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• Monitoring the progress of DG R&Ifunded health research projects and publication of annual progress reports. • Establishment of a Scientific Panel with experts from the EU corporate, governmental and academic sectors, and leading international scientists, to provide an external expert perspective on future research needs and priorities. • Organisation of annual scientific workshops to bring together the leaders of EU-funded research projects, members of the AXLR8 Scientific Panel and other selected experts to discuss the progress of currently funded projects, identify knowledge gaps, and recommend strategic priorities for future research in Europe. • Promotion of scientific, stakeholder and public awareness and communication on the outcome of AXLR8 workshops and on ‘21st century’ approaches to toxicology and risk assessment. • Promotion of active engagement by regulators to ensure that authorities are kept informed about progress at the research and development level and that regulatory considerations are understood and fed back to the scientists developing <strong>3R</strong>s methods in order to encourage and lay the groundwork for more efficient acceptance of alternative approaches in the future. AXLR8 Scientific Panel A cornerstone of the AXLR8 project is its Scientific Panel, which is a platform for information exchange and critical discourse with co-ordinators of EU DG R&I-funded FP6/7 health projects and independent experts in toxicology (in vitro, in silico and mammalian), systems biology and bioinformatics and risk assessment. The AXLR8 Scientific Panel meets at the annual AXLR8 workshops and supports the AXLR8 Consortium in monitoring research progress and in the identification of future needs and priorities. The current membership of the AXLR8 Scientific Panel is listed in Table 2. AXLR8 Workshops The first AXLR8 workshop (AXLR8-1) was held in Potsdam, Germany, from 31 May to 2 June 2010. Participation was limited to the co-ordinators of FP6/7-funded health projects, representatives of national <strong>3R</strong>s centres in EU Member States and Japan, leading US scientists working to advance the 21st century toxicology approach, representatives from the European Commission DGs R&I and Joint Research Centre, and members of the AXLR8 Scientific Panel and the Consortium. The second AXLR8 workshop (AXLR8-2) was held in Berlin, Germany from 22-25 May 2011 with a focus on developing a ‘roadmap to innovative toxicity testing’. Among the more than 50 invited participants were representatives of projects funded by the FP6/7 health and environment programmes, the heads of 16 INTRODUCTION Progress Report 2011 & AXLR8-2 Workshop Report
Table 2. Members of the AXLR8 Scientific Panel. European Experts Name Institution Sector Country Nathalie Alépée L’Oréal Cosmetics FR Patric Amcoff OECD Intergovernmental SE Jürgen Borlak Fraunhofer Institute Research institute DE Steffen Ernst Pharmaceuticals SE Julia Fentem Unilever Consumer products UK Ellen Fritsche University of Duesseldorf Academic Joanna Jaworska Procter & Gamble Consumer products BE Robert Landsiedel BASF Chemicals DE Maurice Whelan European Governmental IT Commission DE International Experts Name Institution Sector Country Harvey Clewell The Hamner Institutes Research institute US for Health Sciences Robert Kavlock Environmental Governmental US Protection Agency Hajime Kojima National Institute of Health Sciences Governmental JP Representatives of EU-Funded Projects Name Institution Project Country Manuel Carrondo Instituto de Biologia VITROCELLOMICS PT Experimental e Tecnologica Barry Hardy Douglas Connect OpenTox, ToxBank CH Jürgen Hescheler Universität Köln ESNATS, DETECTIVE DE Jos Kleinjans Maastricht University carcinoGENOMICS, NL DETECTIVE Carl-Fredrik Mandenius Linköping University INVITROHEART, SE VITROCELLOMICS Michael Schwarz Universität Tübingen ReProTect, COACH DE Flavia Zucco Consiglio Nazionale delle Richerche LIINTOP IT INTRODUCTION Progress Report 2011 & AXLR8-2 Workshop Report 17
Page 1 and 2: ALTERNATIVE TESTING STRATEGIES PROG
Page 3 and 4: ALTERNATIVE TESTING STRATEGIES PROG
Page 5 and 6: TABLE OF CONTENTS 1. 2. EXECUTIVE S
Page 7: Update on EPA’s ToxCast Programme
Page 10 and 11: challenges, needs, and priorities f
Page 13 and 14: 1INTRODUCTION It is the aim of the
Page 15: and progress of these multidiscipli
Page 19: • OECD Joint Meeting Special Sess
Page 22 and 23: ACuteTox Optimisation & Pre-Validat
Page 24 and 25: to robotic screening platforms; and
Page 26 and 27: ased on functional parameters inclu
Page 28 and 29: Table 1. Outliers identified by com
Page 30 and 31: showed that for some compounds the
Page 32 and 33: Computer-based prediction of metabo
Page 34 and 35: three reference compounds revealed
Page 36 and 37: a calibration curve constructed. Th
Page 38 and 39: cell lines) or 48 hours (A704 cells
Page 40 and 41: multivariate CART results did not c
Page 42 and 43: probability) ~50% of the substances
Page 44 and 45: Publications 2010-11 Hoffmann S, Ki
Page 46 and 47: Per Artursson Uppsala University Up
Page 48 and 49: their genotoxic and carcinogenic po
Page 50 and 51: Table 1. Overview of carcinoGENOMIC
Page 52 and 53: D12.23 3 monthly Project M42 √ Bo
Page 54 and 55: annual carcinoGENOMICS meeting in N
Page 56 and 57: M3.5 Decision of most M40 Postponed
Page 58 and 59: M3.4 Identification of most suitabl
Page 60 and 61: WP1 with input from other partners
Page 62 and 63: Partners Project Co-ordinator Jos K
Page 64 and 65: 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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vitro assessment of allergens. Eds:
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S.F. Martin Universitätsklinikum F
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idging the gap to human volunteer s
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combinations of transcriptomics, me
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normal animals who usually exhibit
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Workshop proposals Concepts of data
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VITROCELLOMICS Reducing Animal Expe
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esulting of the project was the abi
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Figure 3. Four-compartment artifici
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embryonic stem cells differentiatin
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196 3AXLR8-2 WORKSHOP REPORT
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Workshop participants were divided
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08.45 - 09.15 ACuteTox Annette Kopp
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3.3 Workshop Presentations 202
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Table 1. A sampling of current toxi
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Table 2. EPA activities: a timeline
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Why is a Consortium Needed While th
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the development of new more relevan
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in particular for fundamental resea
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compared to controls. Most interest
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epidermis to known allergens and UV
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The Virtual Liver Spatial-Temporal
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A B C D E Figure 2. Tissue reconstr
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Figure 4. Mechanisms of how hepatoc
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in rat liver in vivo (Figure 5A). H
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The IMI eTOX Project Efforts to Dev
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deliverables, which can only be ach
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A series of publications related to
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Update on EPA’s ToxCast Programme
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Phase I of ToxCast involved the eva
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Endpoint Brief Description of Bioac
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includes approximately 150 chemical
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information. For each slice, distan
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Judson RS, Houck KA, Kavlock RJ, et
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Embryonic Stem Cell Approaches Towa
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perhaps be tested efficiently in al
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compared gene and protein expressio
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cost and time, allowing more chemic
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Toxicol Appl Pharmacol. 2011; 251,
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functions, establish relationships
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cellular behaviours are captured fr
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assay. PLoS One. 2011; 6, e18540. 7
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learning algorithm called Support V
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Compound Potency Vehicle Concentrat
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mediated inhibition of RXR function
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References Basketter DA, Evans P, F
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When considering consumer exposure,
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in the induction of skin sensitisat
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has reacted, when the peptide deple
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of presentations and discussions, t
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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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362
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