Das Projekt "Short-term in vitro assays for long-term toxicity (PREDICTOMICS)" wird vom Umweltbundesamt gefördert und von Bayer AG durchgeführt. The development of new pharmaceutical compounds will be more efficient if human relevant toxicology information early in the selection process is available. While acute toxicity can be reasonably detected during the early preclinical stages of drug development, long-term toxicity is more difficult to predict, relying almost exclusively on animal experiments Animal experimentation of this kind is expensive and time consuming, raises ethical issues and do not necessarily represent a toxicological relevance to man. This project address the urgent need to develop in vitro based systems which are capable of predicting long term toxicity in humans. The major objectives of this project are:1)To develop advanced cell culture systems which as best possible represents the human liver and kidney in vivo. This will be achieved using combined strategies namely:co-cultures of resident cell types,targeted cell transformation,stem cell technology and new developments in organotypic cell culture (i.e. perfusion cultures and 3D cultures).2)To identify specific early mechanistic markers of toxin induced cell alterations by using integrated genomic,proteomic and cytomic analysis.3)To establish and prevalidate a screening platform (cell systems together with analysis tools) which is unambiguously predictive of toxin induced chronic renal and hepatic disease.This proposal is unique in it's mechanistic integration of the three levels of cellular dynamics (genome, proteome and cytome) together with advanced cell culture technology to detect early events of cellular injury. Only with such an integrated approach will in vitro techniques ever be applicable to predicting chronic toxicity in man. This project,if successful will(1) contribute to the replacement of animal testing in drug development, (2) increase ... Prime Contractor: Fundacion Hospital Universitario 'La Fe', Experimental Hepatology Unit, Research Center; Valencia; Espana.
Das Projekt "Optimisation and pre-validation of an in vitro test strategy for predicting human acute toxicity (A-CUTE-TOX)" wird vom Umweltbundesamt gefördert und von Fraunhofer-Institut für Toxikologie und Experimentelle Medizin (ITEM) durchgeführt. Validated alternative test methods are urgently required for safety toxicology of drugs, chemicals and cosmetics. Both REACH and 7th amendment of Cosmetics Directive call for the broad replacement of animal experiments on a short-term. While some animal tests for topical toxicity have been successfully replaced one by one by alternative methods, systemic toxicities require new test strategies in order to achive an adequate safety level. The aim of A-Cute-Tox is to develop a simple and robust in vitro t esting strategy for prediction of human acute systemic toxicity, which could replace the animal acute toxicity tests used today. The involvement of ECVAM in the project management and that of regulators (such as ECB) guarantees of the follow-up. The Scie ntific objectives of the project are: 1. Compilation, critical evaluation and generation of high quality in vitro and in vivo data for comparative analysis. 2. Identifying factors (ADE, metabolism and organ specificity) that influence the correlation betwe en in vitro toxicity (concentration) and in vivo toxicity (dosage), and to define an algorithm that accounts for this. 3. Explore innovative tools and cellular systems to identify new end-points and strategies to better anticipate animal and human toxicit y. 4. To design a simple, robost and reliable in vitro test strategy amenable for robotic testing, associated with the prediction model for acute toxicity. The project will develop the concepts required to compose testing strategies via the continuous imp lementation of novel in vitro and in silico alternatives. The approach requires the dimensions of a transnational Integrated Project, involving prominent toxicity research groups in the EU, close monitoring by and input from the regulatory community and p rofessional managerial steering. In return, it offers the realistic opportunity to achive a substantial reduction of animal experiments in acute systemic toxicity assessments. Prime Contractor: University of Oulu, Administration, Research and Innovation Services; Oulu; Suomi/Finland.
Das Projekt "Development of a high throughput genomics-based test for assessing genotoxic and carcinogenic properties of chemical compounds in vitro (CARCINOGENOMICS)" wird vom Umweltbundesamt gefördert und von European Bioinformatics Institute (EBI), Microarray Informatics Team durchgeführt. The major aim of CARCINOGENOMICS is to develop in vitro methods for assessing the carcinogenic potential of compounds, as an alternative to current rodent bioassays for genotoxicity and carcinogenicity. The major goal is to develop a battery of mechanism-based in vitro tests accounting for various modes of carcinogenic action. These tests will be designed to cover major target organs for carcinogenic action e.g. the liver, the lung, and the kidney. The novel assays will be based on the application of 'omics' technologies (i.e. genome-wide transcriptomics as well as metabonomics) to robust in vitro systems (rat/human), thereby also exploring stem cell technology, to generate 'omic' responses from a well-defined set of model compounds causing genotoxicity and carcinogenicity. Phenotypic markers for genotoxic and carcinogenic events will be assessed for the purpose of anchoring gene expression modulations, metabolic profiles and mechanism pathways. Through extensive biostatistics, literature mining, and analysis of molecular-expression datasets, differential genetic pathways will be identified capable of predicting mechanisms of chemical carcinogenesis in vivo. Furthermore, generated transcriptomic and metabonomic data will be integrated into a holistic understanding of systems biology, and applied to build an iterative in silico model of chemical carcinogenesis. Subsequently, predictive gene expression profiles, typically consisting of some 150-250 genes, will be loaded onto high throughput dedicated DNA-chips, thus accelerating the analysis of transcriptomic responses by a factor of 100. It is expected that the outcome of this project will generate a platform enabling the investigation of large numbers of compounds for their genotoxic and carcinogenic potential, as envisaged under the REACH initiative. This will contribute to speeding the identification of potential harmful substances to man, while lowering costs and reducing animal tests. Prime Contractor: Maastricht, University, Health Risk Analysis and Toxicology (Grat); Maastricht, Nederland.
Das Projekt "Forum for researchers and regulators to meet manufacturers of toxicology test methods (ForInViTox)" wird vom Umweltbundesamt gefördert und von Stiftung zur Förderung der Erforschung von Ersatz- und Ergänzungsmethoden zur Einschränkung von Tierversuchen durchgeführt. Bei dem Projekt werden laufende und bereits beendete EU-Projekte zu Ersatzmethoden für Tierversuche daraufhin untersucht, ob sie zu einem verbreiteten Einsatz der neu entwickelten Methoden geführt haben, bzw. warum dies möglicherweise nicht der Fall war. Parallel dazu werden potentielle Anwender sowie kommerzielle Anbieter solcher Testsysteme befragt, welche Hindernisse einem breiten Einsatz solcher Methoden im Wege stehen. Zusammen mit einer Expertengruppe wurden die Ergebnisse der Erhebungen analysiert, um aus diesen Erkenntnissen ein White Book für die EU zu konzipieren. Gleichzeitig wurden damit die Strukturen für einen Marktplatz entwickelt, bei dem die verschiedenen angesprochenen Gruppen zusammentreffen sollen, um ihre Bedürfnisse, Nachfragen und Angebote aufeinander abstimmen zu können. Hauptauftragnehmer: Expertradet ECB Miljokompetens AB; Sollentuna; SE.
Das Projekt "Development of a novel approach in hazard and risk assessment or reproductive toxicity by a combination and application of in vitro, tissue and sensor technologies (REPROTECT)" wird vom Umweltbundesamt gefördert und von Universitätsklinikum Tübingen Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Abteilung Toxikologie durchgeführt. Validated alternative test methods are urgently required for safety toxicology of drugs, chemicals and cosmetics. While some animal tests for topical toxicity have been successfully replaced one by one by alternative methods, systemic toxicities require new test strategies in order to achieve an adequate safety level of the consumer. In the project, ECVAM takes the lead to manage the development of a conceptual framework in the area of reproductive toxicity. The involvement of all stakeholders in the Project Board including the European Consensus Platform on Alternatives (ECOPA), European regulators, OECD, and Industry guarantees an efficient problem solving approach. Reproductive toxicity offers the opportunities that: i) a substantial number of animals are currently required in in-vivo assays; ii) the reproductive system can be broken down into well-defined sub-elements covering the reproductive cycle; iii) a number of pioneering alternatives have already been developed; and iv) the same animal experiments are carried out for drugs, chemicals and cosmetics. The project is composed of four elements, i.e. a) technological development of in vitro and b) sensor technologies c) the strategical development of a conceptual framework d) the dissemination and implementation activities. The project will develop the concepts required to compose testing strategies via the continuous implementation of novel in vitro and in silico alternatives. Problems to be solved include the development of substantial numbers of alternative test methods making use of advanced technologies. This approach requires the dimensions of a transnational Integrated Project, involving some of the most prominent reproductive toxicity research groups in the EU, close monitoring by and input from the regulatory community and professional managerial steering. In return, it offers the realistic opportunity to achieve a substantial reduction of animal experiment.