Pathway-Based Toxicity: History, Current Approaches and Liver Fibrosis and Steatosis as Prototypes

The Human Toxicology Project Consortium (HTPC) was created to accelerate implementation of the science and policies required to achieve a pathway-based foundation for toxicology as articulated in the 2007 National Research Council report, Toxicity Testing in the 21st Century: a Vision and a Strategy. The HTPC held a workshop, “Building Shared Experience to Advance Practical Application of Pathway-Based Toxicology: Liver Toxicity Mode-of-Action,” in January, 2013, in Baltimore, MD, to further the science of pathway-based approaches to liver toxicity. This review was initiated as a thought-starter for this workshop and has since been updated to include insights from the workshop and other activities occurring in 2013. The report of the workshop has been published elsewhere in this journal (Willett, 2014).JRC.I.5-Systems Toxicolog

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

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

Challenges in integrating skin sensitization data for assessment of difficult to test substances

Difficult to test substances, such as poorly soluble, mildly irritating, or Unknown or Variable Composition Complex reaction products or Biological Materials (UVCBs), producing weak or borderline results in the Local Lymph Node Assay (LLNA), face additional challenges in KE-based in in vitro assays that ultimately necessitates data integration in a weight of evidence (WOE) approach to inform skin sensitization potential. Here we present several case studies using a WOE approach with difficult to test substances and highlight the utility of Toxicological Prioritization Index (ToxPi) as a comparative data visualization and integration tool to compare biological activity as it relates to skin sensitization. The four case study test substances represent two poorly soluble substances, tetrakis (2-ethylbutyl) orthosilicate and decyl palmitate, and two UVCB substances, alkylated anisole and hydrazinecarboximidamide, 2-[(2-hydroxyphenyl)methylene]-, reaction products with 2 undecanone. Data from in vivo and in vitro assays representing multiple key events within the skin sensitization adverse outcome pathway (protein binding, keratinocyte/dendritic cell activation and t-cell proliferation) were gathered from publicly available sources or specifically generated. Incorporating the data on our case study test substances as well as on chemicals of a known sensitization class (sensitizer, irritating non-sensitizer, and non-sensitizer) into ToxPi revealed biological activity profiles which could be grouped using unsupervised hierarchical clustering to inform skin sensitization potential. Using this method, the biological activity profiles for three of the case study test substances concluded to have a lack of skin sensitization potential by traditional WOE were most consistent with non-sensitizing chemicals, whereas the prediction was not as definitive for a positive case study test substance. Visualizing the WOE using bioactivity profiles can provide further support for individual chemical WOE predictions in certain circumstances but is unlikely to replace WOE as a stand-alone prediction due to limitations of the method such as the impact of missing data points

Uncertainty Visualization Tool

The purpose of the Uncertainty Visualization Tool is to provide an easy-to-use graphical representation of the uncertainties associated with all components of a risk assessment, both at the level of each of the parameters that go into a risk estimate as well as the final risk estimate itself. Each section, or module, of the tool contains either input fields for the user to add information or decision points for the user to make. These data are then plotted on a graph that represents a range of values as well as individual case points so users can quickly compare different cases and visualize uncertainty. This tool was developed as a webtool and was last updated on May 1, 2018. In February 2022, the webtool was deactivated and its source code, example database, and additional documentation have been archived here

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

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