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LEGAL NOTICE The views expressed in this publication are the sole responsibility of the authors and do not necessarily reflect the views of the authors’ affiliated institutions or those of the AXLR8 Consortium, Scientific Panel, or the European Commission. The AXLR8 Consortium, Scientific Panel and European Commission are not responsible for any use that might be made of the information contained herein. Cover photo credits: NIH Chemical Genomics Center, iStockPhoto ISBN 978-3-9814126-3-5 © AXLR8 Consortium, 2011 Reproduction is authorised provided the source is acknowledged. Printed in Germany Printed on white chlorine-free paper 4
TABLE OF CONTENTS 1. 2. EXECUTIVE SUMMARY 9 INTRODUCTION 13 PROGRESS REPORTS FROM EU-FUNDED PROJECTS 21 ACuteTox Optimisation & Pre-Validation of an In Vitro Test Strategy for Predicting Human Acute Toxicity 22 carcinoGENOMICS Development of a High-Throughput Genomics-Based Test for Assessing Genotixic & Carcinogenic Properties of Chemical Compounds In Vitro 47 ChemScreen Chemical Substance In Vitro/In Silico Screening System to Predict Human & Ecotoxicological Effects 63 COMICS Comet Assay & Cell Array for Fast & Efficient Genotoxicity Testing 71 ESNATS Embryonic Stem Cell-Based Novel Alternative Testing Strategies 76 INVITROHEART Reducing Animal Experimentation in Drug Testing by Human Cardiomyocyte In Vitro Models Derived from Embryonic Stem Cells 89 LIINTOP Optimisation of Liver & Intestine In Vitro Models for Pharmacokinetics & Pharmacodynamics Studies 94 TABLE OF CONTENTS Progress Report 2011 & AXLR8-2 Workshop Report 5
Page 1 and 2: ALTERNATIVE TESTING STRATEGIES PROG
Page 3: ALTERNATIVE TESTING STRATEGIES PROG
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 and 18: Table 2. Members of the AXLR8 Scien
Page 19: • OECD Joint Meeting Special Sess
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
Page 72 and 73:
obustness, comparing results obtain
Page 74 and 75:
6. Candéias S, Pons B, Viau M, et
Page 76 and 77:
ESNATS Embryonic Stem Cell-Based No
Page 78 and 79:
Table 1. List of deliverables due i
Page 80 and 81:
D3.3.1 Toxicity gene expression sig
Page 82 and 83:
Table 2. List of milestones due in
Page 84 and 85:
Table 3. Test systems corresponding
Page 86 and 87:
Publications 2010-11 1. Peters SJ,
Page 88 and 89:
Marcel Leist Universität Konstanz
Page 90 and 91:
The most significant achievements o
Page 92 and 93:
Figure 3. The Sensor Dish Reader (S
Page 94 and 95:
LIINTOP Optimisation of Liver & Int
Page 96 and 97:
cells express most of the functions
Page 98 and 99:
Figure 3. Scheme of lentivirus gene
Page 100 and 101:
Figure 5. Co-culture set-up. Functi
Page 102 and 103:
Figure 9. Phalloidin-TRITC staining
Page 104 and 105:
Table 1. Values are expressed as pe
Page 106 and 107:
formed with mannitol, atenolol, pro
Page 108 and 109:
Figure 14. Comparison of Digoxin an
Page 110 and 111:
By using the new technology of HCA
Page 112 and 113:
Figure 17. (Left panel) Phalloidin-
Page 114 and 115:
limited amount of data could be pro
Page 116 and 117:
André Guillouzo Institut National
Page 118 and 119:
Objectives The overall aim of this
Page 120 and 121:
Table 2: Milestones achieved in 201
Page 122 and 123:
detected iron (µg/ml) 80 70 6
Page 124 and 125:
in the following order: uncoated ma
Page 126 and 127:
analysis of leukocytes, expression
Page 128 and 129:
2011 the automated protocols will b
Page 130 and 131:
OpenTox Promotion, Development, Acc
Page 132 and 133:
Results The OpenTox Framework The O
Page 134 and 135:
Figure 1. ToxPredict: OpenTox Appli
Page 136 and 137:
scientifically sound manner, so as
Page 138 and 139:
Figure 4. Creating a QPRF report wi
Page 140 and 141:
Figure 7. MaxTox model-building app
Page 142 and 143:
Figure 8. Bioclipse interaction wit
Page 144 and 145:
and model predictions, which they m
Page 146 and 147:
Publications 2010-11 1. Hardy B, Do
Page 148 and 149:
In vitro toxicology using isolated
Page 150 and 151:
(2C-Glo-CYP2C, 3A-Glo-CYP3A) while
Page 152 and 153:
neuronal models 2D (primary culture
Page 154 and 155:
10 and 14 days. The liver-specific
Page 156 and 157:
Frédéric Bois Institut National d
Page 158 and 159:
Figure 1. The Sens-it-iv sphere. 2.
Page 160 and 161:
Figure 2. The updated modular struc
Page 162 and 163:
Technology Module The aim of techno
Page 164 and 165:
Table 1: The final compound list. R
Page 166 and 167:
Table 2. The Sens-it-iv Toolbox. N
Page 168 and 169:
Figure 4. A gene profile for identi
Page 170 and 171:
Figure 7. In vitro T cell priming a
Page 172 and 173:
sessions at congress and meetings (
Page 174 and 175:
7. Gibbs S, van Montfrans C, Kroeze
Page 176 and 177:
vitro assessment of allergens. Eds:
Page 178 and 179:
S.F. Martin Universitätsklinikum F
Page 180 and 181:
idging the gap to human volunteer s
Page 182 and 183:
combinations of transcriptomics, me
Page 184 and 185:
normal animals who usually exhibit
Page 186 and 187:
Workshop proposals Concepts of data
Page 188 and 189:
VITROCELLOMICS Reducing Animal Expe
Page 190 and 191:
esulting of the project was the abi
Page 192 and 193:
Figure 3. Four-compartment artifici
Page 194 and 195:
embryonic stem cells differentiatin
Page 196 and 197:
196 3AXLR8-2 WORKSHOP REPORT
Page 198 and 199:
Workshop participants were divided
Page 200 and 201:
08.45 - 09.15 ACuteTox Annette Kopp
Page 202 and 203:
3.3 Workshop Presentations 202
Page 204 and 205:
Table 1. A sampling of current toxi
Page 206 and 207:
Table 2. EPA activities: a timeline
Page 208 and 209:
Why is a Consortium Needed While th
Page 210 and 211:
the development of new more relevan
Page 212 and 213:
in particular for fundamental resea
Page 214 and 215:
compared to controls. Most interest
Page 216 and 217:
epidermis to known allergens and UV
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
Page 224 and 225:
in rat liver in vivo (Figure 5A). H
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
Page 250 and 251:
cost and time, allowing more chemic
Page 252 and 253:
Toxicol Appl Pharmacol. 2011; 251,
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 278 and 279:
the development of in vitro assays.
Page 280 and 281:
Although the mechanisms underlying
Page 282 and 283:
skin sensitisation, it will aid in
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
Page 290 and 291:
the AOP can be used in qualitative
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
Page 300 and 301:
[Supporting information and databas
Page 302 and 303:
Figure 1. Strategic R&D of chemical
Page 304 and 305:
The Bhas 42 system can sensitively
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
Page 314 and 315:
assay results together with CSBP mo
Page 316 and 317:
them to support multi-day testing i
Page 318 and 319:
CSBP models for both receptor-media
Page 320 and 321:
Hamner Presentations in 2011 • Ch
Page 322 and 323:
human health risk assessment. Risk
Page 324 and 325:
There is a significant scientific c
Page 326 and 327:
phototoxicity and eye irritation, f
Page 328 and 329:
allergy risk assessment rather than
Page 330 and 331:
‘toolbox’ of non-animal methods
Page 332 and 333:
332 3.4 Breakout Group Reports
Page 334 and 335:
Figure 1. An illustration of the me
Page 336 and 337:
methods, and the generally poor und
Page 338 and 339:
3.4.3. Break-Out Group 2: Reproduct
Page 340 and 341:
- Deep-sequencing of birth defect p
Page 342 and 343:
Figure 2. Specific stages of the ma
Page 344 and 345:
3.4.4 Break-Out Group 3: Skin Sensi
Page 346 and 347:
for further progress. Better tools
Page 348 and 349:
sure doses is not straightforward.
Page 350 and 351:
3.5 AXLR8 Scientific Panel Recommen
Page 352 and 353:
Workshop participants underlined th
Page 354 and 355:
could be co-ordinated in a focused
Page 356 and 357:
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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