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Content archived on 2024-06-11

Development of standardised in vitro methodology for hepatic and renal toxicity testing

Objective



The toxicological evaluation of compounds is essential in human risk assessment. In industrial practice, up to now in vitro methods have made only a minor contribution to this type of routine testing which represents about 20% of all laboratory animal use. Currrent in-vitro models are based either on primary cells which dedifferentiate continuously or on permanent cell lines that have lost various organ-specific cell functions. Thus, e.g. loss of biotransformation of xenobiotics is an inherent limitation of the predictive value of current cell cultures employed for toxicity testing. A recent breakthrough with regard to differentiation of cells in culture is the perifusion methodology where culture media are continuously renewed. Thus, a homeostasis of the cell environment is achieved in contrast to standard static culture conditions where waste products accumulate and nutrients are only intermittently supplied. The new perifusion technology has been shown to facilitate the maintenance of a highly differentiated state of cells. Cellular models based on perifusion also offer the new possibility of repetitive or even continuous exposure of cells to toxins.
Therefore, the time has come to develop improved routine in vitro models for toxicity measurement using standardised perifusion technology. Methodologically, the project will be confined to liver and kidney cells. The models established and characterised in the first year will be optimised for assessment of toxicity. Suitable and reliable endpoints of toxicity of relevance to in vivo toxicity testing will be developed in the second year of the project. In parallel an in vivo data base will be established and test compounds selected. The most promising models will be exchanged between the participating groups and prevalidated in the last year of the project. A subsequent validation process is envisaged depending on this prevalidation. This utilisation of innovative state-of-the-art cell culture technology will enable the development and standardisation of in vitro toxicity testing with a reliable predictive value (increased confidence in results). Thus, the project aims to develop measurement methods to improve the comparability of results for in-vitro diagnostic of toxicity e.g. of substances for therapeutic purposes.

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Coordinator

UNIVERSITAET KONSTANZ
EU contribution
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Address
10,Universitaetsstrasse 10
78457 KONSTANZ
Germany

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Participants (8)

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