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the development of in vitro assays. Cell Molec Life Sci. 2010; 67, 4171-84. 51. Giese C, et al. A human lymph node in vitro - Challenges and progress. Artificial Organs 2006; 30, 803-8. 52. Scientific Committee on Consumer Products. Memorandum on Actual Status of Alternative Methods on the Use of Experimental Animals in the Safety Assessment of Cosmetic Ingredients in the European Union. SCCP/1111/07. Brussels: European Commission, 2007, 14pp. 53. Combes R, et al. An overall strategy for the testing of chemicals for human hazard and risk assessment under the EU REACH system. Altern Lab Anim. 2003; 31, 7-19. 54. National Research Council. Toxicity Testing in the Twenty-first Century: A Vision and Strategy. Washington, DC: National Academies Press, 2007. 278 AXLR8-2 WORKSHOP REPORT Progress Report 2011 & AXLR8-2 Workshop Report
Marker Discovery & Their Functional Role in the Adverse Outcome Pathway for Skin Sensitisation Nathalie Lambrechts, Jef Hooyberghs, Rosette Van Den Heuvel, Greet Schoeters Flemish Institute for Technological Research (VITO) Centre for Advanced Research & Development on Alternative Methods (CARDAM) Research Unit Environmental Risk & Health Boeretang 200 BE-2400 Mol, Belgium greet.schoeters@vito.be Website: cardam.eu Background & Objectives European legislation and animal welfare organisations have stimulated research to develop non-animal toxicity tests. Assays for identifying skin sensitisers are highly warranted since all chemicals with annual production volumes above 1 tonne should be tested for this endpoint (Schoeters, 2010). VITO-CARDAM is involved in evaluating adverse health effects of chemicals in relation to allergies. As such, over the years, an assay has been developed with the intention to mimic as closely as possible the human response to skin sensitisers. The assay is based on primary cells of human origin. CD34+ progenitor cells are isolated from human cord blood and differentiated in vitro to dendritic cells (DC), which exhibit characteristics of the professional antigen-presenting cells of the skin (De Smedt et al., 2001). DC are recognised as cellular players in the induction phase of sensitisation and are main actors in the adaptive immune response cascade (Steinman, 2001). Our in vitro research focused on understanding the cellular and molecular changes in DC after exposure to chemical sensitisers. This mechanistic approach is much in line with the National Research Council (NRC) vision for chemical safety assessment, which highlights the need of alternative tests for cellular responses and toxicity pathways with a key function in the development of adverse health effects in humans (Collins et al., 2008). AXLR8-2 WORKSHOP REPORT Progress Report 2011 & AXLR8-2 Workshop Report 279
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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
Page 228 and 229: deliverables, which can only be ach
Page 230 and 231: A series of publications related to
Page 232 and 233: Update on EPA’s ToxCast Programme
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
Page 242 and 243: Judson RS, Houck KA, Kavlock RJ, et
Page 244 and 245: Embryonic Stem Cell Approaches Towa
Page 246 and 247: perhaps be tested efficiently in al
Page 248 and 249: compared gene and protein expressio
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Page 254 and 255: functions, establish relationships
Page 256 and 257: cellular behaviours are captured fr
Page 258 and 259: assay. PLoS One. 2011; 6, e18540. 7
Page 260 and 261: learning algorithm called Support V
Page 262 and 263: Compound Potency Vehicle Concentrat
Page 264 and 265: mediated inhibition of RXR function
Page 266 and 267: References Basketter DA, Evans P, F
Page 268 and 269: When considering consumer exposure,
Page 270 and 271: in the induction of skin sensitisat
Page 272 and 273: has reacted, when the peptide deple
Page 274 and 275: of presentations and discussions, t
Page 276 and 277: Contact Dermatitis. 2005; 53. 16. S
Page 280 and 281: Although the mechanisms underlying
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Page 284 and 285: Figure 3. Scatter plot of robust li
Page 286 and 287: 7. De Smedt A, Van Den Heuvel R, Va
Page 288 and 289: The OECD Adverse Outcome Pathway Ap
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Page 292 and 293: Table 1. Summary of the experimenta
Page 294 and 295: the significance of type 1 versus t
Page 296 and 297: plus the key events that occur acro
Page 298 and 299: Dimitrov, S.D., Low, L.K., Patlewic
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Page 302 and 303: Figure 1. Strategic R&D of chemical
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Page 306 and 307: Table 1. Established reporter cell
Page 308 and 309: elated genes (Hand1, ADAM19, Cmyal,
Page 310 and 311: Publications Carcinogenicity Tanaka
Page 312 and 313: Case Study Approaches for Implement
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Page 320 and 321: Hamner Presentations in 2011 • Ch
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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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