The induction of micronuclei as a measure of genotoxicity

Heddle, John A.; Hite, Mark; Kirkhart, Barbara; Mavournin, Kathleen H.; MacGregor, James T.; Newell, Gordon W.; Salamone, Michael F.

doi:10.1016/0165-1110(83)90047-7

Cited by 660 publications

(101 citation statements)

References 92 publications

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“…However, fish are not normally very useful for certain cytogenetic techniques, such as chromosome aberration tests and sister chromatid exchanges, because they have a large number of small chromosomes (Belpaeme et al, 1996). The MN test has been used successfully as a mutagenic assay since it is simple, reliable, sensitive, and is not strongly dependent on any karyotypic characteristics (Heddle et al, 1983). The methods using fish erythrocytes are not time consuming and can be done without causing suffering to the animals (Minissi et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Micronucleus frequencies in Astyanax bimaculatus (Characidae) treated with cyclophosphamide or vinblastine sulfate

Matsumoto

Cólus

2000

Genet. Mol. Biol.

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Two known mutagenic drugs, cyclophosphamide and vinblastine sulfate, were tested using the micronucleus test in the native fish species, Astyanax bimaculatus, in order to determine which of these drugs and the doses which would be the most adequate for use as positive controls in this species. This Brazilian fish species was chosen because few toxicity studies have used native fish species and this particular species is widely consumed in various regions of Brazil. Three thousand erythrocytes per specimen were scored. Doses of 16 and 8 mg/kg body weight of cyclophosphamide and vinblastine sulfate, respectively, were the most effective in causing micronuclei. Cyclophosphamide was the most mutagenic of the two drugs and is recommended for use as a positive control in A. bimaculatus.
Duas drogas reconhecidas como mutagênicas, ciclofosfamida e vimblastina sulfato, foram avaliadas usando o teste do micronúcleo em uma espécie de peixe nativa, Astyanax bimaculatus, para detectar que droga e quais doses são as mais adequadas para serem usadas como controles positivos para esta espécie. Esta espécie de peixe brasileira foi escolhida devido à escassez de estudos toxicológicos com espécies de peixes nativos e também porque ela é amplamente consumida em algumas regiões do Brasil. Um total de 3000 eritrócitos por espécimen foram contados. As doses de 16 e 8 mg/kg de peso corporal de ciclofosfamida e de vimblastina sulfato, respectivamente, foram as mais efetivas na indução de micronúcleos. A ciclofosfamida mostrou ser o melhor agente mutagênico para ser usado como um controle positivo para Astyanax bimaculatus

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Section: Discussionmentioning

confidence: 99%

Micronucleus frequencies in Astyanax bimaculatus (Characidae) treated with cyclophosphamide or vinblastine sulfate

Matsumoto

Cólus

2000

Genet. Mol. Biol.

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“…Table 2 presents the binomial error in the count of MN cells in an individual animal obtained by scoring 2000, 4000, 8000, or 20,000 RETs as a function of the spontaneous frequency of MN-RETs. It should be noted that the spontaneous frequency in rodent bone marrow or peripheral blood reported by different experienced laboratories has ranged from 0.05% in rat (see individual laboratory values in [14]) to a mean value of 0.2% in the mouse [15,16] and 0.31% in the beagle dog. Since the counting error depends on the background rate and the number of cells scored, we have tabulated values over the range of spontaneous frequencies commonly reported in rodents and recently observed in the beagle dog (manuscript in preparation).…”

Section: Inter-animal Variabilitymentioning

confidence: 99%

Sensitivity of the erythrocyte micronucleus assay: Dependence on number of cells scored and inter-animal variability

Kissling¹,

Dertinger²,

Hayashi³

et al. 2007

Mutation Research/Genetic Toxicology and Environmental Mutagene

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Until recently, the in vivo erythrocyte micronucleus assay has been scored using microscopy. Because the frequency of micronucleated cells is typically low, cell counts are subject to substantial binomial counting error. Counting error, along with inter-animal variability, limit the sensitivity of this assay. Recently, flow cytometric methods have been developed for scoring micronucleated erythrocytes and these methods enable many more cells to be evaluated than is possible with microscopic scoring. Using typical spontaneous micronucleus frequencies reported in mice, rats and dogs, we calculate the counting error associated with the frequency of micronucleated reticulocytes as a function of the number reticulocytes scored. We compare this counting error with the inter-animal variability determined by flow cytometric scoring of sufficient numbers of cells to assure that the counting error is less than the inter-animal variability, and calculate the minimum increases in micronucleus frequency that can be detected as a function of the number of cells scored. The data show that current regulatory guidelines allow low power of the test when spontaneous frequencies are low (e.g., ≤ 0.1%). Tables and formulas are presented that provide the necessary numbers of cells that must be scored to meet the recommendation of the International Working Group on Genotoxicity Testing that sufficient cells be scored to reduce counting error to less than the inter-animal variability, thereby maintaining a more uniform power of detection of increased micronucleus frequencies within each species across the range of spontaneous frequencies observed in these three species.

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“…A description of the two mutagenicity tests is provided in two reviews (Preston et al, 1981;Heddle et al, 1983). Data on all the compounds that have also been tested in /acl mice were compiled from the original Iiterature; the specific references consulted are noted in Table 3.…”

Section: Micronucleus Test and Chromosome Aberration Datamentioning

confidence: 99%

“…Considerably smaller doses gave significant effects in the subchronic studies (28-120 days), due to an accumulation of mutations over the expo· sure period. In the liver, an increase in sensitivity of the test was possible over quite a long time (Friedman and Staub, 1977;23 (rat;IARC, 1978;Watanabe et al, 1982;NIOSH, 1987) Heddle et al, 1983 N-Nitrosomethylurea 2.3 (lOS, liv) no data 8 (Frei and Venitt, 1975) Urethane 130 (lOS, tun) 220 (Heddle et al, 1983) 5000 (Colnaghi et al, 1969 period: after a 28-day exposure to 2-AAF, a dose of 80 mgl kgl day was required to produce a 3-fold increase in mutant frequency, whereas after 120 days' exposure, 11 mgl kgl day sufficed to produce a 3.5-fold increase. The induced mutant frequency was roughly proportional to the integral of dose over time, i.e., the effect depended primarily on the total dose administered, independent of the dosing schedule.…”

Section: Accumulation Ofmutations In Subchronic Studiesmentioning

confidence: 99%

“…In contrast, the background rate of, e.g., micronucleus formation is : : : : : : 2 events/1000 cells; the Iimit of detection is a doubling or tripling of mutant frequency to 4-6 events/1000 cells (Heddle et al, 1983). Background rates and detection Iimits in chromosome aberration assays are similar or slightly higher (Preston et al, 1981).…”

Section: Sensitivity Of /Acl Test Vs Established Mutagenicity Testsmentioning

confidence: 99%

See 1 more Smart Citation

The lacI transgenic mouse mutagenicity assay: quantitative evaluation in comparison to tests for carcinogenicity and cytogenetic damage in vivo

Shephard

Lutz

Schlatter

1994

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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The detection Iimit of the lacl transgenic mouse mutagenicity assay lies, in practice, at approximately a 50-100% increase in mutant frequency in treated animals over controls. The sensitivity of this assay in detecting genotoxins can be markedly improved by subchronic rather than acute application of the test compound. The lac/ transgenic mouse mutagenicity assay was compared quantitatively to rodent carcinogenicity tests and to presently used in vivo mutagenicity assays. With the genotoxic carcinogens tested thus far, a rough correlation between mutagenic potency and carcinogenic potency was observed: on average, to obtain a doubling in lacl mutant frequency the mice bad to be treated with a total dose equal to 50 times the TD 50 daily dose Ievel. This total dose could be administered eilher at a high dose rate within a few days or, preferably, at a low dose rate over several weeks. This analysis also indicated that a lacl experiment using a 250-day exposure period would give a detection Iimit approximately equal to that of a long-term carcinogenicity study. In comparison to the micronucleus test or the chromosome aberration assay, acute sturlies with the presently available lacl system offered no increase in sensitivity. However, subchronic lacl sturlies (3-4-month exposure) resulted in an increase in sensitivity over the established tests by 1-2 orders of magnitude (shown with 2-acetylaminofluorene, N-nitrosomethylamine, N-nitrosomethylurea and urethane). 1t is concluded that a positive result in the lacl test can be highly predictive of carcinogenicity butthat a negative result does not provide a large margin of safety.

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The induction of micronuclei as a measure of genotoxicity

Cited by 660 publications

References 92 publications

Micronucleus frequencies in Astyanax bimaculatus (Characidae) treated with cyclophosphamide or vinblastine sulfate

Micronucleus frequencies in Astyanax bimaculatus (Characidae) treated with cyclophosphamide or vinblastine sulfate

Sensitivity of the erythrocyte micronucleus assay: Dependence on number of cells scored and inter-animal variability

The lacI transgenic mouse mutagenicity assay: quantitative evaluation in comparison to tests for carcinogenicity and cytogenetic damage in vivo

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