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Figure 1. Strategic R&D of chemical risk analysis technologies in Japan. Figure 2. R&D structure of NEDO project. 302 AXLR8-2 WORKSHOP REPORT Progress Report 2011 & AXLR8-2 Workshop Report
The first series the development of HTP in vitro assay systems was initiated by NEDO in 2006 and was finished in 2010 as a 5-year project. The second series of 5-year projects will be started in 2011 for the development of HTP assay systems to detect toxicities such as hepatoxicity, nephrotoxicity, etc. based on 28-day repeated dose oral toxicity tests (Figure 1). The objective of this presentation is to introduce novel HTP assay systems developed by NEDO project members in the 1 st series (2006-2011) into practical use. The R&D being conducted by NEDO (Figure 2) is aimed at establishing HTP assays of carcinogenicity (in partnership with the Hatano Research Institute, Food and Drug Safety Centre), immunotoxicity (Tohoku University), and developmental toxicity (Sumitomo Chemical Co. Ltd.). In addition to these toxicity research groups, technical support groups which have a high-tech multi-colour luciferase reporter assay [National Institute of Advanced Industrial Science and Technology (NIAIST) and Toyobo Co., Ltd.] and human artificial chromosome (HAC) vector method (Tottori University), were involved in this consortium. HTP Assays for Carcinogenicity Using Bhas 42 Cell Transformation and promoters is practical for the screening of carcinogenic chemicals. Most initiators can be detected by various genotoxicity tests, the results of which are used for carcinogenicity prediction by regulatory authorities. In the case of tumour promoters, several methods have been proposed, but none have been routinely applied for regulatory purposes. Using cell transformation assays (CTA), BALB/c 3T3 cells and C3H10T1/2 cells can mimic the process of two-stage animal carcinogenesis. The formation of transformed foci is the consequence of the complex process of transforming cells to malignant state. Since these assays can detect both initiating and promoting activities, it is expected that they will be included as screening tools, but they have yet to be approved as routine screening methods because of the laborious and time-consuming procedures compared to routine genotoxicity assays. In the NEDO project, a sensitive short-term CTA has been developed using Bhas 42 cells that were established from BALB/c 3T3 cells transfected with v-Ha-ras genes. Days0 1 4 7 11 14 21 Medium change Ini$a$on assay Ini$ator Background Promo$on assay Promoter Although multi-stage processes are involved in carcinogenesis, the classical classification of carcinogens as initiators Figure 3. Bhas 42 CTA protocol for initiation assay and promotion assay. 6-well or 96-well plates are used. The cells for cell growth assay are fixed. AXLR8-2 WORKSHOP REPORT Progress Report 2011 & AXLR8-2 Workshop Report 303
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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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Page 254 and 255: functions, establish relationships
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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
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Page 286 and 287: 7. De Smedt A, Van Den Heuvel R, Va
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Page 292 and 293: Table 1. Summary of the experimenta
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Page 296 and 297: plus the key events that occur acro
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Page 310 and 311: Publications Carcinogenicity Tanaka
Page 312 and 313: Case Study Approaches for Implement
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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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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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