Report of the IWGT working group on strategies and interpretation of regulatory in vivo tests: I. Increases in micronucleated bone marrow cells in rodents that do not indicate genotoxic hazards
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- 作者：D.J. Tweats ; D. Blakey ; R.H. Heflich ; A. Jacobs ; S.D. Jacobsen ; T. Morita ; T. Nohmi ; M.R. O’ ; Donovan ; Y.F. Sasaki ; T. Sofuni ; et al.
- 关键词：IWGT ; Genotoxicity tests ; In vivo ; Rodent bone marrow ; Micronucleus ; Specificity ; False positive ; Changes in physiology ; Hypothermia ; Hyperthermia ; Spindle disruption ; Erythropoiesis ; Bone marrow cell toxicity ; Pharmacologically related changes ; Re
- 刊名：Mutation Research/Genetic Toxicology and Environmental Mutagenesis
- 出版年：2007
- 出版时间：3 February 2007
- 年：2007
- 卷：627
- 期：1
- 页码：78-91
- 全文大小：532 K
文摘
In vivo genotoxicity tests play a pivotal role in genotoxicity testing batteries. They are used both to determine if potential genotoxicity observed in vitro is realised in vivo and to detect any genotoxic carcinogens that are poorly detected in vitro. It is recognised that individual in vivo genotoxicity tests have limited sensitivity but good specificity. Thus, a positive result from the established in vivo assays is taken as strong evidence for genotoxic carcinogenicity of the compound tested. However, there is a growing body of evidence that compound-related disturbances in the physiology of the rodents used in these assays can result in increases in micronucleated cells in the bone marrow that are not related to the intrinsic genotoxicity of the compound under test. For rodent bone marrow or peripheral blood micronucleus tests, these disturbances include changes in core body temperature (hypothermia and hyperthermia) and increases in erythropoiesis following prior toxicity to erythroblasts or by direct stimulation of cell division in these cells. This paper reviews relevant data from the literature and also previously unpublished data obtained from a questionnaire devised by the IWGT working group. Regulatory implications of these findings are discussed and flow diagrams have been provided to aid in interpretation and decision-making when such changes in physiology are suspected.