Building Shared Experience to Advance Practical Application of Pathway-Based Toxicology: Liver Toxicity Mode-of-Action

Abstract

Summary A workshop sponsored by the Human Toxicology Project Consortium (HTPC), “Building Shared Experience to Advance Practical Application of Pathway-Based Toxicology: Liver Toxicity Mode-of-Action” brought together experts from a wide range of perspectives to inform the process of pathway development and to advance two prototype pathways initially developed by the European Commission Joint Research Center (JRC): liver-specific fibrosis and steatosis. The first half of the workshop focused on the theory and practice of pathway development; the second on liver disease and the two prototype pathways. Participants agreed pathway development is extremely useful for organizing information and found that focusing the theoretical discussion on a specific AOP is helpful. It is important to include several perspectives during pathway development, including information specialists, pathologists, human health and environmental risk assessors, and chemical and product manufacturers, to ensure the biology is well captured and end use is considered.

Pathway-based toxicity: history, current approaches and liver fibrosis and steatosis as prototypes

“…the 2012 workshop was organized by SeURAt-1 (Safety evaluation Ultimately Replacing Animal testing) Mode-of-Action Working Group and COACH, the project coordination activity. the discussion of this workshop and presentation of the two liver-specific pathways in Section 2 below sets the stage for the 2013 workshop report "Building Shared experience to Advance Practical Application of Pathway-Based toxicology: liver toxicity Mode-of-Action," published in the same issue of this journal (Willett et al, 2014).…”

“…this review provides an overview of the history of pathway development, use of example AOPs, and several ongoing activities associated with pathway development. two prototype pathways in liver toxicity are presented in more detail that are being developed as part of the SeURAt project and that were the subject of a 2013 workshop and report published elsewhere in this journal (Willett, et al, 2014). Pathway activities are converging on a set of definitions and principles to demonstrate confidence -principles based on Bradford-Hill criteria as first applied to MoA frameworks (Boobis et al 2006(Boobis et al , 2008Meek et al, 2014) -that are being formalized in guidance developed by the OeCD (2013) and by others 10 in an effort to globalize and harmonize pathway development.…”

Adverse Outcome Pathways--Organizing Toxicological Information to Improve Decision Making

“…An example for the latter would be the AOP for protein alkylation leading to liver fibrosis that folds formation of reactive oxygen species and release of cytokines and chemokines in response to hepatic cell death into the KER that leads to the activation of Kupffer cells (Fig. 2B) (Landesmann et al, 2012;Willett et al, 2014). KERs should be described to connect a specific pair of KEs independent of the AOP such that they can be reused where possible.…”

Stem cell–derived models to improve mechanistic understanding and prediction of human drug‐induced liver injury

“…The recently developed concepts of adverse outcome pathways and points of departure in the field of systems toxicology should also be considered in the context of phenotyping the response to chemical exposure of hepatocyte‐like cells that express relevant proteins and pathways. To this end, cells expressing genetic reporters for key adaptive pathways such as nuclear erythroid 2 p45‐related factor 2, pregnane X receptor, and nuclear factor kappa B will be useful as a means for understanding the earliest events in the biological response to a drug .…”