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, 38 microbial mutagenicity assays and 17 in vivo micronucleus assays have been initiated or completed. Sixteen in vivo Comet assays have been conducted in one or multiple tissues including blood, liver, kidney, stomach, colon, and brain. In addition, Comet assays have been conducted in vitro, in collaboration with an NIEHS laboratory, 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. An NTP research study designed to examine the effects of low dose benzene exposure in genetically diverse mice has been initiated that may ultimately help to establish lower exposure limits for workers; micronucleus frequencies in blood and bone marrow of benzene-exposed mice will be a major biomarker assessed in this NTP study. 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 examined 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 validation studies in mice have been successfully conducted. 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.