ToxCast and Tox21: High Throughput Screening for Hazard & Risk ...

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Biochemical Assays • Protein families ToxCast HTS Assays ~500 Total Endpoints Cellular Assays • Cell lines – HepG2 human hepatoblastoma – GPCR – A549 human lung carcinoma – HEK 293 human embryonic y kidney y – NR – Kinase • Primary cells – Human endothelial cells – Phosphatase – Human monocytes – Protease – HHuman kkeratinocytes ti t – Other enzyme – Ion channel – Transporter – Human fibroblasts – Human proximal tubule kidney cells – Human small airway epithelial cells – Rat hepatocytes p y – Mouse embryonic stem cells (Sid Hunter) • Assay formats – Radioligand binding – Enzyme activity – Co-activator recruitment Primarily Human / Rat EException: ti ZZebrafish b fi h ddevelopment l t (St (Stephanie h i Padilla) P dill ) Office of Research and Development Computational Toxicology Research Program • Biotransformation competent cells – Primary rat hepatocytes – Primary human hepatocytes • Assay formats – Cytotoxicity – Reporter gene – Gene expression 13 – Biomarker production – High-content imaging for cellular phenotype
Assays Chemicals Office of Research and Development Computational Toxicology Research Program The ToxCast In Vitro Data Set Many hits – median value=50 Fewer in cell-free HTS (Novascreen, red) Many hits are at or near top of tested concentration range A few are in nanomolar range 14
Page 1 and 2: ToxCast and Tox21: High Throughput
Page 3 and 4: Exposure p Grand Challenge for Comp
Page 5 and 6: 4 Robotic Platform Pathway Office o
Page 7 and 8: HTS iin TToxicology i l Test priori
Page 9 and 10: GGoals l of f TToxCast C t and dT T
Page 11 and 12: Comparison p of Volumes for Screeni
Page 13: ToxCast Phase I ToxCast Phase I and
Page 17 and 18: micals Chem Digitizing Legacy in Vi
Page 19 and 20: ToxCast: Multiple Assays and Techno
Page 21 and 22: No Pathology Proliferative Lesions
Page 23 and 24: Office of Research and Development
Page 25 and 26: ToxPi: Prioritizing Chemicals for P
Page 27 and 28: Expanding the ToxPi Approach for Pr
Page 29 and 30: Future ToxPi (Toxicological Priorit
Page 31 and 32: Systems Approaches to Modeling Toxi
Page 33 and 34: Office of Research and Development

ToxCast and Tox21: High Throughput Screening for Hazard & Risk ...

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