Next Generation Testing Strategies for Assessment of Genotoxicity

Project SummaryIt is well recognized that current batteries of genetic toxicology assays exhibit two critical deficienciesFirstthe throughput capacity of in vitro mammalian cell genotoxicity tests is lowand does not meet current needsSecondconventional assays provide simplistic binary callsgenotoxic or non genotoxicIn this scheme there is little or no consideration for potencyand virtually no information is provided about molecular targets and mechanismsThese deficiencies in hazard characterization prevent genotoxicity data from optimally contributing to modern risk assessmentswhere this information is essentialWe will address these major problems with current in vitro mammalian cell genetic toxicity assays by developing methods and associated commercial assay kits that dramatically enhance throughput capacityand delineate genotoxicantsandaposprimary molecular targetswhile simultaneously providing information about potencyOnce biomarkers and a family of multiplexed assays have been developed for these purposesan interlaboratory trial will be performed with prototype assay kits to assess the transferability of the methods Project NarrativeDNA damage that cannot be faithfully repaired results in gene mutation and or chromosomal aberrationsand these effects are known to contribute to cancer and other severe diseasesThusthere is an important need for sensitive assays to evaluate chemicals for genotoxic and other deleterious effectsThe work proposed herein will address issues that have plagued genotoxicity assessments for the last several decadeslow throughputlack of potency metricsand little to no information about molecular targetsWe will address these major problems with current genetic toxicity assays by developing new methods and associated commercial assay kits