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Adverse Outcome Pathways – Organizing Toxicological Information to Improve Decision Making
Edwards, S., C. Tan, Dan Villeneuve, B. Meek, AND C. McQueen. Adverse Outcome Pathways – Organizing Toxicological Information to Improve Decision Making. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS. American Society for Pharmacology and Experimental Therapeutics, Bethesda, MD, 356(1):170-181, (2016).
The number of chemicals for which environmental regulatory decisions are required far exceeds the current capacity for toxicity testing. High throughput screening (HTS) commonly used for drug discovery has the potential to increase this capacity. The adverse outcome pathway (AOP) concept has emerged as a natural framework for connecting high throughput toxicity testing (HTT) results to potential impacts on humans and wildlife populations. An AOP consists of two main components that describe the biological mechanisms driving toxicity. Key events represent biological processes essential for causing the adverse outcome that are also measurable experimentally. Key event relationships capture the biological processes connecting the key events. Evidence documented for each KER based on measurements of the KEs can provide the confidence needed for extrapolating HTT from early key events to overt toxicity represented by later key events based on the AOP. The IPCS mode of action (MOA) framework incorporates information required for making a chemical-specific toxicity determination. Given the close relationship between the AOP and MOA frameworks, it is possible to assemble an MOA by incorporating HTT results, chemical properties including absorption, distribution, metabolism, and excretion (ADME), and an AOP describing the biological basis of toxicity thereby streamlining the process. While current applications focus on the assessment of risk for environmental chemicals, these approaches fit naturally into the safety assessment of pharmaceuticals and well as target discovery and HTS applied to novel drug discovery.
This article reviews the development of Adverse Outcome Pathways and the Mode of Action framework. It then discusses the current application of both these constructs with respect to interpreting high throughput toxicity testing data such as ToxCast. It should provide a brief overview of the state of the science in this field and hopefully will encourage more scientists to contribute to this effort to better inform risk assessment.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
INTEGRATED SYSTEMS TOXICOLOGY DIVISION