Reconciliation of five negative and four positive reports of the activity of dimethylnitrosamine in the mouse bone marrow micronucleus assay.
Five positive and four negative reports of the activity of dimethylnitrosamine (DMN) in the mouse bone marrow micronucleus assay exist in the literature: toxicity and micronucleus experiments have been conducted to resolve this finely balanced conflict of data. The maximum dose at which mice can survive a single treatment with DMN is 10-12.5 mg/kg. A dose of 15 mg/kg is lethal within 4 days while higher doses are lethal within 1-2 days. None the less, micronucleus assays can be conducted with DMN up to dose levels of 100 mg/kg if animals are sampled within 24 h of dosing, i.e. before they die. We have demonstrated clear positive assay responses for DMN at lethal dose levels (30 and 60 mg/kg). At non-lethal (maximum tolerated) dose-levels (10 and 12.5 mg/kg) marginal positive or negative responses were observed. Both the oral and intraperitoneal injection routes of exposure have been studied. These observations enable the nine previous and divergent literature reports to be explained. The present data for DMN focus attention on the need to consider carefully the selection of dose-levels for use in short-term in vivo genotoxicity assays. In particular, it is suggested that many of the conflicts of assay data that exist in the literature may be caused by the failure of investigators to study, adequately, the toxicity of chemicals. It is proposed that positive genotoxicity test data generated only at lethal dose-levels are of no toxicological value.
Zeneca Central Toxicology Laboratory, Nr Macclesfield, Cheshire, UK.
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V
Morrison
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Ashby
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects*; D004128:Dimethylnitrosamine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D015162:Micronucleus Tests; D015203:Reproducibility of Results
D004128:Dimethylnitrosamine