New Technologies Workshop/Session Summary

Genetic Toxicology in the 21st Century Symposium Session

Chairpersons: Brinda Mahadevan, Schering-Plough Research Institute and Raymond Tice, U.S. National Institute of Environmental Health Sciences/National Toxicology Program.

The first speaker, Dr. Ronald Snyder (Schering-Plough Research Institute), summarized the history of genetic toxicology that led to the current standard battery of genotoxicity assays, including in silico analysis, and if the results obtained were optimally interpretable and/or provided value in making regulatory decisions. Dr. Snyder concluded his presentation by elaborating on the use of toxicogenomics in the 21st century to bridge between genotoxicity and carcinogenicity.

Dr. Tice then discussed the efforts between the U.S. National Toxicology Program, the National Institutes of Health Chemical Genomics Center (NCGC), and the U.S Environmental Protection Agency (U.S. EPA) (commonly known as the Tox21 Community) to collaborate on the research, development, validation, and translation of new and innovative test methods that characterize key steps in toxicity pathways. For the purpose of this presentation, Dr. Tice focused on the use of quantitative high throughput screens (HTS) used at the NCGC in 1536-well format to identify genotoxic compounds, including an approach based on increased cytotoxicity in DNA repair deficient chicken DT40 cell lines versus the corresponding wild-type cell line. The coordinated approaches, the lessons learned, and expectations for the future were highlighted.

Dr. Ann Richard (U.S. EPA National Center for Computational Toxicology) introduced ToxCast™, a research program to address chemical screening and prioritization needs for U.S. EPA by using a comprehensive battery of high throughput and high content screens to generate biological fingerprints and predictive signatures. The resulting data is released via a Web site called ACToR (Aggregated Computational Toxicology Resource). In the recently completed Phase I, 320 compounds (predominantly data rich pesticides) were tested in over 500 different assays. Results of a preliminary analysis of data obtained from three HTS assays potentially relevant to and informative of mutagenic and carcinogenic mechanisms in rodents and humans were presented.

Dr. Ray Kemper (Boehringer-Ingelheim Pharmaceuticals) spoke on the in silico prediction of genotoxicity as used in the pharmaceutical industry: current practice and future direction. He explained how computational or in silico prediction of genotoxicity has become an important tool owing to its low cost, ease of use, high throughput, and reasonable success at correctly identifying genotoxic compounds. Dr. Kemper also presented the results from a survey conducted across several major pharmaceutical industries on the current approaches and applications of in silico genotoxicity assessment.

The final speaker in the session, Dr. Daniel Benz (U.S. Food and Drug Administration) began his presentation by pointing out how using computational toxicology means less work. Dr. Benz emphasized the need for using more than one computational toxicology program in evaluating the genotoxic potential of a compound and how this approach will reduce the need for animal toxicological testing and human clinical experience in establishing the safety of U.S. FDA-regulated chemical substances. He also highlighted the importance of computer-based predictive models within the U.S. FDA’s Critical Path Initiative from laboratory concept to commercial product.

The feedback received from the attendees after the symposium session was very positive and an article as an outgrowth of this symposium is being planned. So, stay tuned!