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Table 1. Overview of funding for ‘alternative testing strategies’. Project name FP Total awarded grant (€) From To Predictomics 6 2,259,754 2004 2007 CONAM 6 150,000 2004 2007 ReProTect 6 9,100,000 2005 2009 Sens-it-iv 6 10,999,700 2005 2010 ACuteTox 6 9,000,000 2005 2009 EXERA 6 2,173,492 2005 2010 TOXDROP 6 1,615,888 2005 2006 carcinoGENOMICS 6 10,440,000 2006 2011 VITROCELLOMICS 6 2,940,000 2006 2009 EUPRIM-NET 6 4,800,000 2006 2010 MEMTRANS 6 1,900,000 2006 2009 INVITROHEARTEART 6 2,701,611 2007 2009 LIINTOP 6 2,933,291 2007 2009 ARTEMIS 6 1,984,000 2007 2010 COMICS 6 2,189,385 2007 2010 SCARLET 6 112,840 2007 2008 ForInViTox 6 288,850 2007 2009 InViToPharma 6 578,000 2007 2008 OSIRIS 7 10,000,000 2007 2011 PREDICT-IV 7 11,330,907 2008 2013 ESNATS 7 11,895,577 2008 2012 NanoTEST 7 3,933,271 2008 2011 OpenTox 7 2,975,360 2008 2011 START-UP 7 317,984 2008 2010 AXLR8 7 555,223 2010 2013 CHEMSCREEN 7 3,500,000 2010 2014 SCR&Tox* 7 4,700,000 2010 2015 HeMiBio* 7 4,700,000 2010 2015 DETECTIVE* 7 4,340,000 2010 2015 COSMOS* 7 3,340,000 2010 2015 NOTOX* 7 4,850,000 2010 2015 ToxBank* 7 1,560,000 2010 2015 COACH* 7 1,500,000 2010 2015 Total funding 136,665,133 * Contribution by the DG Research & Innovation, matching funds are provided by COLPIA. 14 INTRODUCTION Progress Report 2011 & AXLR8-2 Workshop Report
and progress of these multidisciplinary initiatives and providing opportunities for communication and dissemination of research results is becoming increasingly important for identifying knowledge gaps, areas of overlap, and opportunities for synergies. The AXLR8 project is supporting this process by providing up-to-date information to DG R&I on the international scientific state-of-the art and on needs and opportunities for future funding of research in Europe. AXLR8 Consortium The past two decades have seen unprecedented scientific and technological advances, including the birth of functional genomics, the explosive growth of computing power and computational biology/bioinformatics, the establishment of robotic platforms for high-throughput screening of chemicals, and the sequencing of the human genome. Together these advances have triggered a revolution in molecular biology, and have made available a wide range of new tools for studying the effects of chemicals on cells, tissues and organisms in a rapid and cost-efficient manner. In the United States, this convergence of factors, coupled with increased recognition of the limitations of conventional in vivo tests and the need to evaluate the safety of an increasingly large number of chemical substances and mixtures, has led authorities to call for shift in toxicity testing towards the elucidation of ‘toxicty pathways’ at the cellular level—an approach termed ‘21st century toxicology’. Recognising the growing need of a focal point for monitoring the increasing number of <strong>3R</strong>s and related multidisciplinary research initiatives worldwide, Humane Society International/United Kingdom (HSI), the Freie Universität Berlin, and the Centre for Advanced R&D on Alternative Methods at the Flemish Institute for Technological Research (CARDAM-VITO) formed the AXLR8 Consortium. The core of the AXLR8 project is a series of annual workshops, which bring together the co-ordinators of EU FP6/7-funded research projects, international scientists, and regulatory and corporate end-users of test methods, to discuss the progress of ongoing activities, identify knowledge gaps and opportunities for synergies, and help to streamline priorities for future research. The AXLR8 project began its activity in 2010 and will continue through 2013. AXLR8 Goals & Objectives The goal of the AXLR8 project is to lay the groundwork in Europe for a transition in toxicology towards a more mechanistic, cell- and computer-based approach, and to direct Europe into a leading position in this advanced research area in the life sciences. Realisation of this goal will depend on the project’s success in fostering effective information sharing and collaboration among research initiatives both at the European and global level. To achieve this goal the following specific objectives are pursued: INTRODUCTION Progress Report 2011 & AXLR8-2 Workshop Report 15
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: 1INTRODUCTION It is the aim of the
Page 17 and 18: Table 2. Members of the AXLR8 Scien
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
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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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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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