A Human Pathways Approach to Disease Research, June 2017

Reality Check• It’s taken decades to replace tests using few animals• So far AOPs have only led to one animal test replacement• Tests using thousands of animals each are still conducted every year
• Nonanimal methods are increasingly being used to trigger animal tests• Aquatic toxicology is exploding• Toxicology represents small percentage of animals used in scienceWhat is Needed• Financial investment by regulatory agencies/governments• Quantitation of AOP elements• More directed AOP network development• Training and outreach to scientific community• Incentives and requirements from• Funding bodies• Journals

Kristie Sullivan
ksullivan@pcrm.org

Thank you for your attention!