Evaluation of a liver micronucleus assay in young rats (IV): A study using a double-dosing/single-sampling method by the Collaborative Study Group for the Micronucleus Test (CSGMT)/Japanese Environmental Mutagen Society (JEMS)–Mammalian Mutagenicity Study Group (MMS)

Takasawa, Hironao; Suzuki, Hiroshi; Ogawa, Izumi; Shimada, Yasushi; Kobayashi, Kazuo; Terashima, Yukari; Matsumoto, Hirotaka; Oshida, Keiyu; Ohta, Ryo; Imamura, Tadashi; Miyazaki, Atsushi; Kawabata, Masayoshi; Minowa, Shigenori; Maeda, Ai; Hayashi, Makoto

doi:10.1016/j.mrgentox.2010.02.010

Cited by 32 publications

(32 citation statements)

References 20 publications

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“…The results are in agreement with recent work which showed an increase in the incidence on micronucleated hepatocytes following a single dose of 2,6-DNT as low as 50 mg/kg or repeated doses as low as 33 mg/kg-day [27][28][29]. In contrast to the current study, previous reports indicated that 2,4-DNT is genotoxic in the rat liver micronucleus assay at 200 mg/kg [28]. The discrepant results for 2,4-DNT may be due to differences in doses used (142 mg/kg-day vs. 200 mg/kg), strain differences [30], or differences in the types of damage detected [36].…”

Section: Discussionsupporting

confidence: 93%

“…The major isomers, 2,4-and 2,6-DNT, have been the subject of more testing than the minor isomers. As in the in the present study, the major isomers have previously given negative results in the bone marrow or peripheral blood micronucleus assays [26][27][28][29]. The negative results in the peripheral blood micronucleus assay suggest that the active metabolites of DNT, produced through enterohepatic circulation [18,19], did not reach the bone marrow.…”

Section: Discussionsupporting

confidence: 69%

“…The negative results in the peripheral blood micronucleus assay suggest that the active metabolites of DNT, produced through enterohepatic circulation [18,19], did not reach the bone marrow. Active metabolites produced in the liver are often short lived and the concentration reaching the bone marrow does not allow for sufficient exposure to induce MN [28,30]. Active metabolites produced in the liver may also be bound to liver tissue [18], never entering systemic circulation.…”

Section: Discussionmentioning

confidence: 99%

“…Recent work has, however, suggested that, at least in the liver, tissue cytotoxicity does not lead to increased DNA migration in the in vivo Comet assay [29,38]. Additionally, work by Rothfuss et al [29] demonstrated an increase in DNA damage in the in vivo liver Comet assay for rats exposed to 100 mg/kg-day of 2,6-DNT for 3 days or 33 mg/kg-day for 29 days [28,29]. Thus, the positive result for 2,6-DNT in the current study appears reliable despite cytotoxicity in two of the doses used.…”

Section: Discussionmentioning

confidence: 99%

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Assessment of the in vivo genotoxicity of isomers of dinitrotoluene using the alkaline Comet and peripheral blood micronucleus assays

Lent

Crouse

Quinn

et al. 2012

Mutation Research/Genetic Toxicology and Environmental Mutagene

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a b s t r a c t Dinitrotoluene (DNT) is a nitroaromatic explosive that exists as six isomers; two major isomers (2,4-and 2,6-DNT) and four minor isomers (2,2,3,and 3,. DNT has been found in soil, surface water, and groundwater near ammunition production plants. The major isomers of DNT are classified as "likely to cause cancer in humans." In vitro studies have provided conflicting data regarding the genotoxicity of the minor isomers. Studies indicate that metabolism in the gut and liver are necessary to convert DNT to genotoxic compounds. As such, in the present study the genotoxicity of isomers of DNT was assessed using two in vivo genotoxicity assays. The Comet assay was used to detect DNA damage in liver cells from male Sprague-Dawley rats following oral exposure (14-day) to individual isomers of DNT. The micronucleus assay was conducted using flow cytometric analysis to detect chromosomal damage in peripheral blood. Treatment with 2,3-, 3,4-, 2,4-, 2,5-and 3,5-DNT did not induce DNA damage in liver cells or increase the frequency of micronucleated reticulocytes (MN-RET) in peripheral blood at the doses tested. Treatment with 2,6-DNT induced DNA damage in liver tissue at all doses tested, but did not increase the frequency of micronucleated reticulocytes (MN-RET) in peripheral blood. Thus, 2,4-DNT and the minor isomers were not genotoxic under these test conditions, while 2,6-DNT was genotoxic in the target tissue, the liver. These results support previous research which indicated that the hepatocarcinogenicity of technical grade DNT (TG-DNT) could be attributed to the 2,6-DNT isomer.Published by Elsevier B.V.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Assessment of the in vivo genotoxicity of isomers of dinitrotoluene using the alkaline Comet and peripheral blood micronucleus assays

Lent

Crouse

Quinn

et al. 2012

Mutation Research/Genetic Toxicology and Environmental Mutagene

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“…After the 4th IWGT, many new data for the LMNT have been published [3][4][5][6][7][8][9][10][11][12]. One reason for this trend was considered to be the ICH-S2(R1) discussion focusing on second in vivo tests that could be done with tissues other than bone marrow (BM)/peripheral blood (PB) [13].…”

Section: Introductionmentioning

confidence: 99%

Recommended protocols for the liver micronucleus test: Report of the IWGT working group

Uno

Morita

Luijten

et al. 2015

Mutation Research/Genetic Toxicology and Environmental Mutagene

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Evaluation of the Pig‐a, micronucleus, and comet assay endpoints in a 28‐day study with ethyl methanesulfonate

Gunther

Coffing

Dickinson

et al. 2014

Environ and Mol Mutagen

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Ethyl methanesulfonate (EMS) was evaluated as part of the validation effort for the rat Pig-a mutation assay and compared with other well-established in vivo genotoxicity endpoints. Male Sprague-Dawley (SD) rats were given a daily dose of 0, 6.25, 12.5, 25, 50, or 100 mg/kg/day EMS for 28 days, and evaluated for a variety of genotoxicity endpoints in peripheral blood, liver, and colon. Blood was sampled pre-dose (Day 1) and at various time points up to Day 105. Pig-a mutant frequencies were determined in total red blood cells (RBCs) and reticulocytes (RETs) as RBC(CD59-) and RET(CD59-) frequencies. The first statistically significant increases in mutant frequencies were seen in RETs on Day 15 and in RBCs on Day 29 with the maximum RET(CD59-) on Day 29 and of RBC(CD59-) on Day 55. The lowest dose producing a statistically significant increase of RET(CD59-) was 12.5 mg/kg on Day 55 and 25 mg/kg for RBC(CD59-) on Day 55. EMS also induced significant increases in % micronucleated RETs (MN-RETs) in peripheral blood on Days 3, 15, and 28. No statistically significant increases in micronuclei were seen in liver or colon. Results from the in vivo Comet assay on Day 29 showed generally weak increases in DNA damage in all tissues evaluated with little evidence for accumulation of damage seen over time. The results with EMS indicate that the assessment of RBC(CD59-) and/or RET(CD59-) in the Pig-a assay could be a useful and sensitive endpoint for a repeat dose protocol and complements other genotoxicity endpoints.

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Evaluation of a liver micronucleus assay in young rats (IV): A study using a double-dosing/single-sampling method by the Collaborative Study Group for the Micronucleus Test (CSGMT)/Japanese Environmental Mutagen Society (JEMS)–Mammalian Mutagenicity Study Group (MMS)

Cited by 32 publications

References 20 publications

Assessment of the in vivo genotoxicity of isomers of dinitrotoluene using the alkaline Comet and peripheral blood micronucleus assays

Assessment of the in vivo genotoxicity of isomers of dinitrotoluene using the alkaline Comet and peripheral blood micronucleus assays

Recommended protocols for the liver micronucleus test: Report of the IWGT working group

Evaluation of the Pig‐a, micronucleus, and comet assay endpoints in a 28‐day study with ethyl methanesulfonate

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