Summary of BioSeek's work for the EPA's ToxCast (TM) program. BioSeek has been a contractor since 2007 for the EPA, using the company's human cell-based BioMAP(R) systems platform.
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BioSeek EPA ToxCast Program
1. BioSeek – EPA ToxCastTM Program
Bridging the Gap From In Vitro to In Vivo
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2. 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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4. ToxCastTM Program Details
Number of Chemical Number of Cost per Target
Phase Purpose
Chemicals Criteria Assays Chemical Date
Data Rich Signature
I 320 552 $20k FY08
(pesticides) Development
Ib 15 Nanomaterials Pilot 166 $10K FY09
Data Rich
IIa >300 Validation >400 ~$20-25k FY09
Chemicals
Known Human
IIb >100 Extrapolation >400 ~$20-25k FY09
Toxicants
Expanded Structure
IIc >300 Extension >400 ~$20-25k FY10
and Use Diversity
IId >12 Nanomaterials PMN >200 ~$15-20K FY09-10
Prediction and
III Thousands Data poor >300 ~$15-20k FY11-12
Prioritization
7/23/2012 CONFIDENTIAL
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5. BioSeek ToxCastTM Data
Now Posted on EPA’s ACToR Public Database
http://actor.epa.gov/
ACToR
Aggregated Computational Toxicology Resource
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6. BioMAP® Analysis of ToxCastTM Phase I Chemicals
Diversity of Mechanisms Distinguished
NFB
cAMP Elevation
DNA Alkylation Mitochondrial Dysfunction
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 Tubulin Inhibition
chemical library using BioMAP primary human cell systems. J.
Biomol. Screen, 2009, 14:1054-66.
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7. BioMAP Endpoints (BSK) in Predictive Signatures
Rat & Rabbit Developmental Toxicity
Knudsen, T.B., Computational Toxicology and Prenatal Development, presentation for
the EPA's Computational Toxicology Community of Practice (8/25/2011)
7 Toxicol Sci. 2011, 124:109-27
8. BioMAP® Analysis of Nanomaterials
ToxCast Phase II Chemicals
• 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.
8 Confidential
9. BioMAP® Profile of Titanium Oxide Nanoparticles
Similarity to Paclitaxel
• Paclitaxel – binds b-tubulin and causes microtubule stabilization
• TiO2 nanoparticles interfere with microtubules (PMID: 18776989)
9 Confidential
10. BioMAP® Analysis of Failed Pharma Compounds
Nicole Kleinstreuer, Society of Toxicology Annual Meeting, March 12,
2012, San Francisco, CA
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11. Publications with BioSeek ToxCastTM Data
Sipes NS, Martin MT, Reif DM, Kleinstreuer NC, Judson RS, Singh AV, Chandler KJ, Dix DJ, Kavlock
RJ, 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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12. 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.
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13. Contacts
BioSeek, LLC
310 Utah, Suite 100
South San Francisco, CA 94030
650-416-7600
www.bioseekinc.com
www.BioMAPSystems.com
Bridging the Gap From In Vitro to In Vivo
BioSeek, LLC
310 Utah, #100
South San Francisco, CA 94080