Clastogenic and aneugenic effects of three benzimidazole derivatives in the in vitro micronucleus test using human lymphocytes.
Three benzimidazole compounds thiabendazole (TBZ), carbendazim (MBC) and mebendazole (MEB) were analysed with the in vitro cytochalasin-B micronucleus test on human lymphocytes. TBZ was tested in isolated lymphocyte cultures and MBC and MEB were tested in both isolated lymphocyte and whole blood cultures. TBZ was tested up to 300 microM with and without S9-mix. Although signs of toxicity, without S9, were observed by a decrease in the division index at 300 microM, an increase in the frequency of micronucleated binucleates was not found with or without S9. MBC and MEB induced a statistically significant concentration-dependent increase in the micronucleus frequency. The effective concentration range for MEB (0.3-1.5 microM) was ten times lower than for MBC (5-25 microM). By means of fluorescence in situ hybridization with a 30 nucleotide oligomer of the alpha centromeric regions, common for all chromosomes, on the induced micronuclei MBC and MEB were found to induce a significant increase of centromere positive micronuclei in a dose-dependent manner. MBC and MEB are poorly soluble in water and therefore have a low bioavailability in vivo. However, increased micronucleus frequencies were found in this in vitro micronucleus study at doses comparable to in vivo plasma levels in mice and should, therefore, not be neglected in the risk evaluation of those compounds.
Van Hummelen
P
P
Laboratorium voor Antropogenetica, Vrije Universiteit Brussel, Belgium.
Elhajouji
A
A
Kirsch-Volders
M
M
D000328:Adult; D000782:Aneuploidy; D000818:Animals; D001562:Benzimidazoles / Q000097:blood / Q000633:toxicity*; D001711:Biotransformation; D002219:Carbamates; D002478:Cells, Cultured; D002875:Chromosomes / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008214:Lymphocytes / Q000187:drug effects* / Q000648:ultrastructure; D008463:Mebendazole / Q000097:blood / Q000633:toxicity*; D015162:Micronucleus Tests; D051381:Rats; D013827:Thiabendazole / Q000097:blood / Q000633:toxicity*
D001562:Benzimidazoles; D002219:Carbamates; D008463:Mebendazole; C006698:carbendazim; D013827:Thiabendazole