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The IMI eTOX Project Efforts to Develop In Silico Tools to Predict In Vivo Toxicity Thomas Steger-Hartmann Investigational Toxicology Bayer Healthcare Müllerstraße 178 D-13353 Berlin, Germany thomas.steger-hartmann@bayer.com Website: etoxproject.eu Background The eTOX project was proposed under the first call of the Innovative Medicines Initiative (IMI; imi.europa.eu) under the title: ‘Integrating bioinformatics and chemoinformatics approaches for the development of expert systems allowing the in silico prediction of toxicities’. IMI is Europe’s largest public-private initiative aiming to speed up the development of better and safer medicines for patients. IMI supports collaborative research projects and builds networks of industrial and academic experts in order to boost pharmaceutical innovation in Europe. IMI is a joint undertaking between the European Union and the pharmaceutical industry association EFPIA. IMI supports research projects in the areas of safety and efficacy, knowledge management and education and training. Under the pillar ‘safety’, eTOX was proposed because the need for improved toxicological databases and prediction tools was identified a bottleneck during early drug development. During these phases, in vivo studies are often unveiling side effects that presently cannot be predicted from the chemistry. However, mechanisms such as cross-target activation or inhibition, or straight chemistry-linked toxicities are amenable to prediction. Early in silico prediction of such cases would increase the quality of drug candidates and ensure a lower attrition rate before and during the first GLP animal studies. This could also reduce the number of animals (<strong>3R</strong>s) used in preclinical studies necessary to select drug. Therefore, the eTOX project aims to build a toxicology database relevant to pharmaceutical development and to elaborate innovative methodological strategies and novel software tools to better predict the toxicological profiles of new chemical entities in early stages of the drug development pipeline based on existing in vivo study results. This is planned 226 AXLR8-2 WORKSHOP REPORT Progress Report 2011 & AXLR8-2 Workshop Report
to be achieved by sharing and jointly exploiting legacy reports of toxicological studies from participating pharmaceutical companies. The project coordinates the efforts of specialists from industry and academia in the wide scope of disciplines that are required for reliable modelling of the complex relationships existing between molecular and in vitro information, and the in vivo toxicity outcomes of drugs. eTOX began on 1 January 2010. The project is carried out by a consortium comprising 25 organisations (13 pharmaceutical companies, 7 academic groups and 5 SMEs) with complementary expertise. With €5 million from the European Union, the total budget of the project is €13 million, which will fund this initiative during five years. Objectives The key objectives of eTOX are the collection of toxicological data from proprietary (EFPIA) and public sources, the construction of a common toxicological database from which data can be mined and extracted to build expert system or predictive models for in vivo toxicity. The integration of these different objectives into a strategy is depicted in Figure 1. The proposed strategy includes the integration of innovative approaches in the following areas: • Data sharing of previously inaccessible high-quality data from toxicity legacy reports of the participating pharmaceutical companies • Database building and management, including procedures and tools for protecting sensitive data • Ontologies and text mining techniques, with the purpose of facilitating knowledge extraction from and efficient usage of legacy preclinical reports and biomedical literature • Physico-chemical and structurebased approaches for the molecular description of the studied compounds, as well as of their interactions with the anti-targets responsible for secondary pharmacologies • Prediction of DMPK (drug metabolism and pharmacokinetic) properties and incorporation of physiologically-based pharmacokinetic (PBPK) predictions • Bioinformatics and systems biology approaches in order to cope with the complex biological mechanisms that govern in vivo toxicological events • Statistical modelling tools to derive QSAR models. The expectation is that during the last phase of the project, the partners will have a system in their hands, which will allow them to compare a new drug candidate or chemical entity with toxicological results for structurally related compounds (‘readacross’) and to predict its potential in vivo toxicity on the basis of expert systems and QSAR models. The legal framework has been developed which prepares the access of the successful system to the broader public after the end of the project. Deliverables The eTOX has a series of ambitious AXLR8-2 WORKSHOP REPORT Progress Report 2011 & AXLR8-2 Workshop Report 227
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ALTERNATIVE TESTING STRATEGIES PROG
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ALTERNATIVE TESTING STRATEGIES PROG
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TABLE OF CONTENTS 1. 2. EXECUTIVE S
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Update on EPA’s ToxCast Programme
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challenges, needs, and priorities f
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1INTRODUCTION It is the aim of the
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and progress of these multidiscipli
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Table 2. Members of the AXLR8 Scien
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• OECD Joint Meeting Special Sess
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ACuteTox Optimisation & Pre-Validat
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to robotic screening platforms; and
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ased on functional parameters inclu
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Table 1. Outliers identified by com
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showed that for some compounds the
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Computer-based prediction of metabo
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three reference compounds revealed
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a calibration curve constructed. Th
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cell lines) or 48 hours (A704 cells
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multivariate CART results did not c
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probability) ~50% of the substances
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Publications 2010-11 Hoffmann S, Ki
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Per Artursson Uppsala University Up
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their genotoxic and carcinogenic po
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Table 1. Overview of carcinoGENOMIC
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D12.23 3 monthly Project M42 √ Bo
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annual carcinoGENOMICS meeting in N
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M3.5 Decision of most M40 Postponed
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M3.4 Identification of most suitabl
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WP1 with input from other partners
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Partners Project Co-ordinator Jos K
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combine knowledge of critical proce
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defined and published in the form o
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WP6 is devoted to the setup of a so
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Partners Co-ordinator Bart van der
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obustness, comparing results obtain
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6. Candéias S, Pons B, Viau M, et
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ESNATS Embryonic Stem Cell-Based No
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Table 1. List of deliverables due i
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D3.3.1 Toxicity gene expression sig
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Table 2. List of milestones due in
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Table 3. Test systems corresponding
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Publications 2010-11 1. Peters SJ,
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Marcel Leist Universität Konstanz
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The most significant achievements o
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Figure 3. The Sensor Dish Reader (S
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LIINTOP Optimisation of Liver & Int
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cells express most of the functions
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Figure 3. Scheme of lentivirus gene
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Figure 5. Co-culture set-up. Functi
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Figure 9. Phalloidin-TRITC staining
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Table 1. Values are expressed as pe
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formed with mannitol, atenolol, pro
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Figure 14. Comparison of Digoxin an
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By using the new technology of HCA
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Figure 17. (Left panel) Phalloidin-
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limited amount of data could be pro
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André Guillouzo Institut National
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Objectives The overall aim of this
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Table 2: Milestones achieved in 201
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detected iron (µg/ml) 80 70 6
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in the following order: uncoated ma
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analysis of leukocytes, expression
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2011 the automated protocols will b
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OpenTox Promotion, Development, Acc
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Results The OpenTox Framework The O
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Figure 1. ToxPredict: OpenTox Appli
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scientifically sound manner, so as
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Figure 4. Creating a QPRF report wi
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Figure 7. MaxTox model-building app
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Figure 8. Bioclipse interaction wit
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and model predictions, which they m
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Publications 2010-11 1. Hardy B, Do
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In vitro toxicology using isolated
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(2C-Glo-CYP2C, 3A-Glo-CYP3A) while
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neuronal models 2D (primary culture
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10 and 14 days. The liver-specific
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Frédéric Bois Institut National d
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Figure 1. The Sens-it-iv sphere. 2.
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Figure 2. The updated modular struc
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Technology Module The aim of techno
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Table 1: The final compound list. R
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Table 2. The Sens-it-iv Toolbox. N
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Figure 4. A gene profile for identi
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Figure 7. In vitro T cell priming a
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sessions at congress and meetings (
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7. Gibbs S, van Montfrans C, Kroeze
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Page 186 and 187: Workshop proposals Concepts of data
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Page 198 and 199: Workshop participants were divided
Page 200 and 201: 08.45 - 09.15 ACuteTox Annette Kopp
Page 202 and 203: 3.3 Workshop Presentations 202
Page 204 and 205: Table 1. A sampling of current toxi
Page 206 and 207: Table 2. EPA activities: a timeline
Page 208 and 209: Why is a Consortium Needed While th
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Page 218 and 219: The Virtual Liver Spatial-Temporal
Page 220 and 221: A B C D E Figure 2. Tissue reconstr
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Page 228 and 229: deliverables, which can only be ach
Page 230 and 231: A series of publications related to
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Page 234 and 235: Phase I of ToxCast involved the eva
Page 236 and 237: Endpoint Brief Description of Bioac
Page 238 and 239: includes approximately 150 chemical
Page 240 and 241: information. For each slice, distan
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Page 244 and 245: Embryonic Stem Cell Approaches Towa
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Page 254 and 255: functions, establish relationships
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Page 260 and 261: learning algorithm called Support V
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Page 266 and 267: References Basketter DA, Evans P, F
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Contact Dermatitis. 2005; 53. 16. S
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the development of in vitro assays.
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Although the mechanisms underlying
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skin sensitisation, it will aid in
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Figure 3. Scatter plot of robust li
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7. De Smedt A, Van Den Heuvel R, Va
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The OECD Adverse Outcome Pathway Ap
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the AOP can be used in qualitative
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Table 1. Summary of the experimenta
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the significance of type 1 versus t
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plus the key events that occur acro
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Dimitrov, S.D., Low, L.K., Patlewic
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[Supporting information and databas
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Figure 1. Strategic R&D of chemical
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The Bhas 42 system can sensitively
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Table 1. Established reporter cell
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elated genes (Hand1, ADAM19, Cmyal,
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Publications Carcinogenicity Tanaka
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Case Study Approaches for Implement
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assay results together with CSBP mo
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them to support multi-day testing i
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CSBP models for both receptor-media
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Hamner Presentations in 2011 • Ch
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human health risk assessment. Risk
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There is a significant scientific c
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phototoxicity and eye irritation, f
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allergy risk assessment rather than
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‘toolbox’ of non-animal methods
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332 3.4 Breakout Group Reports
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Figure 1. An illustration of the me
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methods, and the generally poor und
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3.4.3. Break-Out Group 2: Reproduct
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- Deep-sequencing of birth defect p
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Figure 2. Specific stages of the ma
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3.4.4 Break-Out Group 3: Skin Sensi
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for further progress. Better tools
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sure doses is not straightforward.
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3.5 AXLR8 Scientific Panel Recommen
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Workshop participants underlined th
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could be co-ordinated in a focused
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focusing on scientific excellence a
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Directory of Projects & Co-ordinato
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Glossary of Terms 2D/3D 3Rs CARDAM/
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