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PubMed1996

Effect of Ziram, Thiram, and Dithane M-45 on bone marrow cells of mice-assessed by micronucleus test.

Micronucleus test is an extensively used protocol to assess the mutagenicity of environmental chemicals. This was developed by Schmid and his co-workers (Matter and Schmid, 1971; Ledebur and Schmid, 1973). The micronucleus test is simple, quick and as sensitive as the chromosome aberration analysis. It is based on the principle that during anaphase, acentric chromatid and chromosome fragments lag behind, where as centric elements move towards the spindle pole. After telophase both the undamaged chromosomes and the centric fragments give rise to the daughter nuclei. The lagging elements are transferred into one or several secondary nuclei, which are as a rule much smaller than the main nucleus, and therefore called micronucleus (Schmid, 1973). The clastogenic effect of various chemicals is measured by micronucleus test. Erythrocytes are two types, the younger ones are polychromatic erythrocytes (PCE), which stain bluish and the older, the normo chromatic erythrocytes (NCE) which stain reddish. A few hours after the completion of last mitosis the erythroblasts expel their nucleus for unknown reasons and the micronucleus alone remains in the cytoplasm of the Polychromatic erythrocytes, and they are easily recognisable. Erythrocyte micronucleus represents the consequence of chromosomal aberrations induced during preceding mitotic division of erythrocytes (Matter and Grauwiler, 1974).

Animals↗
PubMed1993

Lack of predictivity of bone marrow micronucleus test versus testis micronucleus test: comparison with four carcinogens.

In vivo somatic chromosome mutation tests are usually carried out using the bone marrow micronucleus test in the mouse. This test is also considered predictive for the study of clastogenic effects in germ cells. However, it has been reported that the sensitivity of the bone marrow micronucleus test is insufficient to detect unstable compounds or short-lived metabolites and the use of target cells with metabolic activity (hepatocytes) has been questioned. In order to analyze in vivo micronucleus induction in cells with metabolic enzyme activity, we compared the sensitivity of somatic and germ cells to four carcinogens in the bone marrow and spermatid micronucleus test in the mouse. Three procarcinogens with a complex metabolic pattern (dimethylnitrosamine, diethylnitrosamine and 1,1-dimethylhydrazine) and one direct unstable mutagen (beta-propiolactone) were tested. All four carcinogens were not detected by the bone marrow micronucleus test but were detected in the mouse spermatid micronucleus test in which they induced clear clastogenic effects, as was the case in a previous study in liver micronucleus test. In conclusion, this study demonstrates that the bone marrow micronucleus test is not sufficient for the prediction of a clastogenic hazard in germ cells. In addition to a second in vivo test in an organ with metabolic enzymes, i.e., the liver, the spermatid micronucleus test can be performed when a specific risk to the testis is likely.

Animals↗
PubMed1995

A comparative study of TK6 human lymphoblastoid and L5178Y mouse lymphoma cell lines in the in vitro micronucleus test.

Micronucleus induction was compared in human lymphoblastoid TK6 and mouse lymphoma L5178Y cell lines treated with model clastogens and spindle poisons, i.e., X-rays, methyl methanesulfonate, ethyl methanesulfonate, mitomycin C, colcemid, and vincristine. The spontaneous micronucleated cell (MNC) frequency was stable and reproducible in both cell lines. All clastogens and spindle poisons studied here induced micronuclei in both cell lines. They increased MNC frequency at lower concentrations or caused a greater increase at the same concentration in TK6 cells. These clastogens and spindle poisons, however, were also more toxic to TK6 than to L5178Y cells and when comparison was based on cytotoxicity, they showed more efficient MNC induction in L5178Y cells. In conclusion, neither cell line was superior to the other, and both of them can be used as target cells in the in vitro micronucleus assay.

Animals↗
PubMed1986

Sex difference in the micronucleus test. The Collaborative Study Group for the Micronucleus Test.

Since sex difference seemed to be one of the most urgent issues to be clarified among many parameters in protocols for the micronucleus test, the collaborative study group for the micronucleus test, consisting of members of the Japanese Environmental Mutagen Society, focused on this subject first. 20 clastogens were examined for sex-related differences of response in the micronucleus test with male and female mice at 20 participating laboratories, one at each laboratory. The results obtained were analyzed and 10 out of the 20 compounds were chosen for further tests for confirmation and re-examination. As a rule, each retested compound was evaluated at 2 laboratories with different strains of mice. The overall results of the first and second trials indicate that (1) all compounds induced micronuclei in both male and female mice, (2) 2-acetylaminofluorene (2-AAF), benzene, benzo[a]pyrene (B[a]P), and 7,12-dimethylbenzanthracene (DMBA) induced significantly higher incidences of micronuclei in males than in females, (3) ethyl methanesulfonate induced more micronuclei in females than in males, and (4) the other compounds showed almost the same responses in males and females or slightly higher responses in males than in females. The higher susceptibility of male mice to 2-AAF, B[a]P, and DMBA has, to our knowledge, not previously been reported. Based upon these results, we suggest that the use of male mice is sufficient for general screening by the micronucleus test.

Animals↗
PubMed1988

Strain difference in the micronucleus test. The Collaborative Study Group for the Micronucleus Test.

The Collaborative Study Group for the Micronucleus Test, a task group of the Environmental Mutagen Society of Japan, has earlier addressed the question of sex difference as a source of variation in the micronucleus test. Strain difference, another issue in test protocols requiring urgent clarification, was selected as the subject of the second study. Male mice of strains Slc:ddY (ddY), CRJ: CD-1(ICR) (CD-1), Slc:BDF1 (BDF1), and ms:Hal (ms) were treated with 6 different chemicals chosen from various classes of micronucleus inducers: colchicine, 7,12-dimethylbenz[a]anthracene, ethyl methanesulfonate, N-ethyl-N-nitrosourea, 6-mercaptopurine, and potassium chromate. All 4 strains gave positive results with all 6 chemicals, although ms tended to show the highest responses. ddY and CD-1 were low responders, while BDF1 was intermediate between ms and the other two. Although ms seemed superior to the other strains, its high responses became manifest mostly at high dose levels. ms was not always the most sensitive strain; it responded moderately to ethyl methanesulfonate. Also the background level of micronucleated polychromatic erythrocytes was the highest in ms, but this did not explain the apparent high sensitivity of this strain. Despite the strain differences, it can be concluded that any of the other strains used seems to suffice as a tester for the micronucleus test.

Animals↗
PubMed1995

Protocol recommended by the CSGMT/JEMS.MMS for the short-term mouse peripheral blood micronucleus test. The Collaborative Study Group for the Micronucleus Test (CSGMT) (CSGMT/JEMS.MMS, The Mammalian Mutagenesis Study Group of the Environmental Mutagen Society of Japan).

Although the target cells for the bone marrow (BM) and peripheral blood (PB) micronucleus tests are the same, erythroblasts, the PB method offers important advantages over the BM method. We propose a protocol for the short-term peripheral blood micronucleus test. This assay is intended primarily for the identification of a wide variety of chemical clastogens and spindle poisons, and secondarily for risk assessment. The recommended experiment size, seemingly small, has adequate detection power. Experimental results obtained from Collaborative Study Group for the Micronucleus Test (CSGMT) studies and data collected from a survey of the literature provided the basis of the proposed protocol. Our protocol, designed for mice, includes the following features. (i) The maximum tolerated dose (MTD) is determined experimentally with a small number of animals treated i.p. or per os (or by other routes, if called for) in a dose-finding test, which can be conducted simultaneously with tests for finding both number of treatments and optimal sampling time. (ii) At least three groups of five mice (at least four effective animals per group), males or females, are given i.p. or per os doses of, for example, the MTD, 1/2 MTD and 1/4 MTD once, twice or more, 24 h apart. (iii) Peripheral blood samples are taken before treatment (the 0 time control) and twice at 48 and 72 h for a single treatment, once between 24 and 36 h after the second treatment for double treatments, or once 24 h after the final treatment for multiple dosing. Or, if an optimal sample time is established in a preliminary test, samples are taken at that time, (iv) Samples are stained with acridine orange, and 2000 immature erythrocytes per animal are examined. (v) The combined data of 0 time samples are the negative control.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1979

Mutagenic evaluation of nitroparaffins in the Salmonella typhimurium/mammalian-microsome test and the micronucleus test.

Three nitroparaffins (nitroethane, 1-nitropropane, and 2-nitropropane) were studied in the Salmonella typhimurium/mammalian microsome (Ames) test, with and without microsomal activation systems. Nitroethane and 2-nitropropane also were studied in an in vivo mutagenic (micronucleus) test. These studies were undertaken because these solvents are widely used in the chemical and pharmaceutical industries and 2-nitropropane was reported to cause liver cancer in rats exposed by the inhalation route. Neither nitroethane nor 1-nitropropane was active in the Ames test with Salmonella tester-strains TA1537, TA92, TA98, or TA100. However, 2-nitropropane produced a significant increase in revertants in all of these tester strains, particularly strain TA100, where 3 microliter/plate doubled the number of revertants in the presence of microsomal enzymes. Negative results were obtained with both nitroethane and 2-nitropropane in micronucleus tests. These studies have shown that 2-nitropropane has the potential for causing point mutations in a microbial test system. However, this compound probably will not cause a chromosome mutation of the clastogenic type.

Alkanes↗
PubMed1989

Effect of erythropoietin on the micronucleus test.

The micronucleus test is used widely as an in vivo short-term assay for potential carcinogens. In the present study, results of the micronucleus test were affected by the rate of erythropoiesis in the bone marrow erythropoietin, a growth factor for the erythroblast, which was used to induce erythropoiesis. The highest frequency of micronucleated polychromatic erythrocytes (MPCE) and a dose-response relationship between erythropoietin doses and MPCE frequency were seen 30 hr after injection of 1,1-dimethylhydrazine (DMH) to mice administered 24 hr previously with erythropoietin. The effect of erythropoietin was maximal when erythropoietin was given 24 hr before DMH, indicating that accelerating the multiplication of erythroblasts will increase the frequency of micronuclei induced by mutagens. Induction of MPCE in the bone marrow by four other compounds--benzo(a)pyrene, 2-naphthylamine, mitomycin C, and vincristine--was also increased by pretreatment with erythropoietin.

1,2-Dimethylhydrazine↗
PubMed1988

N,N-diethylphenylacetamide, an insect repellent: absence of mutagenic response in the in vitro Ames test and in vivo mouse micronucleus test.

N,N-diethylphenylacetamide (DEPA), a promising new insect repellent, was tested for mutagenicity in the in vitro Ames Salmonella/microsome mutagenicity test and the in vivo mouse micronucleus test. For the Ames test, DEPA was assayed both in the presence and absence of Aroclor 1254-induced rat-liver S-9 mix (5 and 20% S-9 fraction), using five tester strains of Salmonella typhimurium--TA97a, TA98, TA100, TA102 and TA104. For the micronucleus test, mice were exposed to DEPA through ip injection for 2 and 5 days in separate experiments, and bone marrow and peripheral blood were sampled 6 and 48 hr after the final injection, respectively. DEPA did not induce a mutagenic response in the Ames test, and mouse bone marrow and peripheral blood micronucleus tests. DEPA was not considered cytotoxic, as a depression of the percentage PCE was not observed at any dose in the range of 1 to 100 mg/kg body weight with either treatment protocol of the micronucleus test.

Acetamides↗
PubMed1995

Study of the genotoxic activity of six halogenated acetonitriles, using the SOS chromotest, the Ames-fluctuation test and the newt micronucleus test.

Three short-term assays (the SOS chromotest, the Ames-fluctuation test and the newt micronucleus test) were carried out to evaluate the genotoxicity of six halogenated acetonitriles identified in chlorinated waters (monochloro-, dichloro-, trichloro-, monobromo-, dibromo- and bromochloroacetonitrile). With the SOS chromotest, three of the chemicals studied (dichloro-, dibromo- and bromochloroacetonitrile) were found to induce primary DNA damage in Escherichia coli PQ37. In the Ames-fluctuation test, all the compounds except dibromoacetonitrile showed mutagenic activity on Salmonella typhimurium strain TA100. The newt micronucleus assay detected a clastogenic effect on the peripheral blood erythrocytes of Pleurodeles waltl larvae for all the six haloacetonitriles studied. Moreover, two structure-activity relationships were noted: (1) the genotoxic activity of haloacetonitriles containing bromine substituents appeared higher than the corresponding chlorinated acetonitriles and (2) the clastogenic activity of the chlorinated acetonitriles increased with the number of chlorine substituents.

Acetonitriles↗
PubMed1998

Evaluation of the in vitro micronucleus test as an alternative to the in vitro chromosomal aberration assay: position of the GUM Working Group on the in vitro micronucleus test. Gesellschaft für Umwelt-Mutations-forschung.

In order to license a pharmaceutical or chemical, a compound has to be tested for several genotoxicity endpoints, including the induction of chromosomal aberrations in vitro. A working group within the GUM has evaluated published data on the in vitro micronucleus test with the aim of judging its suitability as a replacement for the in vitro chromosomal aberration test. After strict rejection criteria were applied, a database including 96 publications and 34 compounds was obtained. For 30 of these compounds, data on both tests were available. For 24 of the 30, concordant results in both test systems were obtained (80% correlation). The discordant results in 6 compounds can be explained by a known or suspected aneugenic potential of these compounds. Considering that cell types and test protocols were extremely heterogeneous, this correlation is rather encouraging. Comparison of the different protocols, and experience established within the working group yielded several recommendations for the routine use of the in vitro micronucleus test. Although many cell lines are suitable, those most often used in genotoxicity testing (e.g. CHL, CHO, V79, human lymphocytes, L5178Y mouse lymphoma cells) are recommended. Cytochalasin B may be used in the case of human lymphocytes; however, the possibility of its interaction with aneugenic test compounds should be considered. For continuously dividing cell lines, cytochalasin B is not recommended by the working group. Although, there seems to be flexibility in the choice of treatment and sampling times, the average generation time of the chosen cell line of choice should be taken into account when determining sampling time, and treatment of cells for at least one cell cycle duration is recommended. The use of appropriate cytotoxicity tests is strongly recommended. Although studies on some parameters of the test protocol may be useful, the introduction of the in vitro micronucleus test into genotoxicity testing and guidelines should not be delayed. Even in its present state, the in vitro micronucleus is a reliable genotoxicity test. Compared with the chromosomal aberration test, it detects aneugens more reliably, it is faster and easier to perform, and it has more statistical power and the possibility of automation.

Animals↗
PubMedDate not supplied

Micronucleus test with mouse peripheral blood erythrocytes by acridine orange supravital staining: the summary report of the 5th collaborative study by CSGMT/JEMS.MMS. The Collaborative Study Group for the Micronucleus Test.

The main goal of the Collaborative Study Group for the Micronucleus Test (CSGMT) was to validate a new method for the micronucleus test, recently introduced by Hayashi et al. (1990), using mouse peripheral blood cells stained supravitally with acridine orange (AO). The micronucleus tests were performed on CD-1 mice using 23 chemicals with various modes of action. As a rule, one chemical was studied by two participants. Peripheral blood sampled from the same animal was examined 0, 24, 48, and 72 h (or longer) after treatment. The frequencies of micronucleated peripheral reticulocytes (MNRETs) were recorded based on observation of 1000 reticulocytes per mouse. All chemicals induced MNRETs dose-dependently. Interlaboratory differences in the induction of MNRETs were in an acceptable range for most chemicals tested. Although differences were observed with some chemicals, there were no discrepancies in qualitative judgment. Most chemicals gave the greatest response 48 h after treatment, which was less variable than in the bone marrow assay (greatest response, 24-48 h). These results suggest that the peripheral blood assay using the AO supravital staining technique generates reproducible and reliable data to evaluate the clastogenicity of chemicals. This makes the peripheral blood micronucleus assay an attractive alternative to the conventional bone marrow assay.

Acridine Orange↗
PubMed1994

Study of the genotoxic activity of five chlorinated propanones using the SOS chromotest, the Ames-fluctuation test and the newt micronucleus test.

Three short-term assays (the SOS chromotest, the Ames-fluctuation test and the newt micronucleus test) were carried out to evaluate the genotoxicity of five chlorinated propanones identified in several chlorinated waters (monochloropropanone, 1,1-dichloropropanone, 1,3-dichloropropanone, 1,1,1-trichloropropanone and 1,1,3-trichloropropanone). In the SOS chromotest, all the compounds except monochloropropanone were found to induce primary DNA damage in Escherichia coli. With the fluctuation test, all five chloropropanones showed mutagenic activity on Salmonella typhimurium strain TA100. The newt micronucleus assay detected a clastogenic effect on the peripheral blood erythrocytes of Pleurodeles waltl larvae only for 1,3-dichloropropanone and 1,1,3-trichloropropanone. Moreover, two structure-activity relationships are noticeable: (1) chloropropanones with chlorine substituents on both carbon positions (1,3-DCP and 1,1,3-TCP) are by far more genotoxic than chloropropanones substituted only on one carbon position (1,1-DCP and 1,1,1-TCP); (2) the increase of the number of chlorine substituents decreases the mutagenic activity (fluctuation test) of the chlorinated propanones studied.

Acetone↗
PubMed1995

Use of the SOS chromotest, the Ames-fluctuation test and the newt micronucleus test to study the genotoxicity of four trihalomethanes.

Three short-term assays (the SOS chromotest, the Ames-fluctuation test and the newt micronucleus test) were carried out to evaluate the genotoxicity of four trihalomethanes (chloroform, bromodichloromethane, chlorodibromomethane and bromoform). With the SOS chromotest, all the chemicals studied except chloroform were found to induce primary DNA damage in Escherichia coli PQ37. In the Ames-fluctuation test, only bromoform showed mutagenic activity on Salmonella typhimurium strain TA100. The newt micronucleus assay detected a clastogenic effect on the peripheral blood erythrocytes of Pleurodeles waltl larvae for bromodichloromethane and bromoform. It appeared that the presence of bromine substituent(s) generally led to significant genotoxic activity. Moreover, the use of the metabolic system significantly increased the genotoxicity of the brominated trihalomethanes in the SOS chromotest. Unlike previous investigations in which the SOS chromotest was always the least interesting assay, this study exhibited the good efficiency of this in vitro test on E.coli for the detection of trihalomethanes with bromine substituents.

Animals↗
PubMed1998

Evaluation of the rat micronucleus test with bone marrow and peripheral blood: summary of the 9th collaborative study by CSGMT/JEMS. MMS. Collaborative Study Group for the Micronucleus Test. Environmental Mutagen Society of Japan. Mammalian Mutagenicity Study Group.

The mouse has traditionally been used for the micronucleus test, with bone marrow the usual target organ. The aim of the 9th collaborative study by CSGMT was to evaluate the suitability of the rat for the micronucleus test, with bone marrow and peripheral blood as the target organ. Since the rat spleen eliminates circulating micronucleated erythrocytes, a rat peripheral blood micronucleus assay might not be feasible. Thirty-four Japanese laboratories and six overseas laboratories participated in this collaboration, and 40 chemicals were studied. As a rule, rat bone marrow and peripheral blood were analyzed using acridine orange staining. Among 36 mouse micronucleus-positive rat carcinogens, 34 of which had been evaluated by CSGMT, we observed 33 positive and three negative results with rat bone marrow and 30 positive, three equivocal, and three negative responses with rat peripheral blood. Of the two mouse micronucleus-negative rat carcinogens, acrylonitrile was positive in rat bone marrow and 4,4'-methylene bis(2-chloroaniline) was negative in both rat bone marrow and peripheral blood. Two chemicals reported to be mouse micronucleus-negative and rat-positive, azobenzene and Solvent Yellow 14, and one chemical reported to be mouse-positive and rat-negative, 1,2-dimethylhydrazine, gave positive responses in rat bone marrow and peripheral blood. The concordance between bone marrow and peripheral blood with rats was 92%. The concordance between rat and mouse erythrocytes was 88%. We concluded that the rat micronucleus assay, using either bone marrow or peripheral blood, can be used as an alternative to the mouse micronucleus assay.

Animals↗
PubMed1982

An evaluation of the mutagenic potential of 2-(2',4'-diaminophenoxy)ethanol using the micronucleus test.

The micronucleus test in mice was used to investigate the mutagenic potential of 2-(2',4'-diaminophenoxy)ethanol. The test compound was administered by oral gavage to CD-1 mice (ICR derived) as 2 equal dosages of 250,500 and 1000 mg/kg bodyweight. Bone-marrow smears were examined for the presence of micronucleated cells in 2000 polychromatic erythrocytes per animal. In addition, the ratio of normochromatic to polychromatic erythrocytes was scored to provide an indication of the toxicity of the test compound to bone marrow cells. No increase in the incidence of micronucleated polychromatic erythrocytes was observed for any group dosed with 2-(2',4'-diaminophenoxy)ethanol, although evidence of bone-marrow toxicity was observed at all 3 dosages.

Animals↗
PubMed1984

Genotoxic effects of ethyl acrylate and methyl acrylate in the mouse evaluated by the micronucleus test.

The micronucleus test was used to study the mutagenic effects of ethyl acrylate and methyl acrylate. Investigated compounds were administered to Balb C male mice by i.p. injection in two doses, separated by a period of 24 h. Ethyl acrylate at doses of 225-1800 mg/kg, and methyl acrylate at doses of 37.5-300 mg/kg significantly induce chromosome damage resulting in micronuclei formation in bone marrow polychromatic erythrocytes. Both investigated compounds significantly decrease the ratio of polychromatic to normochromatic erythrocytes. Positive results provide evidence of clastogenic activity of ethyl acrylate and methyl acrylate.

Acrylates↗
PubMed1995

Evaluation of the micronucleus test in vitro using Chinese hamster cells: results of four chemicals weakly positive in the in vivo micronucleus test.

A rapid and simple procedure for the micronucleus test (MNT) in vitro using Chinese hamster ovary (CHO) cells was established in our laboratory. The assay is intended to quickly screen chromosomal aberrations in vitro within the framework of industrial genotoxicity studies. To test the sensitivity of the assay in the experiments described here, four substances, classified as noncarcinogens but reported as weak inducers of micronuclei (MN) in bone-marrow cells of mice, were evaluated in the MNT in vitro. Of the four compounds, ascorbic acid, phenol, and 2,6-diaminotoluene proved to be genotoxic in the MNT in vitro. Titanium dioxide, which could not be dissolved in the culture medium, did not induce MN. The MNT in vitro proved to be quick and relatively simple and to yield highly reproducible results when testing the four chemicals.

Animals↗