Repeated-dose liver micronucleus test of 4,4′-methylenedianiline using young adult rats

Sanada, Hisakazu; Koyama, Naomi; Wako, Yumi; Kawasako, Kazufumi; Hamada, Shuichi

doi:10.1016/j.mrgentox.2014.06.001

Cited by 4 publications

(2 citation statements)

References 18 publications

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“…These discordant results might be due to the unsuitability of the BM MN assay for the detection of micronuclei by active metabolite(s) or unstable chemicals, which will be discussed in more detail in the individual papers [46,60].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the repeated-dose liver and gastrointestinal tract micronucleus assays with 22 chemicals using young adult rats: Summary of the collaborative study by the Collaborative Study Group for the Micronucleus Test (CSGMT)/The Japanese Environmental Mutagen Society (JEMS) – Mammalian Mutagenicity Study Group (MMS)

Hamada

Ohyama

Takashima³

et al. 2015

Mutation Research/Genetic Toxicology and Environmental Mutagene

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The repeated-dose liver micronucleus (RDLMN) assay using young adult rats has the potential to detect hepatocarcinogens. We conducted a collaborative study to assess the performance of this assay and to evaluate the possibility of integrating it into general toxicological studies. Twenty-four testing laboratories belonging to the Mammalian Mutagenicity Study Group, a subgroup of the Japanese Environmental Mutagen Society, participated in this trial. Twenty-two model chemicals, including some hepatocarcinogens, were tested in 14- and/or 28-day RDLMN assays. As a result, 14 out of the 16 hepatocarcinogens were positive, including 9 genotoxic hepatocarcinogens, which were reported negative in the bone marrow/peripheral blood micronucleus (MN) assay by a single treatment. These outcomes show the high sensitivity of the RDLMN assay to hepatocarcinogens. Regarding the specificity, 4 out of the 6 non-liver targeted genotoxic carcinogens gave negative responses. This shows the high organ specificity of the RDLMN assay. In addition to the RDLMN assay, we simultaneously conducted gastrointestinal tract MN assays using 6 of the above carcinogens as an optional trial of the collaborative study. The MN assay using the glandular stomach, which is the first contact site of the test chemical when administered by oral gavage, was able to detect chromosomal aberrations with 3 test chemicals including a stomach-targeted carcinogen. The treatment regime was the 14- and/or 28-day repeated-dose, and the regime is sufficiently promising to incorporate these methods into repeated-dose toxicological studies. The outcomes of our collaborative study indicated that the new techniques to detect chromosomal aberrations in vivo in several tissues worked successfully.

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Section: Discussionmentioning

confidence: 99%

Evaluation of the repeated-dose liver and gastrointestinal tract micronucleus assays with 22 chemicals using young adult rats: Summary of the collaborative study by the Collaborative Study Group for the Micronucleus Test (CSGMT)/The Japanese Environmental Mutagen Society (JEMS) – Mammalian Mutagenicity Study Group (MMS)

Hamada

Ohyama

Takashima³

et al. 2015

Mutation Research/Genetic Toxicology and Environmental Mutagene

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“…The National Toxicology Program (NTP (1986)) reported structural chromosomal aberrations and increases in SCE in mouse bone marrow, but these results cannot be fully evaluated because of a lack of detail in reporting. Micronucleus tests in mice and rats gave positive results in the liver after repeated administration of 4,4 0 -MDA over 14 or 28 days while no effects were observed in the bone marrow or the peripheral blood after single and up to three consecutive treatments (Hamada et al, 2015;Morita et al, 1997;Sanada et al, 2015;Shelby et al, 1993;Suzuki et al, 2005). Mutagenicity on erythropoietic cells was reported in a Pig-a/PIGRET assay in rats after repeated treatment with 4,4 0 -MDA (Sanada et al, 2014).…”

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confidence: 99%

Comparative evaluation of three methylene dianiline isomers in the bacterial reverse mutation assay, the in vitro gene mutation test, and the in vitro chromosomal aberration test

Unterberger-Henig

2022

Toxicol Ind Health

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4,4′-MDA is classified as a genotoxic carcinogen based on numerous in vitro and animal data. The consequential assumption that a safe threshold does not exist is not only applied to 4,4′-MDA but also to its structural isomers and impurities 2,2′- and 2,4′-MDA in the absence of substance-specific data. This constitutes a problem in human risk assessments for all three substances as the inherent risks of 2,2′- and 2,4′-MDA and their contribution as impurities to that of 4,4′-MDA are essentially unknown. A comparative in vitro genotoxicity dataset consisting of the bacterial reverse mutation (Ames) test and the chromosomal aberration test in human lymphocytes (both performed according to the current OECD Guidelines) was generated for all three isomers. Furthermore, an in vitro gene mutation test in Chinese hamster ovary (CHO) cells (HPRT locus assay) was conducted with 2,4′-MDA. The results indicate differences regarding the genotoxic mechanism and potential, respectively, between the three structures and suggest that the no-threshold assumption for 4,4′-MDA may not be appropriate for 2,2′- and 2,4′-MDA.

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N-acetyltransferase 2 acetylator genotype-dependent N-acetylation and toxicity of the arylamine carcinogen β-naphthylamine in cryopreserved human hepatocytes

et al. 2022

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Repeated-dose liver micronucleus test of 4,4′-methylenedianiline using young adult rats

Cited by 4 publications

References 18 publications

Comparative evaluation of three methylene dianiline isomers in the bacterial reverse mutation assay, the in vitro gene mutation test, and the in vitro chromosomal aberration test

N-acetyltransferase 2 acetylator genotype-dependent N-acetylation and toxicity of the arylamine carcinogen β-naphthylamine in cryopreserved human hepatocytes

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