Collaborative study on fifteen compounds in the rat-liver Comet assay integrated into 2- and 4-week repeat-dose studies

Rothfuß, Andreas; O’Donovan, Mike; Boeck, Marlies De; Bron, Dominique; Czich, Andreas; Custer, Laura; Hamada, Shuichi; Plappert‐Helbig, Ulla; Hayashi, Makoto; Howe, Jonathan; Kraynak, Andrew R.; Leede, Bas-jan van der; Nakajima, Masahiro; Priestley, Catherine; Thybaud, Véronique; Saigo, Kazuhiko; Sawant, Satin G.; Shi, Jing; Storer, Richard D.; Struwe, Melanie; Vock, Esther; Galloway, Sheila M.

doi:10.1016/j.mrgentox.2010.07.006

Cited by 103 publications

(87 citation statements)

References 72 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].…”

Section: Discussionsupporting

confidence: 92%

“…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%

“…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: 92%

Section: Discussionsupporting

confidence: 69%

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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“…Several designs for administration of substances in the in vivo Comet assay are described in the literature (Hartmann et al, 2003(Hartmann et al, , 2004Burlinson et al, 2007;Vasquez, 2010;Rothfuss et al, 2010Rothfuss et al, , 2011.…”

Section: Administration Of Dosesmentioning

confidence: 99%

“…Thus, a concurrent assessment of cytotoxicity for the correct interpretation of the in vivo Comet assay data is recommended (Hartmann et al, 2003;Rothfuss et al, 2010).…”

Section: Investigation Of Cytotoxicitymentioning

confidence: 99%

Minimum Criteria for the acceptance ofin vivoalkaline Comet Assay Reports

2012

EFSA Journal

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The in vivo alkaline Comet assay detects primary DNA damage in various organs and tissues of exposed animals and can be used to assess the genotoxicity of a great variety of chemical compounds, which include food additives, flavourings, food contact materials, foodborne by-products, pesticides, contaminants, etc. Among the various versions of the assay, the alkaline method (pH of DNA unwinding and electrophoresis buffer > 13) identifies the broadest spectrum of DNA damage and is, therefore, recommended for regulatory purposes. It can detect double-and single-strand breaks, alkalilabile lesions that are expressed as single-strand breaks and single-strand breaks arising as DNA repair intermediates. No OECD Test Guideline yet exists for the Comet assay but internationally agreed protocols are available for performing this test. Since establishing of an OECD Test Guideline for this assay will require some further time, there is a need for an agreed approach on the minimum requirements on conduction and reporting of the in vivo Comet assay, which should be fulfilled for the purposes of EFSA during this transition period.

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Preclinical Safety Testing

Müller¹,

Husar²

2013

The Textbook of Pharmaceutical Medicine

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Collaborative study on fifteen compounds in the rat-liver Comet assay integrated into 2- and 4-week repeat-dose studies

Cited by 103 publications

References 72 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

Minimum Criteria for the acceptance ofin vivoalkaline Comet Assay Reports

Preclinical Safety Testing

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