RECONCILIATION OF 5 NEGATIVE AND 4 POSITIVE REPORTS OF THE ACTIVITY OF DIMETHYLNITROSAMINE IN THE MOUSE BONE-MARROW MICRONUCLEUS ASSAY

Five positive and four negative reports of the activity of dimethylnit rosamine (DMN) in the mouse bone marrow micronucleus assay exist in th e literature: toxicity and micronucleus experiments have been conducte d to resolve this finely balanced conflict of data. The maximum dose a t 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 let hal within 1-2 days. None the less, micronucleus assays can be conduct ed with DMN up to dose levels of 100 mg/kg if animals are sampled with in 24 h of dosing, i.e. before they die. We have demonstrated clear po sitive 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) ma rginal 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 report s to be explained. The present data for DMN focus attention on the nee d 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 mag b e caused by the failure of investigators to study, adequately, the tox icity of chemicals. It is proposed that positive genotoxicity test dat a generated only at lethal dose-levels are of no toxicological value.