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assay. PLoS One. 2011; 6, e18540. 7. Kleinstreuer N, Judson R, Reif D, et al. Environmental Impact on Vascular Development Predicted by High-Throughput Screening (HTS). Environ Hlth Perspect. 2011 [In press]. (doi:10.1289/ehp.1103412). 8. Knudsen TB, Daston GP. Virtual Tissues and Developmental Systems Biology. In: Comprehensive Toxicology: Developmental Toxicology (editors: GP Daston and TB Knudsen), Elsevier: New York, 2010, pp 347-358. 258 AXLR8-2 WORKSHOP REPORT Progress Report 2011 & AXLR8-2 Workshop Report
The GARD Test A Novel Assay for Prediction of Skin Sensitisers Malin Lindstedt & Carl Borrebaeck Department of Immunotechnology Lund University Biomedical Centre D13 SE-22184 Lund, Sweden malin.lindstedt@immun.lth.se carl.borrebaeck@immun.lth.se Website: sens-it-iv.eu Background & Objectives Prediction of sensitising properties of chemicals used within industry and research is an important aspect of safety assessment of chemicals. Such predictions are currently performed with the use of the mouse Local Lymph Node Assay (LLNA) (Basketter et al., 2002). Due to European legislation that regulates the use of animals within, e.g., cosmetic and pharmaceutical industries, the need of novel assays is urgent. Yet to date, no validated non-animal replacements are available for identification of sensitising substances. An in vitro alternative to these animal models should exhibit improved reliability, accuracy and importantly correlate to human reactivity. The objective of the here reported research has thus been to develop in vitro assays for prediction of sensitising chemicals. GARD—the ‘Genomic Allergen Rapid Detection’ test (Johansson et al., 2011)—is such an assay, which has been developed for assessing the ability of a compound to induce skin sensitisation, which results in the disease known as allergic contact dermatitis (ACD). GARD is based on MUTZ-3 (Mastersson et al., 2002), a myeloid cell line with a phenotype and transcriptional profile similar to dendritic cells (DCs), which are essential for the initiation of the immune response leading up to ACD. The readout of the assay is the analysis of the transcriptional levels of 200 genes, which has been identified as differentially regulated in sensitisers, compared to non-sensitisers. Following data acquisition from DNA microarrays, the predictions are performed with a machine- This assay was developed within the 6 th framework Sens-it-iv programme. Partner: Department of Immunotechnology, Lund University, Sweden Contract number: LSHB-CT-2005-018681 AXLR8-2 WORKSHOP REPORT Progress Report 2011 & AXLR8-2 Workshop Report 259
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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
Page 208 and 209: Why is a Consortium Needed While th
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Page 218 and 219: The Virtual Liver Spatial-Temporal
Page 220 and 221: A B C D E Figure 2. Tissue reconstr
Page 222 and 223: Figure 4. Mechanisms of how hepatoc
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Page 226 and 227: 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
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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
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Page 280 and 281: Although the mechanisms underlying
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Page 292 and 293: Table 1. Summary of the experimenta
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Page 302 and 303: Figure 1. Strategic R&D of chemical
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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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