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