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

Taylor Rycroft

doi:10.14573/altex.1906201

Abstract

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, Key Events, or Adverse Outcomes; 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 Molecular Initiating Events, Key Events, or Adverse Outcomes; and identify AOPs that contain the Molecular Initiating Events, Key Events, or Adverse Outcomes 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 https://igbb.github.io/AOPERA_HTML. 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.

Highlights

Adverse outcome pathways (AOPs) describe the cascade of physiological events that link toxicant exposure to a downstream adverse health outcome (Ankley et al, 2010)
In order to aid with the process, we have developed the Adverse Outcome Pathway Exploratory Research Assistant (AOPERA), an online tool implementing the described process
The practitioner must confirm whether their chemical is characterized or uncharacterized. − Level 0: The practitioner does not know anything about the toxicity of their chemical. − Level 1: The practitioner knows that their chemical causes an adverse outcomes (AOs) but does not know the upstream molecular initiating events (MIEs) or key events (KEs). − Level 2: The practitioner knows that their chemical causes a KE but does not know upstream or downstream KEs or the MIE and AO. − Level 3: The practitioner knows their chemical causes a MIE but does not know the downstream KEs or AO

Summary

Introduction

Adverse outcome pathways (AOPs) describe the cascade of physiological events that link toxicant exposure to a downstream adverse health outcome (Ankley et al, 2010). By mapping connected key events (KEs) or changes in biological state that are measurable and essential to the progression of a defined biological disturbance, AOPs offer a novel alternative for mechanistically assessing a wide array of substances with limited toxicity data (Vinken et al, 2013; Villeneuve et al, 2014). AOPs are increasingly gaining support in toxicology communities of practice because they offer more information than a traditional lethal concentration (e.g., LC50) value and they help expand the hazard profiles of chemicals to a broader set of acute (e.g., skin sensitization) and chronic outcomes (e.g., developmental defects). AOPs are being assessed for their potential to inform regulatory decisions, such as setting occupational exposure limits or reference doses (Perkins et al, 2015; Wittwehr et al, 2017).

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