Adverse Outcome Pathways: From Research to Regulation



September 3-5, 2014
William H. Natcher Conference Center
National Institutes of Health
Bethesda, Maryland, USA

Videocasts of Workshop Plenary Sessions on NIH Website

  • Day 1 (Wednesday, Sept. 3; 6 hr 28 min)
  • Day 2 (Wednesday, Sept. 4; 3 hr 25 min)
  • Day 3 (Wednesday, Sept. 5; 2 hr 12 min)

Summaries of Breakout Group Discussions

The traditional model of toxicology testing, which involves treating animals with test substances and observing outcomes, may not be sufficient to serve future scientific and regulatory needs. The science of toxicology is turning towards a new model based on a better understanding of toxicity mechanisms, which will enable prediction of toxic effects in humans.

A key element of a mechanistic understanding of a specific toxicity is the construction of an adverse outcome pathway for that toxicity. An adverse outcome pathway is a conceptual framework constructed from existing knowledge that relates exposure of a type of toxic substance to subsequent molecular and cellular changes that result in illness or injury to an individual or population.

Effective communication between researchers and regulators is a critical determinant of whether new methods or approaches are efficiently translated from the scientific bench to regulatory decision-making practice. This workshop brought together over 100 scientists from industry, academia, U.S. and international regulatory agencies, and animal welfare groups to explore how scientific progress in adverse outcome pathway concepts can improve regulatory assessment of chemical toxicity.

Workshop Presentations

Please note: Most presentation files are large (2 MB or larger) and may take a few moments to open.

Opening Session


Innovation in Toxicology at NCATS
Christopher Austin, U.S. National Center for Advancing Translational Sciences

From Mode of Action to Adverse Outcome Pathways: Moving Towards Regulatory Applicability
Bette Meek, University of Ottawa

What is an AOP (and What ISN’T It?)
Donna Mendrick, U.S. Food and Drug Administration (FDA)

Session 1: Building Upon Other Efforts

AOP Activities at the OECD
Joop de Knecht, Organisation for Economic Co-operation and Development (OECD)

AOP Knowledge Base/Wiki Tool Set
Steven Edwards, U.S. Environmental Protection Agency (EPA)

Outcomes from the March Somma Lombardo Workshop
Edward Perkins, U.S. Army

Session 2: AOPs Under Development

Embryonic Vascular Disruption and Adverse Prenatal Outcomes
Nicole Kleinstreuer, ILS/NICEATM

Using Adverse Outcome Pathway Analysis to Identify Gaps in High-Throughput Screening for Thyroid Disruption 
Katie Paul, Bayer CropScience

Application of the Adverse Outcome Pathway (AOP) Concept to Neurotoxicology: A Challenging Approach
Ellen Fritsche, IUF Dusseldorf

AOP Development: After the Heights of the Mountains – the Hardship of the Plains; the Example of Liver Fibrosis
Brigitte Landesmann, European Commission Joint Research Center (JRC)

Fish Early Life Stage: Developing AOPs to Support Targeted Reduction and Replacement
Dan Villeneuve, EPA

Adverse Outcome Pathway for Effects of Anticoagulant Rodenticides on Predatory Birds
Barnett Rattner, U.S. Geological Survey, U.S. Department of the Interior

Adverse Outcome Pathway (AOP) for Sustained Aryl Hydrocarbon Receptor Activation Leading to Rodent Liver Tumor Promotion
Ted Simon, Ted Simon LLC

Developing AOPs from PPAR Activation Leading to Reproductive Toxicity
Malgorzata Nepelska, European Union Joint Research Centre

Framework for Computationally-Predicted AOPs
Shannon Bell, EPA

Session 3: Case Studies: Regulatory Uses for Well-Identified AOPs

Testing of the Predictive Power and Robustness of an AOP Construct for Bile Salt Export Pump Inhibition to Cholestatic Injury
Mathieu Vinken, Vrije Universiteit Brussel

An Adverse Outcome Pathway (AOP) Framework for Screening for Potential Endocrine Disruption
David Dix, EPA

AOPs and Regulatory Decisions: Problem Formulation, Development and Acceptance
Rita Schoeny, EPA

Identifying Integrated In Vitro/In Silico Testing Strategies (IATA/ITS) by Mapping to the Skin Sensitization AOP
Joanna Matheson, U.S. Consumer Product Safety Commission

Session 4: The Risk Context

Exposure and Dosimetry Considerations for AOPs
John Wambaugh, EPA

Ozone-Induced Lung Inflammation and Injury: From Mechanism to Adversity in Humans
Robert Devlin, EPA

Suspected Modes of Action Affected by Pesticides Exposure: Informing an Adverse Outcomes Pathway (AOP) for Cancer
Michael Alavanja, U.S. National Cancer Institute

Breakout Group 1: The Process of Regulatory Acceptance

Breakout Group Summary Presentation
David Dix, EPA, and Craig Rowlands, The Dow Chemical Company

AOP Development Processes in OECD and Regulatory Agency Acceptance
Working Group of National Coordinators, OECD Test Guidelines Programme
Christine Olinger and Melissa Panger, EPA

How Do We Establish Scientific Confidence in AOPs?
Rick Becker, American Chemistry Council

Regulatory Acceptance: How to Strengthen Protection of Susceptible Populations in AOP Approaches
Ruthann Rudel, Silent Spring Institute

Breakout Group 2: Using AOPs for Regulatory Decisions: Confidence and Criteria

Breakout Group Summary Presentation
Suzanne Fitzpatrick, FDA, and Annie Jarabek, EPA

Contaminants in the Food Supply: How the AOP Concept Can Help Regulators Make Decisions Using Arsenic as a Case Study
Christina Powers, EPA

Decision Analytic Approach to Advance Application of AOPs in Risk Assessment: Characterization Criteria to Establish Confidence 
Annie Jarabek, EPA

Using Evidence-Based Toxicology to Evaluate AOPs 
Thomas Hartung, Center for Alternatives to Animal Testing, Johns Hopkins University

Breakout Group 3: Taking Qualitative AOPs to the Next (Quantitative) Level

Breakout Group Summary Presentation
Nicole Kleinstreuer, ILS/NICEATM, and Kristie Sullivan, Physicians Committee for Responsible Medicine

A Quantitative AOP for Skin Sensitization
Gavin Maxwell, Unilever

A Conceptual Model that Enables Quantitative Integration of Data Into an AOP
Catherine Willett, Humane Society of the United States

Applying Semantic and Network Methods in AOP Knowledge
David Wild, University of Indiana School of Informatics and Computing

Presentations by Junior Investigators with Outstanding Poster Abstracts

Quantitative Weight of Evidence Model for Assessing Adverse Outcome Pathways 
Dasha Agoulnik, University of Massachusetts Lowell/U.S. Army Engineer Research and Development Center

Developmental Neurotoxicity of Epigallocatechin Gallate by Interference With beta-1-Integrin Function: A Novel AOP Framework Supporting Neurodevelopmental Toxicity Research and Risk Assessment
Marta Barenys, Liebniz Research Institute of Environmental Medicine

Cross-Species Extrapolation of an Adverse Outcome Pathway for Ecdysteroid Receptor Activation 
Carlie LaLone, EPA

Short-Term Atrazine Exposure Alters the Plasma Metabolome of Male C57BL/6 Mice and Disrupts Specific Metabolic Pathways
Zhoumeng Lin, University of Georgia

Hands-On Demonstration/Training

Entering an AOP into the OECD Wiki
Stephen Edwards, EPA

Introduction to Effectopedia
Hristo Aladjov, OECD