ToxSci Advance Access first published online on March 31, 2009
This version published online on April 9, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp067
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Published by Oxford University Press 2009.
Current and future application of genetic toxicity assays: the role and value of in vitro mammalian assays
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* Office of Science & Engineering Laboratories, U.S. Food and Drug Administration, Center for Devices and Radiological Health, White Oak, Silver Spring MD 20993
Office of Pharmaceutical Sciences, U.S. Food and Drug Administration, Center for Drug Evaluation and Research, White Oak, Silver Spring MD 20993
¶ Office of New Drugs, U.S. Food and Drug Administration, Center for Drug Evaluation and Research, White Oak, Silver Spring MD 20993
Division of Genetic and Reproductive Toxicology, U.S. Food and Drug Administration, National Center for Toxicological Research, Jefferson AR 72079
Office of New Animal Drug Evaluation, U.S. Food and Drug Administration, Center for Veterinary Medicine, Rockville MD 20855
|| Office of Nutrition, Labeling, and Dietary Supplements, U.S. Food and Drug Administration, Center for Food Safety and Applied Nutrition, College Park MD 20740
||| Office of Pollution Prevention and Toxics, U.S. Environmental Protection Agency, Washington DC 20460
|||| Office of Public Health Science, Food Safety and Inspection Service, U.S. Department of Agriculture, Washington DC 20250
3 To whom correspondence should be addressed: at FDA/CDRH/OSEL/DB, Bldg. 64/3020, 10903 New Hampshire Avenue, Silver Spring MD 20993. email: rosalie.elespuru{at}fda.hhs.gov
Received October 30, 2008; revision received March 2, 2009; accepted March 20, 2009
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Abstract |
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With the advent of new technologies (e.g., genomics, automated analyses, and in vivo monitoring), new regulations (e.g., the reduction of animal tests by the European REACH), and new approaches to toxicology (e.g., Toxicity Testing in the 21st Century National Research Council, 2007), the field of regulatory genetic toxicology is undergoing a serious re-examination. Within this context, Toxicological Sciences has published a series of articles in its Forum Section on the theme, "Genetic Toxicity Assessment: Employing the Best Science for Human Safety Evaluation" (beginning with Goodman et al., 2007). As a contribution to the Forum discussions, we present current methods for evaluating mutagenic/genotoxic risk using standard genotoxicity test batteries, and suggest ways to address and incorporate new technologies. We recognize that the occurrence of positive results in relation to cancer prediction has led to criticism of in vitro mammalian cell genetic toxicity assays. We address criticism of test results related to weak positives, associated only with considerable toxicity, only seen at high concentrations, not accompanied by positive results in the other tests of standard test batteries, and/or not correlating well with rodent carcinogenicity tests. We suggest that the problems pointed out by others with these assays already have been resolved, to a large extent, by international groups working to update assay protocols, and by changes in data interpretation at regulatory agencies. New guidances at the U.S. Environmental Protection Agency (EPA) and the U.S. Food and Drug Administration (FDA) improve data evaluation and help refocus risk assessment. We discuss the results of international groups working together to integrate new technologies and evaluate new tests, including human monitoring. We suggest that strategies for identifying human health risks should naturally change to integrate new technologies; however, changes should be made only when justified by strong scientific evidence of improvement in the risk assessment paradigm.
1 FDA GeneTox Network
2 CDER Genetic Toxicology Subcommittee
4 Present address: Genetic Toxicology Regulatory and Training Services, 19806 Greenside Terrace, Montgomery Village MD 20886