88 results on '"Krul C"'
Search Results
2. P22-29 Virtual human platform for safety assessment (VHP4Safety): assessing the safety of chemicals and pharmaceuticals based on human data
- Author
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Kienhuis, A., primary, Krul, C., additional, and Legler, J., additional
- Published
- 2022
- Full Text
- View/download PDF
3. Personal Assistance NQF4 SB: TVET FIRST
- Author
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T Krul, C Esterhuyse, P Atkins, S Paarman & A Rasmus
- Published
- 2013
4. Expression profiling of colon cancer cell lines and colon biopsies: towards a screening system for potential cancer-preventive compounds
- Author
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van Erk, M J, Krul, C A M, Caldenhoven, E, Stierum, R H, Peters, W H, Woutersen, R A, and van Ommen, B
- Published
- 2005
5. Development of an in silico platform to assess developmental and reproductive toxicity (DART)
- Author
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van der Voet, M, primary, Steijaert, M., additional, van Noort, V., additional, Bhalla, D., additional, Teunis, M., additional, Lankhaar, J.-W., additional, Poppelaars, E., additional, Corradi, M., additional, Verbeke, T., additional, Keizer, G., additional, Krul, C, additional, Currie, R., additional, Rooseboom, M., additional, Pieters, R., additional, and Wildwater, M., additional
- Published
- 2021
- Full Text
- View/download PDF
6. Determination of N-nitrosodimethylamine in artificial gastric juice by gas chromatographymass spectrometry and by gas chromatography-thermal energy analysis
- Author
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Dallinga, J W, Krul, C A M, Tenfelde, A, Moonen, E J C, van Doorn, D, Schothorst, R C, and Vermeer, I T M
- Published
- 2001
7. Safer chemicals using less animals: kick-off of the European ONTOX project
- Author
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Vinken, M., Benfenati, E., Busquet, F., Castell, J., Clevert, D.A., de Kok, T.M., Dirven, H., Fritsche, E., Geris, L., Gozalbes, R., Hartung, T., Jennen, D., Jover, R., Kandarova, H., Kramer, N., Krul, C., Luechtefeld, T., Masereeuw, R., Roggen, E., Schaller, S., Vanhaecke, T., Yang, C., Piersma, A.H., Vinken, M., Benfenati, E., Busquet, F., Castell, J., Clevert, D.A., de Kok, T.M., Dirven, H., Fritsche, E., Geris, L., Gozalbes, R., Hartung, T., Jennen, D., Jover, R., Kandarova, H., Kramer, N., Krul, C., Luechtefeld, T., Masereeuw, R., Roggen, E., Schaller, S., Vanhaecke, T., Yang, C., and Piersma, A.H.
- Abstract
The 3Rs concept, calling for replacement, reduction and refinement of animal experimentation, is receiving increasing attention around the world, and has found its way to legislation, in particular in the European Union. This is aligned by continuing high-level efforts of the European Commission to support development and implementation of 3Rs methods. In this respect, the European project called "ONTOX: ontology-driven and artificial intelligence-based repeated dose toxicity testing of chemicals for next generation risk assessment" was recently initiated with the goal to provide a functional and sustainable solution for advancing human risk assessment of chemicals without the use of animals in line with the principles of 21st century toxicity testing and next generation risk assessment. ONTOX will deliver a generic strategy to create new approach methodologies (NAMs) in order to predict systemic repeated dose toxicity effects that, upon combination with tailored exposure assessment, will enable human risk assessment. For proof-of-concept purposes, focus is put on NAMs addressing adversities in the liver, kidneys and developing brain induced by a variety of chemicals. The NAMs each consist of a computational system based on artificial intelligence and are fed by biological, toxicological, chemical and kinetic data. Data are consecutively integrated in physiological maps, quantitative adverse outcome pathway networks and ontology frameworks. Supported by artificial intelligence, data gaps are identified and are filled by targeted in vitro and in silico testing. ONTOX is anticipated to have a deep and long-lasting impact at many levels, in particular by consolidating Europe's world-leading position regarding the development, exploitation, regulation and application of animal-free methods for human risk assessment of chemicals.
- Published
- 2021
8. Reconstructed 3-D Human Skin Comet Assay: Intra and Interlaboratory Reproducibility with Five Chemicals.: P98
- Author
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Downs, T, Reus, A, Reisinger, K, Krul, C, and Pfuhler, S
- Published
- 2012
9. The 3 dimensions of Organ-on-a-chip
- Author
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Grootaers, G., Ostendorf, R., Bobeldijk, I., Hanemaaijer, R., Kooter, I., Sandt, H. van de, Steeg, E. van de, and Krul, C.
- Subjects
Life ,Health ,Predictive Health Technologies ,MHR - Metabolic Health Research ,Healthy Living - Published
- 2016
10. Regulatory acceptance and use of the extended one generation reproductive toxicity study within Europe
- Author
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Schiffelers, M.J.W.A., Blaauboer, B.J., Bakker, W.E., Hendriksen, C.F.M., Krul, C., and Instituut CIVO-Toxicologie en Voeding TNO
- Subjects
Regulatory acceptance and use ,Barriers and drivers ,Reproductive toxicity testing ,Life ,Rattus ,RAPID - Risk Analysis for Products in Development ,REACH ,Animalia ,ELSS - Earth, Life and Social Sciences ,EOGRTS - Abstract
The two-generation study (OECD TG 416) is the standard requirement within REACH to test reproductive toxicity effects of chemicals with production volumes >100. tonnes. This test is criticized in terms of scientific relevance and animal welfare. The Extended One Generation Reproductive Toxicity Study (EOGRTS), incorporated into the OECD test guidelines in 2011 (OECD TG 443) has the potential to replace TG 416, while using only one generation of rats and being more informative. However, its regulatory acceptance proved challenging. This article reconstructs the process of regulatory acceptance and use of the EOGRTS and describes drivers and barriers influencing the process. The findings derive from literature research and expert interviews. A distinction is made between three sub-stages; The stage of Formal Incorporation of the EOGRTS into OECD test guidelines was stimulated by retrospective analyses on the value of the second generation (F2), strong EOGRTS advocates, animal welfare concern and changing US and EU chemicals legislation; the stage of Actual Regulatory Acceptance within REACH was challenged by legal factors and ongoing scientific disputes, while the stage of Use by Industry is influenced by uncertainty of registrants about regulatory acceptance, high costs, the risk of false positives and the manageability of the EOGRTS.
- Published
- 2015
11. Boer en boerin zonder boerderij : Jacob Beeker
- Author
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Krul, C., Winkel, E., Krul, C., and Winkel, E.
- Abstract
Aan Jersey-stierkalfjes zit zo weinig vlees, dat ze normaalgesproken kort na hun geboorte als slachtafval worden afgevoerd. “Dat moet anders!”, dachten Jacob Beeker (41) en Linda Heemskerk (36). Al hadden ze geen land, ze besloten de stieren groot te brengen en het vlees te vermarkten.
- Published
- 2016
12. 'Je zal je droomboerderij maar op Funda tegenkomen!'
- Author
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Krul, C. and Krul, C.
- Abstract
Een puzzelend boer, dat is Sander Kerkhoffs (35) van sAnders Hof in Etten: “Je moet puzzelen en rekenen tot je een landbouwvorm hebt gevonden die reëel is en bij je past. En in je achterhoofd ga je er natuurlijk helemaal voor.” Inmiddels heeft hij 25 zeugen rondlopen op een 6,5 hectare tellende boerderij.
- Published
- 2016
13. Speurwerkprogramma 2015-2018 LSH VP 203 Jaarplan 2015
- Author
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Krul, C. and Bongers, P.M.
- Subjects
Kennisontwikkeling ,Work and Employment ,ELSS - Earth, Life and Social Sciences Themalijn ,Healthy Living - Published
- 2014
14. Vermindering van het aantal proefdieren in dierstudies
- Author
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Schoen, E., Spaan, S., Loo, P. van, and Krul, C.
- Subjects
Life ,Research Nutrition ,RAPID - Risk Assessment Products in Development ,ELSS - Earth, Life and Social Sciences - Published
- 2014
15. Validation: Truth or dare!
- Author
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Teunis, M., primary, Pieters, R., additional, and Krul, C., additional
- Published
- 2015
- Full Text
- View/download PDF
16. Lessons learned from the ‘SLIM’ project: Regulatory acceptance and use of 3R methods
- Author
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Krul, C., primary, Schiffelers, M.-J., additional, Teunis, M., additional, and Pieters, R., additional
- Published
- 2015
- Full Text
- View/download PDF
17. UV-induced effects
- Author
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Liebsch, M., Spielmann, H., Pape, W., Krul, C., Deguercy, A., Eskes, C.A.M., and TNO Kwaliteit van Leven
- Subjects
ultraviolet radiation ,radiation hazard ,Erythrocytes ,Ultraviolet Rays ,review ,radiation exposure ,Physiological Sciences ,Cosmetics ,acute toxicity ,Animal Testing Alternatives ,Hemolysis ,in vivo study ,phototoxicity ,Drug Stability ,comet assay ,micronucleus ,Animals ,Humans ,Animalia ,human ,European Union ,gene mutation ,cosmetic ,hypoxanthine phosphoribosyltransferase ,Skin ,standardization ,model ,nonhuman ,Photosensitizing Agents ,Dermatitis, Photoallergic ,Mutagenicity Tests ,genotoxicity ,photosensitization ,ultraviolet A radiation ,DNA ,cell line ,Skin Irritancy Tests ,priority journal ,validation process ,Consumer Product Safety ,Health ,allergenicity ,DNA damage ,chromosome aberration ,animal testing replacement ,point mutation ,Mutagens ,Dermatitis, Phototoxic - Abstract
Regulatory requirements: According to the current Notes for Guidance of the Scientific Committee on Cosmetic Products and Non-Food Products (SCCNFP), cosmetic ingredients and mixtures of ingredients absorbing UV light (in particular UV filter chemicals used, for example, to ensure the light stability of cosmetics or used in sun protection products) should be tested for acute phototoxic and photogenotoxic potential. Testing for photosensitisation (immunological photoallergy) potential is not specifically required, but it is nevertheless often performed. Acute phototoxicity: Due to a thorough multi-stage and multi-centre validation trial (1992-1998) the In Vitro 3T3 Neutral Red Uptake Phototoxicity Test (3T3-NRU-PT) had already gained acceptance by the SCCNFP in 1998, and it is recommended by the EMEA/CPMP as a basic preclinical test for acute phototoxicity. It was accepted as Method No. 41 in Annex V to Directive 67/548/EEC in the year 2000, and was accepted as the new Test Guideline 432 by the OECD in 2002. The 3T3-NRU-PT is regarded as a basic screen for identifying acute phototoxic potential. Two additional in vitro tests, formally evaluated in controlled blind trials, the RBC Phototoxicity Test (RBC-PT) and the Human 3-D Skin Model Phototoxicity Test (H3D-PT), are regarded as useful and important adjunct tests to overcome some limitations of the 3T3-NRU-PT, namely the fairly low UVB tolerance of the 3T3 fibroblasts and the inability to model the bioavailability of test materials topically applied to the skin. In addition, the RBC-PT permits an evaluation of the phototoxic mechanisms involved. In conclusion, the identification of acute phototoxic hazards is now regarded as being sufficiently covered by in vitro tests, so that animal testing for that endpoint can now be 100% replaced. Photogenotoxicity: In the area of photogenotoxicity, almost the whole battery of in vitro genetic toxicity tests have been (or are currently being) converted into test protocols of photogenotoxicity tests. Tests exclusively predictive for gene mutation, for example, the Photo-Ames (P-Ames) Test and the Photo-Thymidine Kinase Test (P-TKT), have become less important than tests for clastogenic effects (for example, the Photo-Chromosome Aberration Test [P-CAT] and the Photo-Micronucleus Test [P-MNT]). In addition, a number of promising indicator tests, such as the Photo-Comet Assay (P-Comet) have been developed. Although routinely used, to date none of the new photogenotoxicity tests have been formally validated. Therefore, the P-MNT and the P-Comet are currently being evaluated in a formal interlaboratory validation study. It is expected that these in vitro photogenotoxicity test methods may become available as validated and accepted methods within the next five years. Photoallergy (Photosensitisation): In the area of photoallergy (photosensitisation), as development of predictive in vitro tests for delayed contact sensitisation (allergenicity) potential without the involvement of light, due to a lack of ability to model the complex mechanisms underlying allergy, no promising in vitro methods to predict photo-sensitisation potential are currently in sight (see the section on skin sensitisation). One in vitro screening method, which models the covalent binding of a light activated chemical to human serum albumin, may become relevant. However, while the binding of an excited chemical to proteins is a prerequisite for photoallergy, this is not a sufficient predictor on its own. The only promising alternatives currently under development are in vivo refinements, like the Photo Local Lymph Node Assay (PLLNA). Once a reliable and predictive in vitro test battery and strategy for the assessment of "dark" sensitisation potential have been developed and accepted, their adaptation into similar photosensitisation testing will become possible.
- Published
- 2005
18. Non-animal test strategy for safety and efficacy assessmenst of plant- and food-derived
- Author
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Pieters, R., primary, Perze, C. Chamorro, additional, Ten Klooster, J.-P., additional, Vaessen, S., additional, Veldman, R.-J., additional, Teunis, M., additional, and Krul, C., additional
- Published
- 2014
- Full Text
- View/download PDF
19. SLIM: A smart way from innovations to humans; case studies to accelerate the acceptance and implementation of alternative methods to animal experiments for safety assessment
- Author
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Teunis, M., primary, Kegler, D., additional, Raaijmakers, J., additional, Van de Valk, J., additional, Vandebriel, R., additional, Woutersen, R., additional, Pieters, R., additional, and Krul, C., additional
- Published
- 2014
- Full Text
- View/download PDF
20. TNO's dynamic large intestinal model : a valuable tool to study the metabolism of food-borne glucosinolates by human colonic microflora
- Author
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Humblot, Constance, Krul, C., Philippe, C., Vermeulen, Marc, Nuenen, M.V., Rabot, Sylvie, Unité de recherche d'Écologie et Physiologie du Système Digestif (UEPSD), Institut National de la Recherche Agronomique (INRA), and ProdInra, Migration
- Subjects
[SDV] Life Sciences [q-bio] ,[SDV]Life Sciences [q-bio] - Published
- 2000
21. Comet assay in reconstructed 3D human epidermal skin models--investigation of intra- and inter-laboratory reproducibility with coded chemicals
- Author
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Reus, A. A., primary, Reisinger, K., additional, Downs, T. R., additional, Carr, G. J., additional, Zeller, A., additional, Corvi, R., additional, Krul, C. A. M., additional, and Pfuhler, S., additional
- Published
- 2013
- Full Text
- View/download PDF
22. Better prediction of immunogenicity of biopharmaceuticals in humans, is it possible?
- Author
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Folkertsma, Simon, primary, Fabriek, Babs O., additional, van Mierlo, Geertje, additional, Tielen, F.J., additional, Entink, R. Klein, additional, Reefman, E., additional, and Krul, C., additional
- Published
- 2013
- Full Text
- View/download PDF
23. Prevalidation of a human T cell proliferation assay to identify immunosuppressive compounds
- Author
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Ten Klooster, J.P., primary, Teunis, M., additional, Kleensang, A., additional, Krul, C., additional, Van Loveren, H., additional, Corsini, E., additional, Vandebriel, R., additional, and Pieters, R., additional
- Published
- 2011
- Full Text
- View/download PDF
24. Toxicological behaviour and characterisation of nanomaterials: A systematic approach
- Author
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van Acker, F., primary, Mulderij, M., additional, Wouters, M., additional, Reinders, S., additional, Krul, C., additional, and Kuper, F., additional
- Published
- 2011
- Full Text
- View/download PDF
25. Development and characterisation of an in vitro photomicronucleus test using ex vivo human skin tissue
- Author
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Reus, A. A., primary, van Meeuwen, R. N. C., additional, de Vogel, N., additional, Maas, W. J. M., additional, and Krul, C. A. M., additional
- Published
- 2010
- Full Text
- View/download PDF
26. Application of the threshold of toxicological concern-concept in safety assessment of chemically complex food matrices
- Author
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Rennen, M., primary, Koster, S., additional, Krul, C., additional, Krul, L., additional, and Houben, G., additional
- Published
- 2010
- Full Text
- View/download PDF
27. Animal-free genotoxicity testing: The COLIPA program
- Author
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Pfuhler, S., primary, Carmichael, P., additional, Fowler, P., additional, Curren, R., additional, Krul, C., additional, Ouedraogo, G., additional, Reisinger, K., additional, Marrec-Fairley, M., additional, Kirst, A., additional, and Hewitt, N., additional
- Published
- 2010
- Full Text
- View/download PDF
28. Development and characterization of an in vivo skin photomicronucleus assay in rats
- Author
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Reus, A. A., primary, Usta, M., additional, van Meeuwen, R. N. C., additional, Maas, W. J. M., additional, Robinson, S. A., additional, Kenny, J. D., additional, Pruimboom-Brees, I., additional, Clements, P. J., additional, Lynch, A. M., additional, and Krul, C. A. M., additional
- Published
- 2010
- Full Text
- View/download PDF
29. Determination of N -nitrosodimethylamine in artificial gastric juice by gas chromatography–mass spectrometry and by gas chromatography–thermal energy analysis
- Author
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Dallinga, J W, primary, Krul, C A M, additional, Tenfelde, A, additional, Moonen, E J C, additional, Vermeer, I T M, additional, van Doorn, D, additional, and Schothorst, R C, additional
- Published
- 2001
- Full Text
- View/download PDF
30. Application of a dynamic in vitro gastrointestinal tract model to study the availability of food mutagens, using heterocyclic aromatic amines as model compounds
- Author
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Krul, C, primary, Luiten-Schuite, A, additional, Baan, R, additional, Verhagen, H, additional, Mohn, G, additional, Feron, V, additional, and Havenaar, R, additional
- Published
- 2000
- Full Text
- View/download PDF
31. Antimutagenic activity of green tea and black tea extracts studied in a dynamic in vitro gastrointestinal model
- Author
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Krul, C., Luiten-Schuite, A., Tenfelde, A., Ommen, B. van, Verhagen, H., and Havenaar, R.
- Published
- 2001
- Full Text
- View/download PDF
32. Analysis of urinary caffeine metabolites to assess biotransformation enzyme activities by reversed-phase high-performance liquid chromatography
- Author
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Krul, C. and Hageman, G.
- Published
- 1998
- Full Text
- View/download PDF
33. The Virtual Human Platform for Safety Assessment (VHP4Safety) project: Next generation chemical safety assessment based on human data.
- Author
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Kienhuis A, Krul C, van Engelen J, Evelo CT, Hessel E, Hoekman J, Kramer N, Krop E, Masereeuw R, Moors E, Negro SO, Piersma AH, Pieters R, Teunis M, Willighagen E, and Legler J
- Abstract
The Virtual Human Platform for Safety Assessment (VHP4Safety) project aims to build a Virtual Human Platform (VHP) to protect human health and revolutionize the safety assessment of chemicals and pharmaceuticals by transitioning from animal-based to human-based approaches. The goal of this article is to introduce the project and its interdisciplinary approach to co-creation with multiple academic, regulatory, industrial and societal partners covering the entire safety assessment knowledge chain. Three research lines drive the project: 1) building the VHP; 2) feeding the VHP with human data; and 3) implementing the VHP. The project focusses on three case studies that incorporate human relevant scenarios not included in current animal-based safety assessment strategies. The VHP is built on tools and services, including pharmacokinetic and computational models, and integrates several data sources within each case study, including data on human physiology, epidemiology, toxicokinetic and -dynamic parameters, as well as data on chemical characteristics and exposures. In addition, the VHP integrates new data generated within the project using new approach methodologies representing key events within adverse outcome pathways. Implementation of the VHP is investigated using an innovation systems approach, engaging stakeholders and organizing training and education. Central to the VHP4Safety project is our co-creative approach, which facilitated by biannual designathons and hackathons that foster active involvement of all project participants from over 30 partner organizations. By integrating technological innovations with transparency and stakeholder collaboration, the VHP4Safety project will help shape the transition to the next generation safety assessment in which animal testing becomes redundant.
- Published
- 2024
- Full Text
- View/download PDF
34. Beyond Animal Testing Index: Benchmarking tool for a world beyond animal testing.
- Author
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Krul C, De Moor A, Stegmeijer K, Stoop R, Van Luijk J, and Prins JB
- Subjects
- Animals, Animal Testing Alternatives, European Union, Benchmarking, Medicine
- Abstract
While the original definition of replacement focuses on the replacement of the use of animals in science, a more contemporary definition focuses on accelerating the development and use of predictive and robust models, based on the latest science and technologies, to address scientific questions without the use of animals. The transition to animal free innovation is on the political agenda in and outside the European Union. The Beyond Animal Testing Index (BATI) is a benchmarking instrument designed to provide insight into the activities and contributions of research institutes to the transition to animal free innovation. The BATI allows participating organizations to learn from each other and stimulates continuous improvement. The BATI was modelled after the Access to Medicine Index, which benchmarks pharmaceutical companies on their efforts to make medicines widely available in developing countries. A prototype of the BATI was field-tested with three Dutch academic medical centers and two universities in 2020-2021. The field test demonstrated the usability and effectiveness of the BATI as a benchmarking tool. Analyses were performed across five different domains. The participating institutes concluded that the BATI served as an internal as well as an external stimulus to share, learn, and improve institutional strategies towards the transition to animal free innovation. The BATI also identified gaps in the development and implementation of 3R technologies. Hence, the BATI might be a suitable instrument for monitoring the effectiveness of policies. BATI version 1.0 is ready to be used for benchmarking at a larger scale.
- Published
- 2024
- Full Text
- View/download PDF
35. DARTpaths, an in silico platform to investigate molecular mechanisms of compounds.
- Author
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Bhalla D, Steijaert MN, Poppelaars ES, Teunis M, van der Voet M, Corradi M, Dévière E, Noothout L, Tomassen W, Rooseboom M, Currie RA, Krul C, Pieters R, van Noort V, and Wildwater M
- Subjects
- Software, Algorithms
- Abstract
Summary: Xpaths is a collection of algorithms that allow for the prediction of compound-induced molecular mechanisms of action by integrating phenotypic endpoints of different species; and proposes follow-up tests for model organisms to validate these pathway predictions. The Xpaths algorithms are applied to predict developmental and reproductive toxicity (DART) and implemented into an in silico platform, called DARTpaths., Availability and Implementation: All code is available on GitHub https://github.com/Xpaths/dartpaths-app under Apache license 2.0, detailed overview with demo is available at https://www.vivaltes.com/dartpaths/., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2022. Published by Oxford University Press.)
- Published
- 2023
- Full Text
- View/download PDF
36. Towards a reporting guideline for developmental and reproductive toxicology testing in C. elegans and other nematodes.
- Author
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van der Voet M, Teunis M, Louter-van de Haar J, Stigter N, Bhalla D, Rooseboom M, Wever KE, Krul C, Pieters R, Wildwater M, and van Noort V
- Abstract
Implementation of reliable methodologies allowing Reduction, Refinement, and Replacement (3Rs) of animal testing is a process that takes several decades and is still not complete. Reliable methods are essential for regulatory hazard assessment of chemicals where differences in test protocol can influence the test outcomes and thus affect the confidence in the predictive value of the organisms used as an alternative for mammals. Although test guidelines are common for mammalian studies, they are scarce for non-vertebrate organisms that would allow for the 3Rs of animal testing. Here, we present a set of 30 reporting criteria as the basis for such a guideline for Developmental and Reproductive Toxicology (DART) testing in the nematode Caenorhabditis elegans . Small organisms like C. elegans are upcoming in new approach methodologies for hazard assessment; thus, reliable and robust test protocols are urgently needed. A literature assessment of the fulfilment of the reporting criteria demonstrates that although studies describe methodological details, essential information such as compound purity and lot/batch number or type of container is often not reported. The formulated set of reporting criteria for C. elegans testing can be used by (i) researchers to describe essential experimental details (ii) data scientists that aggregate information to assess data quality and include data in aggregated databases (iii) regulators to assess study data for inclusion in regulatory hazard assessment of chemicals., (Published by Oxford University Press 2021.)
- Published
- 2021
- Full Text
- View/download PDF
37. Safer chemicals using less animals: kick-off of the European ONTOX project.
- Author
-
Vinken M, Benfenati E, Busquet F, Castell J, Clevert DA, de Kok TM, Dirven H, Fritsche E, Geris L, Gozalbes R, Hartung T, Jennen D, Jover R, Kandarova H, Kramer N, Krul C, Luechtefeld T, Masereeuw R, Roggen E, Schaller S, Vanhaecke T, Yang C, and Piersma AH
- Subjects
- Animal Testing Alternatives, Animals, Computer Simulation, European Union, Humans, In Vitro Techniques, Risk Assessment, Artificial Intelligence, Gene Ontology, Toxicity Tests
- Abstract
The 3Rs concept, calling for replacement, reduction and refinement of animal experimentation, is receiving increasing attention around the world, and has found its way to legislation, in particular in the European Union. This is aligned by continuing high-level efforts of the European Commission to support development and implementation of 3Rs methods. In this respect, the European project called "ONTOX: ontology-driven and artificial intelligence-based repeated dose toxicity testing of chemicals for next generation risk assessment" was recently initiated with the goal to provide a functional and sustainable solution for advancing human risk assessment of chemicals without the use of animals in line with the principles of 21
st century toxicity testing and next generation risk assessment. ONTOX will deliver a generic strategy to create new approach methodologies (NAMs) in order to predict systemic repeated dose toxicity effects that, upon combination with tailored exposure assessment, will enable human risk assessment. For proof-of-concept purposes, focus is put on NAMs addressing adversities in the liver, kidneys and developing brain induced by a variety of chemicals. The NAMs each consist of a computational system based on artificial intelligence and are fed by biological, toxicological, chemical and kinetic data. Data are consecutively integrated in physiological maps, quantitative adverse outcome pathway networks and ontology frameworks. Supported by artificial intelligence, data gaps are identified and are filled by targeted in vitro and in silico testing. ONTOX is anticipated to have a deep and long-lasting impact at many levels, in particular by consolidating Europe's world-leading position regarding the development, exploitation, regulation and application of animal-free methods for human risk assessment of chemicals., (Copyright © 2021 Elsevier B.V. All rights reserved.)- Published
- 2021
- Full Text
- View/download PDF
38. Validation of the 3D Skin Comet assay using full thickness skin models: Transferability and reproducibility.
- Author
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Reisinger K, Blatz V, Brinkmann J, Downs TR, Fischer A, Henkler F, Hoffmann S, Krul C, Liebsch M, Luch A, Pirow R, Reus AA, Schulz M, and Pfuhler S
- Subjects
- Cosmetics, Humans, Reproducibility of Results, Skin drug effects, Comet Assay standards, Cross-Linking Reagents adverse effects, DNA Damage, Micronucleus Tests methods, Mutagenicity Tests methods, Mutagens adverse effects, Skin pathology
- Abstract
Recently revised OECD Testing Guidelines highlight the importance of considering the first site-of-contact when investigating the genotoxic hazard. Thus far, only in vivo approaches are available to address the dermal route of exposure. The 3D Skin Comet and Reconstructed Skin Micronucleus (RSMN) assays intend to close this gap in the in vitro genotoxicity toolbox by investigating DNA damage after topical application. This represents the most relevant route of exposure for a variety of compounds found in household products, cosmetics, and industrial chemicals. The comet assay methodology is able to detect both chromosomal damage and DNA lesions that may give rise to gene mutations, thereby complementing the RSMN which detects only chromosomal damage. Here, the comet assay was adapted to two reconstructed full thickness human skin models: the EpiDerm™- and Phenion
® Full-Thickness Skin Models. First, tissue-specific protocols for the isolation of single cells and the general comet assay were transferred to European and US-American laboratories. After establishment of the assay, the protocol was then further optimized with appropriate cytotoxicity measurements and the use of aphidicolin, a DNA repair inhibitor, to improve the assay's sensitivity. In the first phase of an ongoing validation study eight chemicals were tested in three laboratories each using the Phenion® Full-Thickness Skin Model, informing several validation modules. Ultimately, the 3D Skin Comet assay demonstrated a high predictive capacity and good intra- and inter-laboratory reproducibility with four laboratories reaching a 100% predictivity and the fifth yielding 70%. The data are intended to demonstrate the use of the 3D Skin Comet assay as a new in vitro tool for following up on positive findings from the standard in vitro genotoxicity test battery for dermally applied chemicals, ultimately helping to drive the regulatory acceptance of the assay. To expand the database, the validation will continue by testing an additional 22 chemicals., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2018
- Full Text
- View/download PDF
39. Considering new methodologies in strategies for safety assessment of foods and food ingredients.
- Author
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Blaauboer BJ, Boobis AR, Bradford B, Cockburn A, Constable A, Daneshian M, Edwards G, Garthoff JA, Jeffery B, Krul C, and Schuermans J
- Subjects
- Animals, Biotransformation, Cell Culture Techniques, Humans, Quantitative Structure-Activity Relationship, Food Safety
- Abstract
Toxicology and safety assessment are changing and require new strategies for evaluating risk that are less depending on apical toxicity endpoints in animal models and relying more on knowledge of the mechanism of toxicity. This manuscript describes a number of developments that could contribute to this change and implement this in a stepwise roadmap that can be applied for the evaluation of food and food ingredients. The roadmap was evaluated in four case studies by using literature and existing data. This preliminary evaluation was shown to be useful. However, this experience should be extended by including examples where experimental work needs to be included. To further implement these new insights in toxicology and safety assessment for the area of food and food ingredients, the recommendation is that stakeholders take action in addressing gaps in our knowledge, e.g. with regard to the applicability of the roadmap for mixtures and food matrices. Further development of the threshold of toxicological concern is needed, as well as cooperation with other sectors where similar schemes are under development. Moreover, a more comprehensive evaluation of the roadmap, also including the identification of the need for in vitro experimental work is recommended., (Copyright © 2016 ILSI Europe. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2016
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40. Integrated analysis of toxicity data of two pharmaceutical immunosuppressants and two environmental pollutants with immunomodulating properties to improve the understanding of side effects-A toxicopathologist׳s view.
- Author
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Kuper CF, Vogels J, Kemmerling J, Fehlert E, Rühl-Fehlert C, Vohr HW, and Krul C
- Subjects
- Animals, Azathioprine toxicity, Benzo(a)pyrene toxicity, Cyclosporine toxicity, Dose-Response Relationship, Drug, Female, Hexachlorobenzene toxicity, Humans, Lymphoid Tissue immunology, Male, Multivariate Analysis, Principal Component Analysis, Rats, Inbred Strains, Rats, Wistar, Sex Factors, Translational Research, Biomedical statistics & numerical data, Environmental Pollutants toxicity, Immunosuppressive Agents toxicity, Lymphoid Tissue drug effects, Lymphoid Tissue pathology, Toxicity Tests, Subacute methods, Translational Research, Biomedical methods
- Abstract
Data in a toxicity test are evaluated generally per parameter. Information on the response per animal in addition to per parameter can improve the evaluation of the results. The results from the six studies in rats, described in the paper by Kemmerling, J., Fehlert, E., Rühl-Fehlert, C., Kuper, C.F., Stropp, G., Vogels, J., Krul, C., Vohr, H.-W., 2015. The transferability from rat subacute 4-week oral toxicity study to translational research exemplified by two pharmaceutical immunosuppressants and two environmental pollutants with immunomodulating properties (In this issue), have been subjected to principal component analysis (PCA) and principal component discriminant analysis (PC-DA). The two pharmaceuticals azathioprine (AZA) and cyclosporine A (CSA) and the two environmental pollutants hexachlorobenzene (HCB) and benzo(a)pyrene (BaP) all modulate the immune system, albeit that their mode of immunomodulation is quite diverse. PCA illustrated the similarities between the two independent studies with AZA (AZA1 and AZA2) and CSA (CSA1 and CSA2). The PC-DA on data of the AZA2 study did not increase substantially the information on dose levels. In general, the no-effect levels were lower upon single parameter analysis than indicated by the distances between the dose groups in the PCA. This was mostly due to the expert judgment in the single parameter evaluation, which took into account outstanding pathology in only one or two animals. The PCA plots did not reveal sex-related differences in sensitivity, but the key pathology for males and females differed. The observed variability in some of the control groups was largely a peripheral blood effect. Most importantly, PCA analysis identified several animals outside the 95% confidence limit indicating high-responders; also low-to-non-responders were identified. The key pathology enhanced the understanding of the response of the animals to the four model compounds., (Copyright © 2015 Elsevier B.V. All rights reserved.)
- Published
- 2015
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41. The transferability from rat subacute 4-week oral toxicity study to translational research exemplified by two pharmaceutical immunosuppressants and two environmental pollutants with immunomodulating properties.
- Author
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Kemmerling J, Fehlert E, Kuper CF, Rühl-Fehlert C, Stropp G, Vogels J, Krul C, and Vohr HW
- Subjects
- Administration, Oral, Animals, Azathioprine toxicity, Benzo(a)pyrene toxicity, Cyclosporine toxicity, Female, Guidelines as Topic, Hexachlorobenzene toxicity, Humans, Immunity, Humoral drug effects, Lymphoid Tissue immunology, Lymphoid Tissue pathology, Macrophages drug effects, Macrophages metabolism, Male, Organ Size drug effects, Organ Specificity, Rats, Inbred Strains, Rats, Wistar, Reactive Oxygen Species metabolism, Environmental Pollutants toxicity, Immunosuppressive Agents toxicity, Lymphoid Tissue drug effects, Toxicity Tests, Subacute methods, Translational Research, Biomedical methods
- Abstract
Exposure to chemicals may have an influence on the immune system. Often, this is an unwanted effect but in some pharmaceuticals, it is the intended mechanism of action. Immune function tests and in depth histopathological investigations of immune organs were integrated in rodent toxicity studies performed according to an extended OECD test guideline 407 protocol. Exemplified by two immunosuppressive drugs, azathioprine and cyclosporine A, and two environmental chemicals, hexachlorobenzene and benzo[a]pyrene, results of subacute rat studies were compared to knowledge in other species particular in humans. Although immune function has a high concordance in mammalian species, regarding the transferability from rodents to humans various factors have to be taken into account. In rats, sensitivity seems to depend on factors such as strain, sex, stress levels as well as metabolism. The two immunosuppressive drugs showed a high similarity of effects in animals and humans as the immune system was the most sensitive target in both. Hexachlorobenzene gave an inconsistent pattern of effects when considering the immune system of different species. In some species pronounced inflammation was observed, whereas in primates liver toxicity seemed more obvious. Generally, the immune system was not the most sensitive target in hexachlorobenzene-treatment. Immune function tests in rats gave evidence of a reaction to systemic inflammation rather than a direct impact on immune cells. Data from humans are likewise equivocal. In the case of benzo[a]pyrene, the immune system was the most sensitive target in rats. In the in vitro plaque forming cell assay (Mishell-Dutton culture) a direct comparison of cells from different species including rat and human was possible and showed similar reactions. The doses in the rat study had, however, no realistic relation to human exposure, which occurs exclusively in mixtures and in a much lower range. In summary, a case by case approach is necessary when testing immunotoxicity. Improvements for the translation from animals to humans related to immune cells can be expected from in vitro tests which offer direct comparison with reactions of human immune cells. This may lead to a better understanding of results and variations seen in animal studies., (Copyright © 2015 Elsevier B.V. All rights reserved.)
- Published
- 2015
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42. Regulatory acceptance and use of the Extended One Generation Reproductive Toxicity Study within Europe.
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Schiffelers MJ, Blaauboer BJ, Bakker WE, Hendriksen CF, and Krul C
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- Europe, Chemical Industry legislation & jurisprudence, Government Regulation, Guidelines as Topic, Reproduction drug effects, Toxicity Tests methods
- Abstract
The two-generation study (OECD TG 416) is the standard requirement within REACH to test reproductive toxicity effects of chemicals with production volumes >100 tonnes. This test is criticized in terms of scientific relevance and animal welfare. The Extended One Generation Reproductive Toxicity Study (EOGRTS), incorporated into the OECD test guidelines in 2011 (OECD TG 443) has the potential to replace TG 416, while using only one generation of rats and being more informative. However, its regulatory acceptance proved challenging. This article reconstructs the process of regulatory acceptance and use of the EOGRTS and describes drivers and barriers influencing the process. The findings derive from literature research and expert interviews. A distinction is made between three sub-stages; The stage of Formal Incorporation of the EOGRTS into OECD test guidelines was stimulated by retrospective analyses on the value of the second generation (F2), strong EOGRTS advocates, animal welfare concern and changing US and EU chemicals legislation; the stage of Actual Regulatory Acceptance within REACH was challenged by legal factors and ongoing scientific disputes, while the stage of Use by Industry is influenced by uncertainty of registrants about regulatory acceptance, high costs, the risk of false positives and the manageability of the EOGRTS., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2015
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43. Regulatory acceptance and use of 3R models for pharmaceuticals and chemicals: expert opinions on the state of affairs and the way forward.
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Schiffelers MJ, Blaauboer BJ, Bakker WE, Beken S, Hendriksen CF, Koëter HB, and Krul C
- Subjects
- Animals, Animals, Laboratory, Europe, Humans, Models, Animal, Models, Theoretical, Animal Testing Alternatives standards, Drug Industry trends, Risk Assessment methods, Risk Assessment standards
- Abstract
Pharmaceuticals and chemicals are subjected to regulatory safety testing accounting for approximately 25% of laboratory animal use in Europe. This testing meets various objections and has led to the development of a range of 3R models to Replace, Reduce or Refine the animal models. However, these models must overcome many barriers before being accepted for regulatory risk management purposes. This paper describes the barriers and drivers and options to optimize this acceptance process as identified by two expert panels, one on pharmaceuticals and one on chemicals. To untangle the complex acceptance process, the multilevel perspective on technology transitions is applied. This perspective defines influences at the micro-, meso- and macro level which need alignment to induce regulatory acceptance of a 3R model. This paper displays that there are many similar mechanisms within both sectors that prevent 3R models from becoming accepted for regulatory risk assessment and management. Shared barriers include the uncertainty about the value of the new 3R models (micro level), the lack of harmonization of regulatory requirements and acceptance criteria (meso level) and the high levels of risk aversion (macro level). In optimizing the process commitment, communication, cooperation and coordination are identified as critical drivers., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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44. State of the art on alternative methods to animal testing from an industrial point of view: ready for regulation?
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Ashton R, De Wever B, Fuchs HW, Gaca M, Hill E, Krul C, Poth A, and Roggen EL
- Subjects
- Animal Experimentation legislation & jurisprudence, Animal Testing Alternatives methods, Animals, Consensus Development Conferences as Topic, Europe, Industry legislation & jurisprudence, Information Dissemination, Research, Risk Assessment methods, Animal Testing Alternatives legislation & jurisprudence, Government Regulation, Toxicity Tests methods
- Abstract
Despite changing attitudes towards animal testing and current legislation to protect experimental animals, the rate of animal experiments seems to have changed little in recent years. On May 15-16, 2013, the In Vitro Testing Industrial Platform (IVTIP) held an open meeting to discuss the state of the art in alternative methods, how companies have, can, and will need to adapt and what drives and hinders regulatory acceptance and use. Several key messages arose from the meeting. First, industry and regulatory bodies should not wait for complete suites of alternative tests to become available, but should begin working with methods available right now (e.g., mining of existing animal data to direct future studies, implementation of alternative tests wherever scientifically valid rather than continuing to rely on animal tests) in non-animal and animal integrated strategies to reduce the numbers of animals tested. Sharing of information (communication), harmonization and standardization (coordination), commitment and collaboration are all required to improve the quality and speed of validation, acceptance, and implementation of tests. Finally, we consider how alternative methods can be used in research and development before formal implementation in regulations. Here we present the conclusions on what can be done already and suggest some solutions and strategies for the future.
- Published
- 2014
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45. International ring trial of the epidermal equivalent sensitizer potency assay: reproducibility and predictive-capacity.
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Teunis MA, Spiekstra SW, Smits M, Adriaens E, Eltze T, Galbiati V, Krul C, Landsiedel R, Pieters R, Reinders J, Roggen E, Corsini E, and Gibbs S
- Subjects
- Allergens chemistry, Animal Testing Alternatives, Animals, Cells, Cultured, Epidermis immunology, Humans, In Vitro Techniques, Interleukin-18 immunology, Interleukin-18 metabolism, Local Lymph Node Assay, Mice, Predictive Value of Tests, Reproducibility of Results, Toxicity Tests methods, Allergens adverse effects, Dermatitis, Allergic Contact etiology, Epidermis drug effects
- Abstract
This study describes the international ring trial of the epidermal-equivalent (EE) sensitizer potency assay. This assay does not distinguish a sensitizer from a non-sensitizer, but may classify known skin sensitizers according to their potency. It assesses the chemical concentration resulting in 50% cytotoxicity (EE-EC50) or the 2-fold increase in IL-1α (IL-1α2x). Four laboratories received 13 coded sensitizers. Reproducible results were obtained in each laboratory. A binary prediction model, EC50≥7 mg/ml=weak to moderate sensitizer and EC50<7 mg/ml=strong to extreme sensitizer had an accuracy of 77%. A superior EE (EC50 and IL-1α2x) correlation was observed with human in vivo DSA05 data compared to LLNA-EC3 data. Human in vivo NOEL and LLNA-EC3 data correlated to a similar extent to in vitro EE data. Our results indicate that this easily transferable EE potency assay is suitable for testing chemical allergens of unknown potencies and may now be ready for further validation, providing complementary potency information to other assays already undergoing validation for assessing skin sensitization potential.
- Published
- 2014
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46. Identification of biomarkers to detect residual pertussis toxin using microarray analysis of dendritic cells.
- Author
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Vaessen SF, Verkoeijen S, Vandebriel RJ, Bruysters MW, Pennings JL, Bos R, Krul CA, and Akkermans AM
- Subjects
- Cells, Cultured, Humans, Pertussis Toxin toxicity, Biomarkers, Pharmacological analysis, Dendritic Cells drug effects, Gene Expression Profiling, Microarray Analysis, Pertussis Toxin analysis, Pertussis Vaccine standards, Technology, Pharmaceutical methods
- Abstract
In this study we aimed to identify genes that are responsive to pertussis toxin (PTx) and might eventually be used as biological markers in a testing strategy to detect residual PTx in vaccines. By microarray analysis we screened six human cell types (bronchial epithelial cell line BEAS-2B, fetal lung fibroblast cell line MRC-5, primary cardiac microvascular endothelial cells, primary pulmonary artery smooth muscle cells, hybrid cell line EA.Hy926 of umbilical vein endothelial cells and epithelial cell line A549 and immature monocyte-derived dendritic cells) for differential gene expression induced by PTx. Immature monocyte-derived dendritic cells (iMoDCs) were the only cells in which PTx induced significant differential expression of genes. Results were confirmed using different donors and further extended by showing specificity for PTx in comparison to Escherichia coli lipopolysaccharide (LPS) and Bordetella pertussis lipo-oligosaccharide (LOS). Statistical analysis indicated 6 genes, namely IFNG, IL2, XCL1, CD69, CSF2 and CXCL10, as significantly upregulated by PTx which was also demonstrated at the protein level for genes encoding secreted proteins. IL-2 and IFN-γ gave the strongest response. The minimal PTx concentrations that induced production of IL-2 and IFN-γ in iMoDCs were 12.5 and 25IU/ml, respectively. High concentrations of LPS slightly induced IFN-γ but not IL-2, while LOS and detoxified pertussis toxin did not induce production of either cytokine. In conclusion, using microarray analysis we evaluated six human cell lines/types for their responsiveness to PTx and found 6 PTx-responsive genes in iMoDCs of which IL2 is the most promising candidate to be used as a biomarker for the detection of residual PTx., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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47. Transfer of a two-tiered keratinocyte assay: IL-18 production by NCTC2544 to determine the skin sensitizing capacity and epidermal equivalent assay to determine sensitizer potency.
- Author
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Teunis M, Corsini E, Smits M, Madsen CB, Eltze T, Ezendam J, Galbiati V, Gremmer E, Krul C, Landin A, Landsiedel R, Pieters R, Rasmussen TF, Reinders J, Roggen E, Spiekstra S, and Gibbs S
- Subjects
- Cell Line, Cell Survival, Dermatitis, Allergic Contact etiology, Humans, In Vitro Techniques, Keratinocytes metabolism, Reproducibility of Results, Allergens toxicity, Biological Assay, Interleukin-18 metabolism, Keratinocytes drug effects
- Abstract
At present, the identification of potentially sensitizing chemicals is carried out using animal models. However, it is very important from ethical, safety and economic point of view to have biological markers to discriminate allergy and irritation events, and to be able to classify sensitizers according to their potency, without the use of animals. Within the Sens-it-iv EU Frame Programme 6 funded Integrated Project (LSHB-CT-2005-018681), a number of in vitro, human cell based assays were developed which, when optimized and used in an integrated testing strategy, may be able to distinguish sensitizers from non-sensitizers. This study describes two of these assays, which when used in a tiered strategy, may be able to identify contact sensitizers and also to quantify sensitizer potency. Tier 1 is the human keratinocyte NCTC2544 IL-18 assay and tier 2 is the Epidermal Equivalent potency assay. The aim of this study is to show the transferability of the two-tiered approach with training chemicals: 3 sensitizers (DNCB, resorcinol, pPD) and 1 non sensitizer (lactic acid) in tier 1 and 2 sensitizers with different potency in tier 2 (DNCB; extreme and resorcinol; moderate). The chemicals were tested in a non-coded fashion. Here we describe the transferability to naïve laboratories, the establishment of the standard operating procedure, critical points, acceptance criteria and project management. Both assays were successfully transferred to laboratories that had not performed the assays previously. The two tiered approach may offer an unique opportunity to provide an alternative method to the Local Lymph Node Assay (LLNA). These assays are both based on the use of human keratinocytes, which have been shown over the last two decades, to play a key role in all phases of skin sensitization., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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48. The 3T3 neutral red uptake phototoxicity test: practical experience and implications for phototoxicity testing--the report of an ECVAM-EFPIA workshop.
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Ceridono M, Tellner P, Bauer D, Barroso J, Alépée N, Corvi R, De Smedt A, Fellows MD, Gibbs NK, Heisler E, Jacobs A, Jirova D, Jones D, Kandárová H, Kasper P, Akunda JK, Krul C, Learn D, Liebsch M, Lynch AM, Muster W, Nakamura K, Nash JF, Pfannenbecker U, Phillips G, Robles C, Rogiers V, Van De Water F, Liminga UW, Vohr HW, Wattrelos O, Woods J, Zuang V, Kreysa J, and Wilcox P
- Subjects
- 3T3 Cells, Animals, Biological Assay methods, Consumer Product Safety, Cosmetics toxicity, Drug Industry, Mice, Reactive Oxygen Species metabolism, Animal Testing Alternatives methods, Dermatitis, Phototoxic etiology, Neutral Red metabolism, Photosensitizing Agents toxicity, Toxicity Tests methods
- Abstract
This is the report from the "ECVAM-EFPIA workshop on 3T3 NRU Phototoxicity Test: Practical Experience and Implications for Phototoxicity Testing", jointly organized by ECVAM and EFPIA and held on the 25-27 October 2010 in Somma Lombardo, Italy. The European Centre for the Validation of Alternative Methods (ECVAM) was established in 1991 within the European Commission Joint Research, based on a Communication from the European Commission (1991). The main objective of ECVAM is to promote the scientific and regulatory acceptance of alternative methods which are of importance to the biosciences and which reduce, refine and replace the use of laboratory animals. The European Federation of Pharmaceuticals Industries and Association (EFPIA) represent the pharmaceutical industry operating in Europe. Through its direct membership of 31 national associations and 40 leading pharmaceutical companies, EFPIA is the voice on the EU scene of 2200 companies committed to researching, developing and bringing to patients new medicines that improve health and the quality of life around the world. The workshop, co-chaired by Joachim Kreysa (ECVAM) and Phil Wilcox (GSK, EFPIA) involved thirty-five experts from academia, regulatory authorities and industry, invited to contribute with their experiences in the field of phototoxicology. The main objectives of the workshop were: -to present 'in use' experience of the pharmaceutical industry with the 3T3 Neutral Red Uptake Phototoxicity Test (3T3 NRU-PT), -to discuss why it differs from the results in the original validation exercise, -to discuss technical issues and consider ways to improve the usability of the 3T3 NRU-PT for (non-topical) pharmaceuticals, e.g., by modifying the threshold of chemical light absorption to trigger photo-toxicological testing, and by modifying technical aspects of the assay, or adjusting the criteria used to classify a positive response. During the workshop, the assay methodology was reviewed by comparing the OECD Test Guideline (TG 432) with the protocols used in testing laboratories, data from EFPIA and JPMA 'surveys' were presented and possible reasons for the outcomes were discussed. Experts from cosmetics and pharmaceutical industries reported on their experience with the 3T3 NRU-PT and evidence was presented for phototoxic clinical symptoms that could be linked to certain relevant molecules. Brainstorming sessions discussed if the 3T3 NRU-PT needed to be improved and whether alternatives to the 3T3 NRU-PT exist. Finally, the viewpoint from EU and US regulators was presented. In the final session, the conclusions of the meeting were summarized, with action points. It was concluded that the 3T3 NRU-PT identifies phototoxicological hazards with a 100% sensitivity, and thus is accepted as the tier one test that correctly identifies the absence of phototoxic potential. Consequently, positive results in the 3T3 NRU-PT often do not translate into a clinical phototoxicity risk. Possible ways to improve the practical use of this assay include: (i) adaptation of changed UV/vis-absorption criteria as a means to reduce the number of materials tested, (ii) reduction of the highest concentration to be tested, and (iii) consideration of modifying the threshold criteria for the prediction of a positive call in the test., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
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49. Implementation challenges for designing integrated in vitro testing strategies (ITS) aiming at reducing and replacing animal experimentation.
- Author
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De Wever B, Fuchs HW, Gaca M, Krul C, Mikulowski S, Poth A, Roggen EL, and Vilà MR
- Subjects
- Animal Testing Alternatives trends, Animals, Chemical Industry trends, Drug Industry trends, Humans, Models, Biological, Risk Assessment methods, Risk Assessment trends, Toxicity Tests trends, Toxicology trends, Animal Testing Alternatives methods, Toxicity Tests methods, Toxicology methods
- Abstract
At the IVTIP (in vitro testing industrial platform) meeting of November 26th 2009 entitled 'Toxicology in the 21st century ('21C')--working our way towards a visionary reality' all delegates endorsed the emerging concept of the '21C' vision as the way forward to enable a thorough, reliable and systematic approach to future toxicity testing without the use of animals. One of the emerging concepts focused on integrating a defined number of tests modelling in vivo-relevant and well-characterised toxicity pathways representing mechanistic endpoints. At this meeting the importance of Integrated Testing Strategies (ITS) as tools towards reduction and eventually replacement of the animals currently used for hazard identification and risk assessment was recognised. A follow-up IVTIP Spring 2010 meeting entitled 'Integrated In Vitro Testing Strategies (ITS)--Implementation Challenges' was organised to address pending questions about ITS. This report is not a review of the ITS literature, but a summary of the discussions triggered by presented examples on how to develop and implement ITS. Contrasts between pharmaceutical and chemical industry, as well as a list of general but practical aspects to be considered while developing an ITS emerged from the discussions. In addition, current recommendations on the validation of ITS were discussed. In conclusion, the outcome of this workshop improved the understanding of the participants of some important factors that may impact the design of an ITS in function of its purpose (e.g., screening, or early decision making versus regulatory), the context in which they need to be applied (e.g., ICH guidelines, REACH) and the status and quality of the available tools. A set of recommendations of best practices was established and the importance of the applicability of the individual tests as well as the testing strategy itself was highlighted., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
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50. Toxicology in the 21st century--working our way towards a visionary reality.
- Author
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Berg N, De Wever B, Fuchs HW, Gaca M, Krul C, and Roggen EL
- Subjects
- Animal Testing Alternatives methods, Animal Testing Alternatives trends, Animals, European Union, Humans, National Academy of Sciences, U.S., Risk Assessment methods, Risk Assessment trends, Toxicity Tests trends, Toxicology trends, United States, Toxicity Tests methods, Toxicology methods
- Abstract
In November 2009 the In Vitro Testing Industrial Platform (IVTIP) organized a meeting entitled 'Toxicology in the 21st century--working our way towards a visionary reality'. Participating delegates included scientists, key opinion leaders, developers and users of 3Rs-related tests and testing strategies. This paper summarizes the discussions with respect to the conditions required to move the vision towards an applicable reality. It should not be considered as a comprehensive review of technologies that could be relevant for moving the in vitro testing and risk assessment field forward. Overall, the U.S. National Research Council (NRC) vision and strategy for toxicity testing in the 21st century was unanimously considered as the right approach to enable future toxicity testing without animal experimentation. Many elements of this vision were identified in the European initiatives aimed at the development of non-animal based methods. However, the need for concerted actions moving the current state-of-the-art towards a thorough, reliable and systematic approach to future toxicity testing was made evident by the discussions. Among the difficulties and hurdles on the way forward, the lack of physiologically relevant, metabolic competent and robust in vivo, ex vivo and in vitro models of both healthy and diseased people was frequently mentioned. In addition, there was a call for immediate implementation of emerging technologies and paradigms considered to be essential for transferring the vision into the reality of a toxicity-testing system assessing biologically significant perturbations in key pathways which are relevant for human biology. While the unique strengths of each of the available and emerging technologies was recognized, integration of available data and emerging technologies to integrated testing strategies (ITS) was highlighted as the preferred way forward. Method harmonization and standardization, as well as procedures and guidelines for putting together ITS, were urgently requested in order to facilitate proper implementation and acceptance. There was an urgent call for better coordination of the efforts that are ongoing or initiated in the 3Rs arena at national and international level. Education, training, communication and dissemination were addressed. It was recognised that the EPAA, through its 'Platform for Communication and Dissemination', has a very important and central role in this area., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2011
- Full Text
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