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Workshop participants underlined the importance of the higher level of humanrelevant biological understanding that can be achieved by means of an integrated pathway and modelling approach to safety assessment, but noted that a substantial investment in targeted interdisciplinary research and related infrastructure will be required to fully develop each of the key ‘building blocks’ and demonstrate their functional integration before such benefits can be fully realised. It was also noted that early and active interactions with regulatory authorities, regulated industry, and civil society stakeholders will be necessary to achieve timely acceptance and integration of new testing tools and strategies as part of an evolutionary shift in the safety testing and assessment paradigm. During its in camera session aimed at developing an innovative toxicity testing roadmap for consideration under the forthcoming Common Strategic Framework for Future EU Research and Innovation Funding, the AXLR8 Scientific Panel noted the substantial progress that has been made in Europe in the development of ‘alternative testing strategies’ as a product of funding by DG Research & Innovation under FP6 and FP7 (Figure 1). The SEURAT-1 initiative was recognised as an important step towards new experimental and computational approaches to safety testing and assessment, and as a Knowledge Innovative Medicines Initiative (IMI) F6 AXLR8 Co-ordination Action FP7 Projects SEURAT-1 (EU/COLIPA Joint Research Initiative) Long-Term Target: Safety Evaluation Ultimately Replacing Animal Testing (SEURAT) Horizon 2020 SEURAT-2 Time 2011 2012 2013 2014 2015 2016 Figure 1. Illustration of the funding activities of the European Commission DG Research & Innovation within the Health theme of FP6 and FP7 in the context of policy needs, industry requirements and scientific challenges to develop ‘alternative testing strategies for replacing, reducing and refining the use of animals in research’. ■ programmes currently funded via FP6/FP7 ■ future funding programmes 352 AXLR8-2 WORKSHOP REPORT Progress Report 2011 & AXLR8-2 Workshop Report
Proposed Structure of ‘SEURAT-2’ CO-‐ORDINATION ACTION Infrastructure Cancer/ Carcinogenicity Developmental Disorders/Toxicity Specific Target Organ Toxicity Fertility/ Reproductive Toxicity Immune Disorders/ Toxicity Iden-fica-on & understanding of toxic modes of ac-on, elucida-on of cri-cal pathways at molecular & cellular levels Development of experimental & computa-onal systems biology models for specific mode-‐of-‐ac-on events & quan-ta-ve predic-ons Biokine-c modelling & computa-onal chemistry to predict in vivo bioavailability & kine-cs Transla-on research & proof-‐of-‐concept studies to demonstrate & evaluate approaches in safety assessment context Figure 2. Illustration of the proposed SEURAT-2 structure. Six large-scale clusters encompassing five human health effect areas together with cross-cutting infrastructure would be developed under the direction of a central co-ordination action. There should be a strong focus in all clusters on core ‘building blocks’, illustrated here as four distinct projects/research areas; however, the exact number of projects per cluster should be determined on a case-by-case basis. public-private partnership between the Commission and regulated industry, it represents a promising new funding model. Indeed, COLIPA’s direct financial support for this initiative was highly welcomed and favoured over, e.g., in-kind contributions from the private sector. Structurally, the Scientific Panel welcomed the ‘cluster’-type design of SEURAT-1, i.e., multiple project-level ‘building blocks’ organised around a central co-ordinating action (Figure 2). This approach facilitates intense scientific exchange and supervision of the research projects/areas (These objectives could also be pursued through creation of a centralised and highly networked ‘EU Centre for Molecular Toxicology’, where scientists from different disciplines could work at one location toward the same well-defined aim, and through which research and training AXLR8-2 WORKSHOP REPORT Progress Report 2011 & AXLR8-2 Workshop Report 353
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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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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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Page 338 and 339: 3.4.3. Break-Out Group 2: Reproduct
Page 340 and 341: - Deep-sequencing of birth defect p
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Page 346 and 347: for further progress. Better tools
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Page 358 and 359: Directory of Projects & Co-ordinato
Page 360 and 361: Glossary of Terms 2D/3D 3Rs CARDAM/
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