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Member State centres on alternatives to animal testing, the leaders of international efforts to establish advanced molecular toxicology from the United States and Japan, and members of the AXLR8 Scientific Panel and Consortium. Based on a focused discussion of the scientific state-of-the-art and of knowledge gaps and priorities for future EU research funding, the participants developed a ‘roadmap to innovative toxicity testing’. To achieve this goal, building blocks for a pathway-based paradigm were discussed and two case studies focused on reproductive toxicology and skin sensitisation. The discussion and recommendations of the AXLR8 Scientific Panel and the AXLR8 Consortium for a ‘roadmap to innovative toxicity testing’ are published in the final section of this document. They may serve to initiate the discussion on future funding of a ‘SEURAT-2 (‘safety evaluation ultimately replacing animal testing’) project by DG R&I. AXLR8 Outreach & Dissemination A substantial component of the AXLR8 work programme is dedicated to outreach and engagement of a wider audience of stakeholders. This is because the ultimate success of this co-ordination initiative will depend heavily on securing acceptance by a variety of key stakeholders, in particular scientists and regulators, but also policymakers, public interest NGOs, and the European public at large. Scientific workshops and other forums in which AXLR8 has been an invited contributor include the following: Figure 1. Mainstream media coverage of AXLR8 at guardian.co.uk/science/2010/dec/31/animalresearch-alternatives • AXLR8 Workshops 2010-11 and Info Forum • 8th World Congress on Alternatives and Animal Use in the Life Sciences • Competent Authorities for REACH and Classification and Labelling • ecopa Workshops 2010-11 • ESTIV-EUSAAT Congress 2010 • ESTIV 2011 • FELASA-SCAND 2010 Symposium • Human Toxicology Project Symposium 2010 • ILSI-Europe TTC Workshop • i-SUP 2010 Conference • JSAAE-JaCVAM Workshop 2011 • Meeting with the German Ministry for Research and Education • OECD Advisory Group on Molecular Screening and Toxicogenomics 18 INTRODUCTION Progress Report 2011 & AXLR8-2 Workshop Report
• OECD Joint Meeting Special Session on Animal Welfare • OECD Working Party on Manufactured Nanomaterials Steering Group on Alternatives (SG7) • SEURAT-1 Kick-Off Meeting 2011 AXLR8’s activities have also been reported on in the mainstream media, including The Guardian (Figure 1) and The Telegraph, various trade journals and radio programmes, and in the newsletters of the European Society for Toxicology In Vitro, ecopa, and AltTox. In addition, the website axlr8.eu provides ‘one stop shopping’ for links to <strong>3R</strong>srelevant EU research projects and annual progress reports, key international initiatives and publications, and a listing of upcoming meetings and conferences. There you can also register for the periodic AXLR8 e-newsletter, which is sent to a distribution list of over 1,400 subscribers. INTRODUCTION Progress Report 2011 & AXLR8-2 Workshop Report 19
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 16: and progress of these multidiscipli
Page 17: Table 2. Members of the AXLR8 Scien
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
Page 66 and 67: defined and published in the form o
Page 68 and 69:
WP6 is devoted to the setup of a so
Page 70 and 71:
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
Page 76 and 77:
ESNATS Embryonic Stem Cell-Based No
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Table 1. List of deliverables due i
Page 80 and 81:
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
Page 230 and 231:
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
Page 266 and 267:
References Basketter DA, Evans P, F
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When considering consumer exposure,
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in the induction of skin sensitisat
Page 272 and 273:
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
Page 278 and 279:
the development of in vitro assays.
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Although the mechanisms underlying
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skin sensitisation, it will aid in
Page 284 and 285:
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,
Page 310 and 311:
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
Page 358 and 359:
Directory of Projects & Co-ordinato
Page 360 and 361:
Glossary of Terms 2D/3D 3Rs CARDAM/
Page 362:
362
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