Quantitative Genotoxicity Analysis

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DESCRIPTION (provided by applicant): Some oxirane compounds are mutagenic and carcinogenic causing irreversible genotoxic effects. Because of this, oxirane-based dental composite resins must be genetically safe. The goal of this proposal is to identify non-genotoxic reactive monomers suitable for use in oxirane composite resin formulations. The specific aims in this project are: 1) to determine stability of suspected genotoxic functional groups in proposed monomers under physiologically relevant challenges; 2) to evaluate the reactive monomers and homologous series of related chemicals by mechanism based genetic toxicity testing to identify genotoxic and non-genotoxic structures and structure components; 3) to provide genotoxicity data for QSAR (Quantitative Structure Activity Relationships) so that specific and quantifiable relationships between molecular structure and genotoxicity can be identified; 4) to provide recommendations to the program project on structures of monomers that are predicted to be non-genotoxic and; 5) to evaluate the genotoxicity of new monomers developed as a consequence of QSAR predictions for purpose of validating predictions and providing gene-safe monomers for preparation of composite resins. QSAR. Analysis will be in coordination with the Molecular Modeling and Rational Biomaterials Design R01. QSAR predictions for new monomers will be developed in the Integrated Matrix Resin/Adhesives Systems R01. It is planned to evaluate 50 oxirane compounds. This includes three scientifically selected series of monomers and reference chemicals. The three series, aromatic, aliphatic and pyran oxirane monomers, represent those of interest to the program project. In all series, electron withdrawing and electron donating substituents are represented and molecules tat isolate these effects are evaluated. Thus, this project provides a systematic process to tailor the structure of oxirane containing compounds and make them gene-safe dental monomers for the highly reactive resin components of interest to this program project.