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Adverse Outcome Pathways

In our daily lives, we are exposed to many substances used in items such as personal care products and cleaning supplies. Even more substances are used in manufacturing and industrial processes. Ideally, we would have information about the health risks posed by these substances, but events such as the January 2014 Elk River chemical spill in West Virginia remind us that this is not the case. Little or no information was available about the safe exposure limits or health risks associated with the substances released in that spill.

Traditional methods used to gather health information involve treating animals and observing outcomes. However, thousands of substances currently on the market lack full toxicity data, and hundreds of new substances are added to that total every year. Traditional testing methods are too expensive and labor-intensive to fully determine the toxicity of these substances within a reasonable time frame.

There is increasing interest in approaches that gather toxicity data using high-throughput cell- and biochemical-based tests. Each test is designed to assess a specific activity, such as protein binding or receptor activation, for the substance being tested.

Because toxic effects cannot be predicted by any one test, it is important to test a substance using a number of these high-throughput and biochemical tests, and then to evaluate the combined data to predict potential toxic effects. Key to integrating the data generated by this approach is the concept of the "adverse outcome pathway."

Elements of an Adverse Outcome Pathway

Adverse outcome pathways (AOPs) allow us to organize information about biological interactions and toxicity mechanisms into models that describe how exposure to a substance might cause a toxic effect or disease. AOPs are made up of specific elements:

  • A molecular initiating event is an interaction between the toxic substance and an organism, such as binding of the substance to a receptor or protein. This interaction begins the toxicity process.
  • Key events after the molecular initiating event characterize the progression of the toxicity. Early key events can include changes in protein production or molecular signaling that occur in individual cells; later key events can include altered tissue or organ function. The links between key events are described by key event relationships.
  • Adverse outcomes may occur at individual or population levels. An adverse outcome for an individual organism can include disease, impaired development, or impaired reproduction; population adverse outcomes can include changes in population structure or local extinction of a species.

Example elements of an adverse outcome pathway

Using AOPs for Research & Testing

Once an AOP is defined for an adverse outcome, researchers can identify specific cell- or biochemical-based tests that represent the molecular initiating events, key events, and key event relationships for that pathway. A set of tests covering many or all of the steps in the AOP can then be used to screen substances in an efficient, cost-effective manner for those most or least likely to cause an identified adverse outcome. This approach also supports animal welfare goals by minimizing or eliminating animal use.

AOPs clarify the events and mechanisms involved in toxicity, which can help with classification and prioritization of substances for further or future testing. For example, substances lacking the properties needed to cause a molecular initiating event would be unlikely to result in an adverse outcome, so testing of those substances might not be necessary or could at least be postponed. AOPs can be linked together by common key events to form AOP networks, which are helpful in understanding more complex toxicity endpoints such as cancer or developmental defects.

The process of defining AOPs and AOP networks can also help researchers and test method developers identify areas needing improved characterization. Knowledge gaps that prevent an AOP from being fully defined indicate the need for more basic research; key events that are not represented by any suitable tests suggest future areas for test method development.

AOP Development is an International Effort

The Organisation for Economic Co-operation and Development (OECD) supports international standardization of testing methods to assess substance toxicity. In this role, the OECD is actively supporting AOP development. OECD maintains a wiki-based interface for developing descriptions of AOPs and issues formal descriptions of well-defined AOPs.

OECD scientists joined colleagues from U.S. government agencies, industry, and academia at a September 2014 workshop organized by NICEATM to discuss the status of AOP development efforts and how AOPs could be applied to regulatory testing. The workshop featured demonstrations of the OECD wiki and of Effectopedia, a data collection and collaboration tool for developing AOPs. A workshop report (Kleinstreuer et al. 2016) was published in 2016.

NICEATM's Integrated Chemical Environment will soon become another tool for applying AOPs to assess substance toxicity, with resources to link tests and their endpoints to AOPs planned for release in fall 2018.