Currently, safety testing of chemicals and drugs is primarily achieved via animal testing. For ethical, scientific and economic reasons, the development of reliable, non-animal based testing approaches is needed. To contribute to this goal, TNO coordinates a new project in which systems biology, kinetic modeling and data mining are applied to integrate clinical data with non-animal based toxicological data.
The Netherlands Organisation for Health Research and Development (ZonMW) granted the project 'Systems toxicology supported data infrastructure for human risk assessment', to continue the development of the current 'ASAT Knowledge Base'. The Knowledge Base is based upon the 'Assuring Safety without Animal Testing' (ASAT) principle, in which human disease data is integrated with data from non-animal models (1). Aim of the new 1.6 M€ project is to understand how chemicals or drugs cause diseases, via the integration of mechanistic data from cultured cells with information from human disease mechanisms. Further, the Knowledge Base will be combined with new experimental data and kinetic models to estimate if effects observed at concentrations of chemicals applied to cell cultures can be translated to effects at expected exposure levels in humans. In this way, non-animal based toxicological risk assessment in relation to realistic exposure may ultimately become feasible.
The ASAT Knowledge Base will be primarily populated with data models to predict major health effects often encountered during the safety evaluation of drugs and chemicals. These are cholestasis (the obstruction of bile flow from the liver to the duodenum), allergic contact dermatitis (the development of allergic skin reactions), and liver cancer. An evaluation how the newly developed models can be implemented in the risk assessment process will be performed, via interactions with OECD, ECHA and ECVAM.
This is an interdisciplinary project, requiring expertise in bioinformatics, IT, mechanistic toxicology, in vitro toxicology, kinetic modeling, as well as genomics technologies to generate non-animal based data. To accommodate this, the project builds upon a strong consortium of the following partners: Rijksuniversiteit Groningen; Radboud University Nijmegen Medical Centre; Rijksinstituut voor Volksgezondheid en Milieu; Maastricht University; Janssen Pharmaceutica NV; Simcyp Limited, and TNO.
Drug induced liver injury
The research group Pharmacokinetics, Toxicology and Targeting (sub-group Drug Metabolism & Toxicology of Prof. dr. G.M.M. Groothuis and subgroup Pharmacokinetics of Dr. J.H. Proost) is focused on the development of in vitro systems with human tissue for drug metabolism and toxicology studies and pharmacokinetic and toxicokinetic modelling. In this project this group will be involved in the part of the project that focusses on drug-induced liver injury, in particular cholestasis, by generating in vitro data on enzymes and transporters involved in bilirubin and bile salt disposition, and in vitro toxicogenomics data, and the development of a biokinetic and PBPK model describing drug-induced cholestasis in the liver.
It is expected that the outcome of the project will deliver a knowledge base ultimately applicable to support non-animal based hazard and risk assessment for chemicals and drugs, concerning cholestasis, allergic contact dermatitis and liver cancer as endpoints. In addition, the ASAT Knowledge Base will be used to liaise with similar international efforts for improving risk assessment.
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