title: 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.
abstract: 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 This paper reviews relevant data from the literature and also previously unpublished data obtained from a questionnaire devised by the IWGT working group.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.
authors.affiliation: Centre for Molecular Genetics and Toxicology, University of Wales, Swansea, UK. djtweats@fish.co.uk
authors.forename: D J
authors.initials: DJ
authors.lastname: Tweats
authors.forename: D
authors.initials: D
authors.lastname: Blakey
authors.forename: R H
authors.initials: RH
authors.lastname: Heflich
authors.forename: A
authors.initials: A
authors.lastname: Jacobs
authors.forename: S D
authors.initials: SD
authors.lastname: Jacobsen
authors.forename: T
authors.initials: T
authors.lastname: Morita
authors.forename: T
authors.initials: T
authors.lastname: Nohmi
authors.forename: M R
authors.initials: MR
authors.lastname: O'Donovan
authors.forename: Y F
authors.initials: YF
authors.lastname: Sasaki
authors.forename: T
authors.initials: T
authors.lastname: Sofuni
authors.forename: R
authors.initials: R
authors.lastname: Tice
mesh_terms: D000814:Aniline Compounds / Q000633:toxicity; D000818:Animals; D001831:Body Temperature; D001854:Bone Marrow Cells / Q000187:drug effects*; D004921:Erythropoietin / Q000235:genetics / Q000633:toxicity; D017408:Guidelines as Topic; D006979:Hyperthermia, Induced; D015162:Micronucleus Tests; D009152:Mutagenicity Tests / Q000379:methods*; D009153:Mutagens / Q000633:toxicity*; D009285:Naphthoquinones / Q000633:toxicity; D019800:Phenol / Q000633:toxicity; D010659:Phenylhydrazines / Q000633:toxicity; D011725:Pyridines / Q000633:toxicity; D012110:Reserpine / Q000633:toxicity; D012377:Rodentia; D012680:Sensitivity and Specificity; D014230:Triazoles / Q000633:toxicity
chemical_list: D000814:Aniline Compounds; C117757:E 5842; D009153:Mutagens; D009285:Naphthoquinones; D010659:Phenylhydrazines; D011725:Pyridines; D014230:Triazoles; C030299:phenylhydrazine; D004921:Erythropoietin; D019800:Phenol; D012110:Reserpine; C023650:aniline; C005090:lawsone