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Your Environment. Your Health.

Adverse Outcome Pathways

Superfund Research Program

The NIEHS Superfund Research Program (SRP) hosted a seminar series focused on adverse outcome pathways (AOPs), which are structured ways to represent biological events leading to adverse health effects. The AOP framework was developed as a means for organizing biological and toxicological knowledge concerning the linkages between molecular-level perturbations of biological systems by stressors and the apical hazards (e.g., disease in humans, reduced survival, growth, reproduction in wildlife) that can result. As such, the AOP framework can help support greater use of mechanistic or pathway-based data in risk assessment and regulatory decision making.

This webinar series was also in support of an NIEHS/NHLBI Workshop, Understanding the Combined Effects of Environmental Chemical and Non-Chemical Stressors: Atherosclerosis as a Model, which took place at NIEHS in Research Triangle Park, North Carolina, April 3 - 4, 2018. The goal of the workshop was to identify key biological mechanisms/pathways of the combined effects of chemical and non-chemical stressors associated with atherosclerosis. A critical research area that requires further exploration is the biological mechanisms and effects of exposure to both environmental chemicals (e.g., air pollution, polycyclic aromatic hydrocarbons, metals, pesticides) and non-chemical stressors (e.g., psychosocial, lifestyle, quality of life, poor nutrition, infectious agents, physical stressors) over time and the roles they may play in the development of disease (e.g., cancer, cardiac, metabolic, neurological). The workshop brought together experts to discuss the state of the science pertaining to underlying biological pathways associated with, when combined, chemical and non-chemical stressors in relation to atherosclerosis. The workshop used the AOP framework to assist in the discussion of the pathways considered by workshop participants.

Session II - Assembling and Assessing AOP Information
November 29, 2017 • 1:00 - 3:00 p.m. EST
To view an archive, visit EPA's CLU-IN Training & Events webpage.

In the second session, presenters discussed the development of AOPs and how they may be used to support hazard and risk assessment.

Carole Yauk, Ph.D., briefly reviewed common AOP development principles, including identifying key events and assembling and weighing the evidence to support key event relationships and the overall AOP. A case study then walked through development of one AOP using the AOP wiki. Using alkylation of DNA as the molecular initiating event, subsequent key events that are measurable and essential were identified. Key event relationships were identified and evaluated by assessing the dose, incidence, and temporal relationships among the events. The essentiality of each event to the adverse outcome, heritable mutations, were assessed, and the empirical evidence supporting the AOP, and any uncertainties, was evaluated.

Ed Perkins, Ph.D., discussed efforts to merge the AOP's simple framework for linking effects to a regulated outcome with more biological pathways and measurements such as omics that try to capture the complexity of biology in order to support hazard and risk assessment. Examples were given on how 'omics and other data can be used in the context of AOPs to assess chemical mixture impacts and how in vitro or in vivo data can be used to determine the likelihood of an AO occurring (e.g., Bayesian AOP networks and mechanistic qAOPs).

The AOP framework provides a logical mechanism based structure for formalizing and visualizing the molecular intersection between chemical and nonchemical stressors. However, the impact and relevance of biomedical research on public health protection from chemical and nonchemical exposures depends both on the understanding of mechanisms embedded in the AOP framework and how exposures themselves affect those mechanisms and the likelihood of adverse outcomes.

Justin Teeguarden, Ph.D., who is part of the SRP Centers at Oregon State University and Texas A&M University, introduced similar frameworks for organizing exposure information (like the aggregate exposure pathway (AEP)) and discussed how they can provide critical information about the magnitude of stress and key information about how environmental concentrations can be related to human exposures. He also discussed how exposures in studies conducted in vitro or animal models can be related to human exposures.


  • Carole Yauk, Ph.D., Genomics Laboratory Lead, Environmental Health Science and Research Bureau, Health Canada
  • Ed Perkins, Ph.D., Army Senior Research Scientist in Environmental Networks and Genetic Toxicology, U.S. Army Corps of Engineers - Engineer Research and Development Center
  • Justin Teeguarden, Ph.D., Biological Systems Scientist, Pacific Northwest National Laboratory


  • Danielle Carlin, Ph.D., Health Scientist Administrator, NIEHS Superfund Research Program

Session I - Introduction to the Adverse Outcome Pathway Framework
October 11, 2017 • 1:00 - 3:00 p.m. EDT
To view an archive, visit EPA's CLU-IN Training & Events webpage.

In the first session, U.S. Environmental Protection Agency (EPA) staff provided an introduction and overview of AOPs and discussed the AOP Knowledge Base, which is designed to house descriptions of the biological mechanisms underlying chemical toxicity in a structured manner.

Daniel Villeneuve, Ph.D., introduced the AOP framework and major principles that guide the development and description of AOPs within the AOP Knowledge Base. He also gave examples of some prominent applications of AOPs.

Stephen Edwards, Ph.D., discussed the design of the AOP Knowledge Base and how this supports both AOP development and use. This included the assembly of AOP networks and their importance when using AOPs. He also discussed methods for developing AOP networks in an automated fashion to complement the expert-driven AOP development efforts within the AOP Knowledge Base.


  • Daniel L. Villeneuve, Ph.D., Research Toxicologist, U.S. Environmental Protection Agency Office of Research and Development
  • Stephen Edwards, Ph.D., Systems Biologist, U.S. Environmental Protection Agency National Health and Environmental Effects Research Laboratory


  • Michelle Olive, Ph.D., ‎Deputy Chief, Atherothrombosis and Coronary Artery Disease Branch, National Health, Lung, and Blood Institute
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