Title: Development of Structure-Activity Relationships for Pharmacotoxicological Endpoints relevant to European Union Legislation
Authors: LESSIGIARSKA Iglika
Publication Year: 2006
JRC N°: JRC37649
URI: http://publications.jrc.ec.europa.eu/repository/handle/JRC37649
Type: PhD Theses
Abstract: In this project quantitative structure-activity relationships (QSARs) were developed for several toxicological endpoints, including chemical cytotoxicity and acute toxicity, and biokinetic parameters related to penetration of chemical compounds through the blood-brain barrier (BBB). QSARs are computer-based mathematical models, which give information about the intrinsic properties of compounds (such as potential biological effects) on the basis of their chemical structure alone. For the regulatory assessment of chemicals and chemical products, the proposed new EU legislation called REACH (Registration, Evaluation and Authorisation of Chemicals) foresees that there will be an increased use of QSARs as an alternative approach to (animal) testing. In this project, QSARs were developed for compound penetration through the BBB in vivo and through several membrane models in vitro, taking into account penetration by both passive diffusion and active transport. The classification of compounds as low or high BBB penetrators was explored and a simple classification QSAR model based on compound lipophilicity and H-bonding ability was obtained. The BBB transport of compounds known to interact with the P-glycoprotein (one of the BBB efflux transport systems) was modelled by 3D-QSAR analysis, using hydrophobic and electrostatic molecular fields. Toxicities to a broad range of biological systems were also investigated, including unicellular organisms like bacteria and algae, isolated human and rodent cells, and in vivo toxicity to Daphnia, fish, rodents and humans. Similarities between the toxic effects for some of these systems were identified. Baseline toxicity effects (relationships between compound toxicity and lipophilicity) attributed to non-polar narcotics were investigated and separate QSARs were obtained for compounds acting by different mechanisms of toxic action or belonging to different chemical types. Classification QSAR models were obtained applying the EU classification scheme for chemical toxicity. The project also includes an investigation of the feasibility of predicting in vivo human toxicity by combining in vitro data and molecular descriptors. The QSAR models developed contributed to a mechanistic understanding of the investigated biological effects. Some of the models could be applied in integrated testing strategies for the assessment of regulatory endpoints based on alternative (non-animal) methods.
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