Comparison of single/multiple-dose protocols using triethylenemelamine and procarbazine hydrochloride for the mouse bone marrow micronucleus test.
Treatment of mice with a single dose of either 4.8 mg/kg of triethylenemelamine (TEM) or 348 mg/kg of procarbazine hydrochloride (PC) induced higher frequencies of micronucleated polychromatic erythrocytes (MPE) after 48 h than after 24 h. The same observation was made when animals were treated with 1.6 or 8 mg/kg of TEM or 116 or 580 mg/kg of PC for 2 consecutive days (double-dose protocol). Surprisingly, the third dose of either 1.6 or 8 mg/kg of TEM caused lower MPE frequencies at the 72-h than at the 48-h sampling time. The observation that lower MPE frequencies after 72 h were also accompanied by reduced bone marrow toxicity might have reflected a drug-related adaptive reaction of the animals, for example the induction of detoxifying enzymes. Mean MPE frequencies as well as bone marrow toxicity were also slightly decreased after the third dose of either 116 or 580 mg/kg of PC, but statistical analysis showed no differences between the 48-h and the 72-h sampling times as regards the MPE frequencies and bone marrow toxicity. In addition to the high mean MPE frequency observed after 2 doses of 116 mg/kg of PC at the 48-h sampling time, a late increase in micronucleus induction was also seen after triple dosing at the 96-h sampling time. The present experiments with TEM and PC showed similar sensitivity for the multiple-dose assays when compared with the single-dose micronucleus test. In the case of the triple-dose assay, bone marrow toxicity proved to be a critical factor for appropriate dose selection. The computerized image analysis system was a convenient and time-saving tool for the automatic scoring of large quantities of cells for micronuclei as well as for the evaluation of bone marrow depression from the entire cell population analyzed for micronuclei.
Romagna
F
F
Drug Safety Assessment-Toxicology, Sandoz Ltd., Basel, Switzerland.
Schneider
B M
BM
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects*; D001854:Bone Marrow Cells; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004912:Erythrocytes / Q000187:drug effects / Q000648:ultrastructure; D051379:Mice; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects*; D015162:Micronucleus Tests / Q000379:methods; D011344:Procarbazine / Q000008:administration & dosage / Q000494:pharmacology*; D012016:Reference Values; D014265:Triethylenemelamine / Q000008:administration & dosage / Q000494:pharmacology*
D011344:Procarbazine; D014265:Triethylenemelamine