Bridging the Gap From In Vitro to In Vivo
BioSeek – EPA ToxCastTM Program
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EPA ToxCastTM Program
EPA ToxCastTM Program
Program to develop a cost-effective approach for efficiently prioritizing the toxicity testing of thousands of chemicals
BioSeek has been a contractor since 2007
Three Phases Phase I – Proof-of-concept
Phase II – Verification / Extension
Phase III – Reduction to Practice
http://www.epa.gov/ncct/toxcast/
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ToxCastTM Program Timeline
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7/23/2012 CONFIDENTIAL4
ToxCastTM Program Details
PhaseNumber of Chemicals
Chemical Criteria
PurposeNumber of
AssaysCost per Chemical
Target
Date
I 320Data Rich
(pesticides)
Signature Development
552 $20k FY08
Ib 15 Nanomaterials Pilot 166 $10K FY09
IIa >300Data Rich Chemicals
Validation >400 ~$20-25k FY09
IIb >100Known Human
ToxicantsExtrapolation >400 ~$20-25k FY09
IIc >300Expanded Structure and Use Diversity
Extension >400 ~$20-25k FY10
IId >12 Nanomaterials PMN >200 ~$15-20K FY09-10
III Thousands Data poorPrediction and Prioritization
>300 ~$15-20k FY11-12
BioSeek ToxCastTM DataNow Posted on EPA’s ACToR Public Database
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ACToR
Aggregated Computational Toxicology Resource
http://actor.epa.gov/
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cAMP Elevation
DNA Alkylation
NFB
Tubulin Inhibition
Mitochondrial Dysfunction
BioMAP® Analysis of ToxCastTM Phase I ChemicalsDiversity of Mechanisms Distinguished
Reference: Houck, K.A., D.J. Dix, R.S. Judson, R.J. Kavlock, J.
Yang and E.L. Berg. 2009. Profiling bioactivity of the ToxCast
chemical library using BioMAP primary human cell systems. J.
Biomol. Screen, 2009, 14:1054-66.
BioMAP Endpoints (BSK) in Predictive SignaturesRat & Rabbit Developmental Toxicity
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Knudsen, T.B., Computational Toxicology and Prenatal Development, presentation for
the EPA's Computational Toxicology Community of Practice (8/25/2011)
Toxicol Sci. 2011, 124:109-27
BioMAP® Analysis of NanomaterialsToxCast Phase II Chemicals
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• Nanomaterials are active and distinguishable by composition
• Reference: Wang, A., E.L. Berg, M. Polokoff, J. Yang; D. Reif, N. Kleinstreuer, S. Marinakos, A.R. Badireddy,
S. Gangwal, C. Matson, M. Wiesner, and K. Houck. Nanomaterial (NM) bioactivity profiling by ToxCast high-
throughput screening (HTS). Society of Toxicology Annual Meeting, March 12, 2012, San Francisco, CA.
Confidential
BioMAP® Profile of Titanium Oxide NanoparticlesSimilarity to Paclitaxel
• Paclitaxel – binds b-tubulin and causes microtubule stabilization
• TiO2 nanoparticles interfere with microtubules (PMID: 18776989)
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BioMAP® Analysis of Failed Pharma Compounds
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Nicole Kleinstreuer, Society of Toxicology Annual Meeting, March 12, 2012, San Francisco, CA
Publications with BioSeek ToxCastTM Data
Sipes NS, Martin MT, Reif DM, Kleinstreuer NC, Judson RS, Singh AV, Chandler KJ, Dix DJ, KavlockRJ, Knudsen TB. Predictive models of prenatal developmental toxicity from ToxCast high-throughput screening data. Toxicol Sci. 2011, 124:109-27
Knudsen, T. B., K. A. Houck, N. Sipes, A. V. Singh, R. Judson, M. T. Martin, A. Weissman, N. Kleinstreuer, H. M. Mortensen, D. Reif, J. R. Rabinowitz, R. W. Setzer, A. M. Richard, D. J. Dix, And R. J. Kavlock. Activity profiles of 309 ToxCast™ chemicals evaluated across 292 biochemical targets. TOXICOLOGY. Elsevier Ireland Limited, Limerick, Ireland, 282(1-2):1-15, (2011).
Kleinstreuer, N. C., R. S. Judson, D. M. Reif, N. S. Sipes, A. V. Singh, K. J. Chandler, R. Dewoskin, D. J. Dix, R. J. Kavlock, And T. B. Knudsen. Environmental Impact on Vascular Development Predicted by High Throughput Screening. ENVIRONMENTAL HEALTH PERSPECTIVES. National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC, Online Edition:1-34, (2011). doi:10.1289/ehp.1103412
Houck, K.A., D.J. Dix, R.S. Judson, R.J. Kavlock, J. Yang and E.L. Berg. 2009. Profiling bioactivity of the ToxCast chemical library using BioMAP primary human cell systems. J. Biomol. Screen, 2009, 14:1054-66.
Judson RS, Houck KA, Kavlock RJ, Knudsen TB, Martin MT, et al. 2009, In Vitro Screening of Environmental Chemicals for Targeted Testing Prioritization: The ToxCast Project. Environ Health Perspect 118(4): doi:10.1289/ehp.0901392
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Presentations with BioSeek ToxCastTM Data
Kleinstreuer, N. C., vEmbryo in silico models:Predicting vascular developmental toxicity, Wiley-
Blackwell Symposium on Computational Embryology: Integration and Modeling of Developmental
Mechanisms, Teratology Society 2012, June 25, 2012, Baltimore, MD.
Wang, A., E.L. Berg, M. Polokoff, J. Yang; D. Reif, N. Kleinstreuer, S. Marinakos, A.R. Badireddy, S.
Gangwal, C. Matson, M. Wiesner, and K. Houck. Nanomaterial (NM) bioactivity profiling by ToxCast
high-throughput screening (HTS). Society of Toxicology Annual Meeting, March 12, 2012, San
Francisco, CA.
Kleinstreuer, N. C., K. Houck, R. Judson, D. Reif, P. Kothiya, M. Martin, T. Knudsen, A. Richard, M.
Polokoff, J. Yang, E.L. Berg, R. Kavlock, and D. Dix. Biological profiling of the ToxCast Phase II
Chemical Library in Primary Human Cell CoCulture Systems. Society of Toxicology Annual Meeting,
March 12, 2012, San Francisco, CA.
Houck, K., Use of primary human cell systems for creating predictive toxicology profiles. SBS Annual
Meeting, 2009, Lille, France.
Houck, K. Evaluation of the ToxCast™ suite of cellular and molecular assay for prediction of in vivo
toxicity. GlobalChem, 2009, Baltimore, MD.
Houck, K., Characteristics of the ToxCast™ In Vitro Datasets from Biochemical and Cellular Assays
(EPA/ORD/NCCT). ToxCast™ Data Analysis Summit, May 14, 2009, RTP, NC.12
Bridging the Gap From In Vitro to In Vivo
Contacts
BioSeek, LLC
310 Utah, Suite 100
South San Francisco, CA 94030
650-416-7600
www.bioseekinc.com
www.BioMAPSystems.com
BioSeek, LLC310 Utah, #100South San Francisco, CA 94080