C6 – Toxicogenomic Approaches to Support Read-Across

Description

The proposed project will combine existing work processes in chemical read-across with toxicogenomics data to define functional approaches that support read-across.  Specifically, we will:

– develop case studies for three chemical classes, one that affects development, one that affects male fertility, and one affecting liver function, showing the ability of gene expression data to identify comparable biological activity between class members, as well as to identify the limits in similarity beyond which biological activity is not equivalent;

• develop pragmatic guidance for the use of connectivity mapping to demonstrate biological equivalency for structurally related compounds, to include
• determine the minimal number of cell types, sampling times and concentrations needed to provide reliable toxicogenomics data to support read-across;
• determine the extent of gene expression overlap needed to ensure toxicologic equivalency;
• recommended approaches and software tools for querying and filtering large connectivity map databases to identify agents with similar biological activity
• check the validity of the toxicogenomic data for a subset of the case study chemicals using an alternative high-throughput data source such as ToxCast.

We will also convene a small working meeting, with European regulators (and/or European scientists familiar with read-across under REACH), to critique our case studies.