Effects of azobenzene and aniline in the rodent bone marrow micronucleus test.
Azobenzene (AZB) is non-carcinogenic in mice, but a potent rat carcinogen, inducing tumours in the spleen and other abdominal organs. The present paper shows that AZB clearly induces micronuclei in the bone marrow of rats at a dose of 375 mg/kg and above. In mice, however, only a marginally positive response was seen at much higher doses, thus reflecting the species-specific carcinogenic effect of the compound. The clastogenic effect of a single dose of AZB was not detectable in the rat 24 h after dosing, but at the 48 h sampling time and later. However, when a multiple-dosing regimen was used, an accumulation of micronucleated polychromatic erythrocytes (PEs) was seen and the effect was detected 24 h after the last dose. Micronucleus induction in rats was paralleled by increased methaemoglobin levels followed by anaemia. This resulted in accelerated erythropoiesis, as indicated by both the increased percentage of PEs in bone marrow and the increased reticulocyte count in peripheral blood. In mice, anaemia and methaemoglobaemia were seen. However, there was no compensatory increase in the percentage of PEs or any consistent change in the reticulocyte count. Stimulation of erythropoiesis could therefore be a contributory factor in the micronucleus induction by AZB seen in rats. One of the major metabolites of AZB, aniline, was also found to cause micronucleus induction in rats. Aniline is also a rat-specific carcinogen. It may therefore be speculated that AZB acts as a carcinogen via the formation of aniline, which might then be metabolized in different ways in rats and mice.
Genetic and Reproductive Toxicology Department, Glaxo Group Research Ltd., Ware, UK.
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E
George
M
M
Andrews
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C
Westmoreland
D000814:Aniline Compounds / Q000633:toxicity*; D000818:Animals; D001391:Azo Compounds / Q000633:toxicity*; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology*; D002273:Carcinogens / Q000633:toxicity*; D003520:Cyclophosphamide / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008815:Mice, Inbred Strains; D015162:Micronucleus Tests; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains; D012016:Reference Values
D000814:Aniline Compounds; D001391:Azo Compounds; D002273:Carcinogens; D003520:Cyclophosphamide; C009850:azobenzene; C023650:aniline