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ICCVAM Biennial Report 2018-2019

Biennial Progress Report 2018-2019 Interagency Coordinating Committee on the Validation of Alternative Methods
https://ntp.niehs.nih.gov/go/892673

Retrofitting Existing Tox21 HTS Assays with Metabolic Capability

The HTS assays that have been run in the Tox21 testing program to date generally lack the metabolic activity found in living systems, which can potentially increase or decrease the toxicity of chemicals. As a result, HTS results may not accurately reflect in vivo activity. Scientists at EPA, NCATS, and NIEHS are using several approaches to address this problem: adding human or rat liver microsomes into the existing assays, transfecting cells with mRNAs encoding human metabolic enzymes, or using metabolically capable human HepaRG cells. The addition of metabolic capacity to HTS assays is expected to improve characterization of the in vivo activity of chemicals in the Tox21 collection. Current efforts focus on retrofitting three types of assays for which a massive amount of data have already been generated: cellular stress-related assays, endocrine disruption assays, and CYP450 enzyme inhibition assays. The retrofitted assays are being used to screen the Tox21 10K chemical library to identify chemicals that are either bioactivated or detoxified by metabolic activity.

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