1,4-Dioxane is not mutagenic in five in vitro assays and mouse peripheral blood micronucleus assay, but is in mouse liver micronucleus assay

Morita, Takeshi; Hayashi, Makoto

doi:10.1002/(sici)1098-2280(1998)32:3<269::aid-em10>3.0.co;2-8

Cited by 35 publications

(9 citation statements)

References 42 publications

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“…1,4-Dioxane has been reported to produce negative results in various in vitro assays such as the bacterial reverse mutation assay and cultured cell assays (Morita & Hayashi, 1998). In some in vivo micronucleus assays, however, 1,4-dioxane exhibited positive results with liver and bone marrow.…”

Section: Discussionmentioning

confidence: 99%

“…In some in vivo micronucleus assays, however, 1,4-dioxane exhibited positive results with liver and bone marrow. Morita and Hayashi (1998) reported a positive result in the liver micronucleus assay using hepatectomized CD-1 mice. Mirkova (1994) reported induction of micronuclei by 1,4-dioxane with the bone marrow erythrocytes of mice.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, positive genotoxicity of 1,4-dioxane has been reported with the in vivo mouse liver and bone marrow micronucleus assay (Roy et al, 2005), although a majority of in vitro assays such as bacterial reverse mutation, Chinese hamster ovary (CHO) chromosomal aberration, CHO sisterchromatid exchange, and CHO micronucleus and mouse lymphoma tk assays showed negative results (Morita & Hayashi, 1998).…”

Section: Introductionmentioning

confidence: 99%

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Two-year inhalation study of carcinogenicity and chronic toxicity of 1,4-dioxane in male rats

Kasai

Kano

Umeda

et al. 2009

Inhalation Toxicology

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Carcinogenicity and chronic toxicity of 1,4-dioxane were examined by inhalation exposure of 50 male F344 rats to 1,4-dioxane vapor at 0 (clean air), 50, 250, or 1250 ppm (v/v) for 6 h/day, 5 days/wk, and 104 wk. Survival rates of 250 and 1250 ppm-exposed groups were decreased near the end of the 2-yr exposure period, due probably to the occurrence of malignant tumors. A statistically significant but marginal decrement of terminal body weight (<10%) was found in the 1250 ppm-exposed group, suggesting slight systemic toxicity. Significant changes in plasma levels of AST, ALT, ALP, and gamma-GTP and relative weight of the liver occurred in the 1250 ppm-exposed group. Dose-dependent and statistically significant increases in incidences of nasal squamous cell carcinomas, hepatocellular adenomas, and peritoneal mesotheliomas were found primarily in the 1250 ppm-exposed group. The incidences of renal cell carcinomas, fibroadenomas in the mammary gland, and adenomas in the Zymbal gland were also increased dose-dependently. Preneoplastic lesions occurred in the nasal cavity and liver of the 1,4-dioxane-exposed groups. As nonneoplastic lesions, the significantly increased incidences of nuclear enlargement, atrophy, and respiratory metaplasia in the nasal cavity were noted at 50 ppm and above. A LOAEL (lowest observed adverse effect level) was determined at 50 ppm for the nasal endpoint of general chronic toxicity. This study provides clear evidence of carcinogenicity for 1,4-dioxane in male rats. A cytotoxic-proliferative and in vivo genotoxic mode of action is suggested to operate in 1,4-dioxane-induced carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Two-year inhalation study of carcinogenicity and chronic toxicity of 1,4-dioxane in male rats

Kasai

Kano

Umeda

et al. 2009

Inhalation Toxicology

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“…The Mgmt gene was substantially up-regulated by administration of most Group-1 carcinogens, including two non-mutagenic carcinogens, 1,4-dioxane and thioacetamide, both of which increased the expression of the Mgmt gene by 290%. The carcinogen 1,4-dioxane has been found to be non-mutagenic in 5 in vitro assays, including a Salmonella assay 20. DNA damage has been observed in rat liver after a single oral administration of 1,4-dioxane (2550 mg/kg)21; however, neither DNA damage nor DNA repair was observed in the livers of F344 rats after a single oral administration of 1,4-dioxane (1000 mg/kg) 22.…”

Section: Discussionmentioning

confidence: 99%

New Short Term Prediction Method for Chemical Carcinogenicity by Hepatic Transcript Profiling following 28-Day Toxicity Tests in Rats

et al. 2011

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We have previously shown the hepatic gene expression profiles of carcinogens in 28-day toxicity tests were clustered into three major groups (Group-1 to 3). Here, we developed a new prediction method for Group-1 carcinogens which consist mainly of genotoxic rat hepatocarcinogens. The prediction formula was generated by a support vector machine using 5 selected genes as the predictive genes and predictive score was introduced to judge carcinogenicity. It correctly predicted the carcinogenicity of all 17 Group-1 chemicals and 22 of 24 non-carcinogens regardless of genotoxicity. In the dose-response study, the prediction score was altered from negative to positive as the dose increased, indicating that the characteristic gene expression profile emerged over a range of carcinogen-specific doses. We conclude that the prediction formula can quantitatively predict the carcinogenicity of Group-1 carcinogens. The same method may be applied to other groups of carcinogens to build a total system for prediction of carcinogenicity.

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“…For example, 1,4-dioxane was reported by several investigators to induce micronuclei in the bone marrow and liver of the treated rats [106][107][108]. However, the lack of consistent supporting in vitro and mechanistic data combined with observation that other investigators did not see similar positive results in their in vivo studies [109,110], led the U.S. EPA to conclude that the mutagenicity was not likely to play an important role in the carcinogenic MOA of 1,4-dioxane.…”

Section: In Vivo Genotoxicity Information Particularly In the Targetmentioning

confidence: 99%

Factors influencing mutagenic mode of action determinations of regulatory and advisory agencies

Eastmond

2012

Mutation Research/Reviews in Mutation Research

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The determination of whether a chemical induces cancer through a mutagenic or genotoxic mechanism frequently plays an important role in evaluating the risks associated with low dose exposure. Although various approaches are employed for making mode of action decisions, a systematic investigation to identify the major factors that influence these determinations has not been performed. To accomplish this, over 40 chemical risk assessments conducted by U.S. or international regulatory agencies and organizations were reviewed to identify components that had played a significant role, either directly or indirectly, in the decision-making process. The major factors identified included the chemical properties of the agent, its metabolites and degradation products; its metabolism and toxicokinetics; genotoxic effects seen in vivo, particularly in the target organ; structural or metabolic similarities to known mutagenic or nonmutagenic chemicals; characteristics of the tumors induced in the animal bioassays; and the origin of the observed effects. The quality of the data, the specific genotoxic endpoint and its sensitivity to assay conditions and toxicity were also important considerations. In all cases, the authoritative groups used a weight-of-evidence approach and, in most cases where evaluations were conducted by more than one authoritative body, similar conclusions were reached. In summary, a critical evaluation of the data as well as expert judgment is necessary in reaching mechanism of action conclusions. These determinations should be made within the broader context of evaluating the chemical's overall toxicity and carcinogenicity.

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1,4-Dioxane is not mutagenic in five in vitro assays and mouse peripheral blood micronucleus assay, but is in mouse liver micronucleus assay

Cited by 35 publications

References 42 publications

Two-year inhalation study of carcinogenicity and chronic toxicity of 1,4-dioxane in male rats

Two-year inhalation study of carcinogenicity and chronic toxicity of 1,4-dioxane in male rats

New Short Term Prediction Method for Chemical Carcinogenicity by Hepatic Transcript Profiling following 28-Day Toxicity Tests in Rats

Factors influencing mutagenic mode of action determinations of regulatory and advisory agencies

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