Identifying Compounds with Genotoxicity Potential Using Tox21 High Throughput Screening Assays

Genotoxicity is a critical component of a comprehensive toxicological profile. The Tox21 Program used five quantitative high throughput screening (qHTS) assays measuring some aspect of DNA damage/repair to provide information on the genotoxic potential of over 10,000 compounds. Included were assays detecting activation of p53, increases in the DNA repair protein ATAD5, phosphorylation of H2AX, and enhanced cytotoxicity in DT40 cells deficient in DNA repair proteins REV3 or KU70/RAD54. Each assay measures a distinct component of the DNA damage response signaling network; >70% of active compounds were detected in only one of the five assays. When qHTS results were compared to results from three standard genotoxicity assays (bacterial mutation, in vitro chromosomal aberration, and in vivo micronucleus), a maximum of 40% of known, direct-acting genotoxicants were active in one or more of the qHTS genotoxicity assays, indicating low sensitivity. This suggests that these qHTS assays cannot in their current form...