ToxSci Advance Access originally published online on March 31, 2009
Toxicological Sciences 2009 109(2):172-179; doi:10.1093/toxsci/kfp067
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Published by Oxford University Press 2009.
Current and Future Application of Genetic Toxicity Assays: The Role and Value of In Vitro Mammalian Assays
,
,1,
,,,,,,,,,2
* Office of Science & Engineering Laboratories, U.S. Food and Drug Administration, Center for Devices and Radiological Health, White Oak, Silver Spring, Maryland 20993
FDA GeneTox Network
CDER Genetic Toxicology Subcommittee
Office of Pharmaceutical Sciences, U.S. Food and Drug Administration, Center for Drug Evaluation and Research, White Oak, Silver Spring, Maryland 20993
¶ Office of New Drugs, U.S. Food and Drug Administration, Center for Drug Evaluation and Research, White Oak, Silver Spring, Maryland 20993
|| Division of Genetic and Reproductive Toxicology, U.S. Food and Drug Administration, National Center for Toxicological Research, Jefferson, Arkansas 72079
||| Office of New Animal Drug Evaluation, U.S. Food and Drug Administration, Center for Veterinary Medicine, Rockville, Maryland 20855
|||| Office of Nutrition, Labeling, and Dietary Supplements, U.S. Food and Drug Administration, Center for Food Safety and Applied Nutrition, College Park, Maryland 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
1 To whom correspondence should be addressed at FDA/CDRH/OSEL/DB, Bldg. 64/3020, 10903 New Hampshire Avenue, Silver Spring, MD 20993. E-mail: rosalie.elespuru{at}fda.hhs.gov.
Received October 30, 2008; accepted March 20, 2009
 |
Abstract |
|---|
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), 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.). 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 and the U.S. Food and Drug Administration 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.
2 Present address: Genetic Toxicology Regulatory and Training Services, 19806 Greenside Terrace, Montgomery Village, MD 20886.