GENETIC TOXICITY IN BACTERIA AND RODENTS

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The Genetic Toxicity Testing contract provides for the assessment of potential adverse genetic effects from exposure to compounds under study by the NTP. Testing systems employed include both in vitro (animal cell-based and bacterial) and in vivo (rats and mice) assays. Three main tests are conducted routinely: in vitro bacterial mutagenicity assays, in vivo rodent peripheral blood micronucleus (MN) assays, and in vivo rodent DNA damage (Comet) assays in multiple tissues. The MN assays now routinely collect data by flow cytometric analysis of prepared blood samples rather than by scoring slides. This innovation has provided greater ability to detect induced chromosomal damage and has improved the objectivity of the test, as well as the speed of data collection. MN and Comet assays are typically conducted with the same set of animals, thereby maximizing data collection from a single treated animal, reducing animal usage, and reducing costs. During the past fiscal year, 18 microbial mutagenicity assays and 26 in vivo micronucleus assays have been initiated or completed. Twelve in vivo Comet assays have been conducted in one or multiple tissues including blood, liver, kidney, stomach, colon, and brain. In addition, in vitro Comet assays have been conducted to compare DNA repair activities among several different cell lines in an effort to better understand the role of certain mutant genes associated with particular cancers. During the next fiscal year, additional emphasis is expected on in vitro measures of gene mutation and chromosomal damageso as to continue to reduce and refine our use of whole animal tests. During this past fiscal year, another animal mutation endpoint that holds promise for application in human clinical and biomonitoring studies in the future, has been investigated in the testing laboratory: the pig-a mutation assay (phosphatidylinositol glycan anchor biosynthesis, class A gene). Mutations in this gene are easily detected in red blood cell samples from laboratory rodents, and updated methods to streamline the assay have been developed, so that integration into existing toxicity tests can be more be accomplished. During the next fiscal year, we will attempt to multiplex this assay with the in vivo MN and Comet assays, increasing the genetic toxicity information that we obtain from test animals to provide an even more comprehensive profile of the genetic toxicity potential of a chemical.