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PubMed2002

A protocol for the in vitro micronucleus test. II. Contributions to the validation of a protocol suitable for regulatory submissions from an examination of 10 chemicals with different mechanisms of action and different levels of activity.

The in vitro micronucleus test is currently used as a screening assay during the early stages of drug development by pharmaceutical companies to identify chemicals likely to produce positive outcomes in the in vitro chromosome aberration assay. For several reasons the assay is being considered as an alternative to the aberration assay-it requires less laboratory time, less material and less training. However, the current screening protocols are not rigorous enough to fully satisfy concerns about genotoxic safety. Using a protocol previously developed by testing 16 chemicals, this manuscript contributes to the validation of the protocol using 10 additional chemicals. Furthermore, conclusions drawn from the developmental effort regarding the need for an extended exposure in the absence of metabolic activation, the number of cells to be counted, and the preferred statistical procedure for the assay are re-examined. The recommended, validated protocol utilizes cytochalasin B and 4h exposures in the presence and in the absence of metabolic activation, specifies the need to test to a relative survival rate of approximately 50%, requires the counting of 2,000 binucleated cells per treatment concentration, and employs a trend test for statistical analysis of the data.

Animals↗
PubMed1988

Micronucleus tests in mice on 39 food additives and eight miscellaneous chemicals.

A total of 47 chemical substances including 32 synthetic food additives, seven additives from natural sources, three trihalogenated methanes, two fluoro-compounds for dental use, one insecticide, and two other compounds were subjected to the micronucleus test in mice. Five compounds, i.e. chlorine dioxide, maltol, potassium bromate, sodium chlorite and sodium dehydroacetate, were found to induce micronuclei after a single ip injection. Potassium bromate, sodium chlorite and sodium dehydroacetate were tested further by oral administration, and potassium bromate showed a clearly positive result. Almost all the compounds which were negative with the single treatment were additionally tested by four or five multiple treatments, but none showed any indication of micronucleus induction.

Animals↗
PubMed1998

[Observation of inducing effect of five kinds of soft wood dust in micronucleus test].

The authors investigated the micronucleus frequencies (MP) in peripheral lymphocytes in 584 workers exposed to five kinds of soft wood dust and found that all kinds of soft wood dust could increase the micronucleus frequency. As the control's 95% confidential upper limit > or = 0.4% is defined as the standard for positivity the micronucleus positive frequency (MPF) in the exposure group is much higher than that in the control group (P < 0.01). Meanwhile the increase of exposure years may increase the MP, and the time-response relationship is evident (r = 0.90, P < 0.01). For different exposures, the MPFs are: 36.2% for linden, 26.3% for fir. 15.7% for lacebark pine, 9.6% for birch and 2.1% for polar. The positive rate of linden and fir exposure are significantly higher than that of the control group (P < 0.01). Water extract of these five kinds of soft wood dust can increase the frequencies of micronucleus in polychromatic red blood cell in mice's sternum marrow, which also showed a dose-response. The correlation coefficients are: 0.86 for linden 0.6 for fir, 0.39 for lacebark pine, 0.76 for birch and 0.73 for polar. All but the lacebark pine have the P value less than 0.01 (P < 0.01). At the dose of 15 g/kg body weight, micronucleus frequency induced by linden was the highest (0.8%), next were fir (0.71%), birch (0.65%), lacebark pine (0.63%), and polar (0.43%). The results from animal test are consistent with those from the exposure workers. These results suggest that there are some substances in soft wood which can induce chromosome aberration.

Adolescent↗
PubMed1991

The micronucleus test in pigs: induction of micronuclei in polychromatic erythrocytes by various doses of X-rays.

This paper describes the results of a study in which pigs were used in the bone marrow micronucleus assay. In a first experiment the spontaneous frequency of micronucleated polychromatic erythrocytes (MPE) among polychromatic erythrocytes (PE) was investigated in 78 animals. It was found that it is low with individual values of 0-4 MPE/1000 PE and a group average of 1.76 +/- 1.06% (mean +/- SD). In a second set of investigations animals were exposed to 0.25, 0.5, 1.0, 1.5, 2.25 and 2.75 Gy of 9-MeV X-irradiation performed as a single whole-body exposure. Time- and dose-dependent changes in micronucleus incidence were observed. Maximal group averages appeared nearly uniform 36 h post irradiation (p.i.). Considering the 36-h values in the dose range of 0-2.25 Gy there is a marked dose-effect relationship (r = 0.971). The data yield best to a regression curve of a third-grade polynomial indicating a complex interaction between dose and micronucleus formation. In conclusion, the results demonstrate that it appears feasible to use swine as target organisms in the micronucleus test to estimate the cytogenetic damage caused by ionizing radiations or, potentially, chemical compounds.

Animals↗
PubMed2001

The in vivo gut micronucleus test detects clastogens and aneugens given by gavage.

A general testing battery for pharmaceuticals includes a bacterial gene mutation assay, an in vitro chromosomal aberration or a gene mutation test on mammalian cells and an in vivo test for chromosome/genome mutations. The aim of this study was to determine whether the in vivo mouse gut micronucleus assay could be a more sensitive method to detect direct clastogens and/or aneugens given orally by gavage than the in vivo bone marrow micronucleus assay (which can also detect indirect genotoxins). Two laboratories collaborated in this project, one analysing bone marrow cells and the other analysing gut cells from the same animals. The reference substances tested in this study were colchicine (COL), carbendazim (CAR), tubulazole (TUB) and griseofulvin (GRI), all known aneugens, and 1,2-dimethylhydrazine (DMH), a colon carcinogen with clastogenic activity. For all substances tested, the in vivo gut micronucleus test was as sensitive as or more sensitive than the in vivo bone marrow micronucleus assay: COL and TUB induced micronuclei in both gut and bone marrow cells; DMH, CAR and GRI induced micronuclei only in gut cells. The results show that the micronucleus test on gut cells is able to detect clastogens and aneugens given orally by gavage, some of which were not detected by the bone marrow micronucleus test.

1,2-Dimethylhydrazine↗
PubMed1987

Micronucleus test in bone marrow of mice treated with 1-nitropropane, 2-nitropropane and cisplatin.

Micronucleus tests were carried out in bone marrow of mice treated with 1-nitropropane, 2-nitropropane and cisplatin. For 1-nitropropane and 2-nitropropane the results were negative. With cisplatin a dose-dependent increase in the number of polychromatic erythrocytes with micronuclei was observed. The lowest positive dose was 0.1 mg/kg (P less than 0.001, Mann-Whitney-Wilcoxon test). The hepatocarcinogen 2-nitropropane showed clastogenic activity in human lymphocytes in vitro in the presence of S9 (Bauchinger et al., 1987). The negative results in bone marrow suggest that short-lived genotoxic metabolites may be formed in the liver but do not reach the bone marrow.

Alkanes↗
PubMed1995

Antimutagenicity of eugenol in the rodent bone marrow micronucleus test.

The antimutagenic effect of eugenol on the mutagenicity of cyclophosphamide (CP), mitomycin C (MMC), ethyl methanesulfonate (EMS) and benzo[a]pyrene (B[a]P) was assessed in the rodent bone marrow micronucleus test using male Swiss mice. Oral administration of eugenol (0.4% in the diet) for 15 days was found to decrease significantly the frequency of micronucleated polychromatic erythrocytes (MPEs) elevated by CP. No effect was found on the frequency of MPEs elevated by MMC, EMS and B[a]P. The results provide some support for antimutagenic potency of eugenol in vivo.

Administration, Oral↗
PubMed1990

Cytogenetic effect of the thiocarbamate herbicides butylate, molinate and vernolate in the mouse bone marrow micronucleus test.

Three thiocarbamate herbicides, butylate (S-ethyl-diisobutylthiocarbamate), vernolate (S-propyl dipropylthiocarbamate) and molinate (S-ethyl-N,N-hexamethylenethiocarbamate) were assayed for cytogenetic effect in the mouse bone marrow micronucleus test. Butylate was inactive in bone marrow, vernolate caused a marginal increase in the incidence of micronucleated polychromatic erythrocytes only at a high toxic dose level. Molinate, the N,N-hexamethylene derivative was, however, strongly active in the bone marrow, causing a high frequency of micronucleated erythrocytes, even at subtoxic concentrations.

Animals↗
PubMed2003

Etoposide and merbarone are clastogenic and aneugenic in the mouse bone marrow micronucleus test complemented by fluorescence in situ hybridization with the mouse minor satellite DNA probe.

The topoisomerase II (topo II) inhibitors etoposide (VP-16) and merbarone (MER) were investigated with the in vivo micronucleus test (MN test) combined with fluorescence in situ hybridization (FISH) using the mouse minor satellite DNA probe to discriminate MN of clastogenic and aneugenic origin. All experiments were performed with male (102/ElxC3H/El) F1 mice bred in the mouse colony of the GSF Research Center. The sample size per experimental group was five animals and 2,000 polychromatic erythrocytes (PCE) were scored per animal from coded slides in the conventional MN test. A separate set of coded slides was used for the FISH analysis. All treatments consisted of single intraperitoneal injections. Colchicine (COL, 3 mg/kg) and mitomycin (MMC, 1 mg/kg) were used as a positive control aneugen and clastogen, respectively, and these compounds produced the expected responses. A dose of 1 mg/kg VP-16 induced 3.44% MNPCE (compared to the concurrent solvent control of 0.37%, P < 0.001) and of these 39.9% (1.4% MNPCE) showed one or more fluorescent signals. MER (7.5-60 mg/kg) increased the MNPCE frequencies in a dose-dependent manner, with 15 mg/kg being the lowest positive dose. At the highest dose of 60 mg/kg of MER, a total of 4.26% MNPCE were found (compared to 0.31% in the concurrent solvent control, P < 0.001) and of these 46.2% (2.0% MNPCE) contained one or more fluorescent signals. The data demonstrate that VP-16 and MER induced both clastogenic and aneugenic events despite their different modes of topo II inhibition.

Aneugens↗
PubMed1993

Reduction of genotoxicity of a creosote-contaminated soil after fungal treatment determined by the Tradescantia-micronucleus test.

The fungal degradation of polyaromatic hydrocarbons (PAH) in a contaminated soil from a hazardous waste site was evaluated in a pilot-scale study. As some PAH are known to be mutagens, the Tradescantia-micronucleus test (TRAD-MCN) was selected to evaluate the genotoxicity of the soil before and after fungal treatment. The genotoxicity test was conducted with Tradescantia clone 4430. Cuttings were exposed for 30 h to different dilutions of soil extracts from the PAH-contaminated soil before and after fungal treatment. Soil extracts before fungal treatment exhibited a relatively strong genotoxic effect in the meiotic pollen mother cells even at a 1% concentration, and the highest concentration without significant effect was 0.25%. After fungal treatment, the depletion of selected PAH was associated with a reduction of the soil genotoxicity. The 2% concentration of the extract from the fungal-treated soil showed genotoxic effects comparable to the 1% soil extract without fungal treatment. These results indicate that the Trad-MCN test has a potential utility for evaluating the efficiency of bioremediation of genotoxic soil contaminants.

Basidiomycota↗
PubMed1990

Evaluation of genotoxicity of clofazimine, an antileprosy drug, in mice in vivo. II. Micronucleus test in bone marrow and hepatocytes.

The antileprosy drug, clofazimine, was tested for its possible genotoxicity using micronucleus (MN) tests in mice. A significantly higher incidence of MN in bone marrow erythrocytes, particularly in polychromatic erythrocytes, as well as in regenerated hepatocytes revealed a positive clastogenic effect of the drug. The drug also had a marked antimitotic effect as indicated by a negative correlation with the dose.

Animals↗
PubMed1999

Genotoxic evaluation of the pyrethroid lambda-cyhalothrin using the micronucleus test in erythrocytes of the fish Cheirodon interruptus interruptus.

In order to develop experimental models able to detect genotoxic effects of pollutants in aquatic organisms, the genotoxicity of the pyrethroid lambda-cyhalothrin was studied using the micronucleus test in erythrocytes of Cheirodon interruptus interruptus. The frequency of micronuclei was examined in blood smears obtained from fishes exposed in vivo to three different concentrations (0.05; 0. 01; 0.001 ug/l) of the compound and sacrificed at nine sampling times (24, 48, 72, 96 h and 8, 12, 15, 19 and 23 days). As a positive control fishes were exposed to 5 mg/l of cyclophosphamide. Results obtained demonstrated the genotoxic effects of the pyrethroid in the experimental model employed. The variation in the micronuclei frequencies in the different sampling times could be related to the blood cell kinetics and the erythrocyte replacement. The results could be considered as a validation of the MN test in fishes for the assessment of genotoxic pollutants.

Animals↗
PubMed1996

The modulatory effect of aminothiols on the clastogenic activity of X-rays assayed by the vivo mouse micronucleus test.

The modulatory effect of AET (S-2-aminoethylisothio-uronium bromide hydrobromide) and WR-2721 (S-2-/3-ami-nopropylamino/ethylphosphorothioic acid) on the clastogenic activity of X-rays was assessed by the in vivo mouse micronucleus test. The frequency of micronucleated polychromatic erythrocytes (MNPCEs) in the peripheral blood of adult male Swiss mice exposed to 5 Gy X-rays alone, or treated with AET or WR-2721, at a does of 200 mg/kg body weight, 15 or 30 minutes prior to X-irradiation, respectively, was determined during a fifteen-day period. The number of micronuclei increased on day 1 post-irradiation in X-irradiated mice and declined thereafter with the frequency of MNPCEs remaining lower in the thiol pre-treated mice. A more effective protection against the clastogenic activity of X-rays in the erythropoietic system was observed after WR-2721 administration than AET application.

Amifostine↗
PubMed2005

DNA damaging effects of carbofuran and its main metabolites on mice by micronucleus test and single cell gel electrophoresis.

The DNA damaging effects of the carbamate pesticide carbofuran and its four metabolites (carbofuranphenol, 3-ketocarbofuran, 3-hydrocarbofuran and nitrosocarbofuran) on mice were evaluated by single cell gel electrophoresis (SCGE) assay and micronucleus test. KM mice were exposed to test compounds with different doses of 0.1, 0.2 and 0.4 mg/kg through intraperitoneal injection two times with an internal of 24 h, and then killed by cervical dislocation 6 h after the second injection. In SCGE assay, isolated mice peripheral blood lymphocytes were employed to determine DNA damaging degree after a 1 h treatment by test compounds and a following electrophoresis. Carbofuran and carbofuranphenol showed negative results in both test and had no obvious toxicity. 3-Hydrocarbofuran and nitrosocarbofuran were positive. 3-Ketocarbofuran could not induce micronucleus formation but caused significant DNA migration in SCGE test. These tests revealed that 3-ketocarbofuran, 3-hydrocarbofuran and nitrosocarbofuran are potential mutagesis and further research is needed.

Animals↗
PubMed2004

An automated scoring procedure for the micronucleus test by image analysis.

The micronucleus assay (MNT) in human lymphocytes is frequently used to assess chromosomal damage as a consequence of environmental mutagen exposure, to assess the effect of mutagens or to search for reduced DNA repair capacity after a mutagenic challenge. We have established an automated scoring procedure for the cytokinesis blocked MNT based on computerized image analysis (Metasystems Metafer 4 version 2.12). To evaluate the results we used the reproducibility of counts, established a dose-response curve for gamma-irradiation and used the ability of the system to differentiate between breast cancer patients and controls as a biological reference, a difference which we had observed before by visual counting. Blood cultures were irradiated with gamma-rays (2 Gy) at the beginning and treated with cytochalasin B during the last 24 h. The slides were stained with Giemsa for visual counting and with DAPI for automated analysis. Our test sample consisted of 73 persons (27 with breast cancer and 26 female and 20 male controls). A comparison between visual counting (controls, mean MN frequency 313) and automated counting (mean MN frequency 106) in slides from the same culture revealed a large drop for the automated counts. However, the automated counts were as reproducible as the visual counts [coefficient of variation (CV) on the sample approximately 20%; CV on repeated counts of the same slides approximately 5%] and both counts were highly correlated. Furthermore, the discrimination between cases and controls improved for automated counting of slides from the same cultures [visual odds rato (OR) < or = 4.0, P = 0.009; automated OR > 16, P < 0.0001], with a strong dependence on the set of parameters used. This improvement was confirmed in a validation sample of an additional 21 controls and 20 cases (OR = 11, P = 0.0018) performed as a prospective or diagnostic test.

Algorithms↗
PubMed1996

Effects of sulphur-containing compounds and X-rays on the mouse erythropoietic system assayed by in-vivo peripheral blood micronucleus test.

PURPOSE: The protective effect of the sulphur-containing agents, MEA (cysteamine HCl), AET (2-aminoethyl-isothiouronium Br.HBr), and WR-2721 (S-2/3-aminopropylamino/ethylphosphorothioic acid) against induction of micronuclei in the erythropoietic system by X-rays was assessed. METHODS: The mouse peripheral blood micronucleus assay was applied. The frequency of micronucleated polychromatic erythrocytes (MNPCE) in the peripheral blood of adult male Swiss mice was determined 24 h after MEA, AET, or WR-2721 treatment, at a dose of 200 mg/kg body weight, and whole-body X-ray exposure to a dose of 6 Gy. RESULTS: After X-irradiation of mice, the number of MNPCE was distinctly increased. MEA, AET, or WR-2721 administration, 15 min prior to X-irradiation resulted in a reduction of the X-ray-induced elevation of the frequency of micronuclei. So, the radioprotection of the sulphur-containing drugs against the induction of MNPCE in the erythropoietic system by X-rays was shown. CONCLUSION: The mouse peripheral blood micronucleus test can be used to screen potential radioprotective agents.

Amifostine↗
PubMed2006

Comparative evaluation of genotoxicity of captan in amphibian larvae (Xenopus laevis and Pleurodeles waltl) using the comet assay and the micronucleus test.

Captan (N-trichloromethylthio-4-cyclohexene-1,2-dicarboximide) is a fungicide used to inhibit the growth of many types of fungi on plants used as foodstuffs. The toxic and genotoxic potentials of captan were evaluated with the micronucleus test (MNT; AFNOR,2000) and the comet assay (CA) using amphibian larvae (Xenopus laevis and Pleurodeles waltl). Acute toxicity results showed that captan was toxic (1) to Xenopus larvae exposed to from 2 mg/L to 125 or 62.5 microg/L, depending on the nature of the water [reconstituted water containing mineral salts or mineral water (MW; Volvic, Danone, France)] and (2) to Pleurodeles exposed to from 2 mg/L to 125 microg/L in both types of water. The MNT results obtained in MW showed that captan (62.5 microg/L) was genotoxic to Xenopus but not genotoxic to Pleurodeles at all concentrations tested. CA established that the genotoxicity of captan to Xenopus and Pleurodeles larvae depended on the concentration, the exposure times, and the comet parameters (tail DNA, TEM, OTM, and TL). The CA and MNT results were compared for their ability to detect DNA damage at the concentrations of captan and the exposure times applied. CA showed captan to be genotoxic from the first day of exposure. In amphibians, CA appears to be a sensitive and suitable method for detecting genotoxicity such as that caused by captan.

Amphibians↗
PubMed2005

Assessment of DNA damage in peripheral blood of heavy smokers with the comet assay and the micronucleus test.

The comet assay (single-cell gel electrophoresis, SCG) is being increasingly used in human biomonitoring for the detection of genotoxic exposures. Cigarette smoking is a well-documented source of a variety of potentially mutagenic and carcinogenic compounds. Therefore, smoking should represent a relevant mutagenic exposure and lead to genotoxic effects in exposed cells. However, our previous investigations as well as several other published studies on human biomonitoring failed to show an effect of smoking on DNA migration in the comet assay, while some other studies did indicate such an effect. Although many factors can contribute to the generation of discrepant results in such studies, clear effects should be obtained after high exposure. We therefore performed a comparative study with healthy male heavy smokers (>20 cigarettes per day) and non-smokers (n=12 in each group). We measured the baseline comet assay effects in fresh whole blood samples and isolated lymphocytes. In addition, the amount of 'formamidopyrimidine DNA-glycosylase (FPG)-sensitive sites' was determined by a combination of the standard comet assay with the bacterial FPG protein. Furthermore, the influence of a repair inhibitor (aphidicolin, APC) on baseline DNA damage was comparatively analysed. Duplicate slides from each sample were processed and analysed separately. In all experiments, a reference standard (untreated V79 cells) was included to correct for assay variability. Finally, to compare the comet assay results with another genetic endpoint, all blood samples were investigated in parallel by the micronucleus test (MNT). Baseline and gamma radiation-induced micronucleus frequencies were determined. None of these approaches revealed a significant difference between heavy smokers and non-smokers with regard to a genotoxic effect in peripheral blood cells.

Adolescent↗