Relevance and Follow-up of Positive Results in In Vitro Genetic Toxicity Testing

The rate of positive compounds in in vitro genetic toxicology tests is known to be high, especially in the in vitro chromosome damage tests (e.g., 25% of approved drugs in the Physician’s Desk Reference were positive in this test).  Further, the rate of false positives for noncarcinogens in in vitro genotoxicity assays has been shown to be extremely high.  Because it is generally considered that data obtained in vitro is a demonstration of the intrinsic genotoxic properties of the test compounds, other data, such as negative results from in vivo tests, are needed to help determine the biological significance of the in vitro positive result. 

It is recognized that some compounds are genotoxic via indirect mechanisms, e.g., impairment of the mitotic spindle, impairment of protein and DNA synthesis, nucleotide mis-incorporation, etc.  For these compounds, the possibility of establishing a safe level, threshold exists.

Finally, while the relevance of in vitro positive results obtained under extreme experimental conditions (e.g., severe cytotoxicity, high concentrations of the test material) is often debated, threshold and weight-of-evidence approaches are currently not well-accepted by the regulatory authorities for DNA-reactive compounds.

n        The HESI membership and key stakeholders recognized the impact of positive results from in vitro genetic toxicity tests as a mutually important issue at the January 2005 Annual Meeting.  This topic was selected to become a component of the HESI scientific portfolio as part of the Emerging Issues Process.

n        The IVGT Subcommittee identified its leadership in early 2005, including a multi-sector, international steering team with representatives from the U.S., Europe and Japan, and has established liaisons with relevant activities already underway both within HESI (e.g., the Genomics Technical Committee, the Cancer Hazard Identification Strategies (CHIS) Project Committee, and the Biological Significance of DNA Adducts Project Committee) and outside of HESI (e.g., most notably, the International Workshop on Genotoxicity Testing, or IWGT).

n        The IVGT Subcommittee steering team submitted an abstract for the Annual Meeting of the Japanese Society of Toxicology in Nagoya in July, 2006.

n        The IVGT Subcommittee held an international workshop June 21-22, 2006 in Washington, DC that focused on appropriate interpretation of in vitro test results and suitable follow-up testing strategies for assessment of in vivo risk of somatic cell genetic damage and cancer induction.

n        The IVGT Subcommittee published the June 2006 workshop proceedings in Mutation Research

n        The IVGT Subcommittee held an international workshop on June 5-6, 2007 in Washington DC to discuss potential HESI workgroup projects and follow-up from the June 2006 meeting