AOPERA: A proposed methodology and inventory of effective tools to link chemicals to adverse outcome pathways

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Taylor E. Rycroft, Christy M. Foran, Adam Thrash, Jeffrey C. Cegan, Robert Zollinger, Igor Linkov, Edward J. Perkins, Natàlia Garcia-Reyero
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New approaches, like the adverse outcome pathway (AOP) framework, have been developed to describe how chem­icals cause toxicity by linking in vitro assays to adverse health outcomes. However, approaches, tools and resources for development of AOPs have not been well described. Here we review information resources for AOP development and define a streamlined process for linking a chemical to an existing AOP. We propose a four-step process to facilitate AOP development: link the uncharacterized chemical directly to molecular initiating events (MIEs), key events (KEs), or adverse outcomes (AOs); identify analogs with toxicological information for the uncharacterized chemical; link the char­acterized chemical (initial chemical if characterized, a characterized analog if initial chemical is not) to MIEs, KEs or AOs; and identify AOPs that contain the MIEs, KEs or AOs that were found in Steps 1 and 3. The process and library of informational resources proposed and tested here served as the foundation for an informational online tool (AOPERA) that helps practitioners identify their current-state knowledge gaps, navigate the four-step process, and connect to rel­evant resources. AOPERA can be found at Additionally, we anticipate that by simplifying and standardizing the process of linking a chemical to a known AOP, we will lower the barrier to entry for this objective and increase its accessibility to new practitioners. In turn, this may increase the demand for new or improved AOPs to which practitioners can link chemicals, thereby contributing to the expansion of the library of known AOPs.

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Rycroft, T. E., Foran, C. M., Thrash, A., Cegan, J. C., Zollinger, R., Linkov, I., Perkins, E. J. and Garcia-Reyero, N. (2020) “AOPERA: A proposed methodology and inventory of effective tools to link chemicals to adverse outcome pathways”, ALTEX - Alternatives to animal experimentation, 37(1), pp. 64–74. doi: 10.14573/altex.1906201.

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