Subchronic toxicity and carcinogenicity studies of 1,2-dichloropropane inhalation to mice

Matsumoto, Michiharu; Umeda, Yumi; Take, Makoto; Nishizawa, Tomoshi; Fukushima, Shoji

doi:10.3109/08958378.2013.800618

Cited by 24 publications

(11 citation statements)

References 17 publications

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“…Two animal experiments had found that inhalation exposure to 1,2-DCP increases the incidence of bronchioloalveolar tumours in mice and that of nasal cavity tumours in rats, although no bile duct tumour development was observed in either species 16 17. It is unclear why the region of tumour development differs between humans and rodents.…”

Section: Discussionmentioning

confidence: 99%

Relationship between cumulative exposure to 1,2-dichloropropane and incidence risk of cholangiocarcinoma among offset printing workers

et al. 2016

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Section: Discussionmentioning

confidence: 99%

Relationship between cumulative exposure to 1,2-dichloropropane and incidence risk of cholangiocarcinoma among offset printing workers

et al. 2016

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“…On the other hand, some in vivo experiments showed that 1,2-DCP-exposed mice developed malignant lung and hepatocellular tumours, suggesting the carcinogenicity of 1,2-DCP and/or its metabolites78. In the liver, a major organ in the metabolism of various compounds, xenobiotics are generally converted to the hydrophilic form by Phase I (oxidation) and Phase II (conjugation) reactions, and are subsequently excreted into the extracellular space by the Phase III (elimination) system9 such as ATP-binding cassette sub-family C member 2 (ABCC2) and ABCG2.…”

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confidence: 99%

Halogenated hydrocarbon solvent-related cholangiocarcinoma risk: biliary excretion of glutathione conjugates of 1,2-dichloropropane evidenced by untargeted metabolomics analysis

Toyoda

Takada

Suzuki

2016

Sci Rep

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Recently, the International Agency for Research on Cancer issued a warning about the carcinogenicity of 1,2-dichloropropane (1,2-DCP) to humans based on an epidemiological study suggesting a relationship between the incidence of cholangiocarcinoma and occupational exposure to halogenated hydrocarbon solvent comprised mostly of 1,2-DCP. Although this dihaloalkane has been used in various industrial fields, there has been no biological evidence explaining the cholangiocarcinoma latency, as well as little understanding of general cholangiocarcinoma risk. In the present study, we explored the biliary excretion of 1,2-DCP metabolites by an untargeted metabolomics approach and the related molecular mechanism with in vitro and in vivo experiments. We hypothesized that the biliary excretion of carcinogens derived from 1,2-DCP contribute to the increased cholangiocarcinoma risk. We found that 1,2-DCP was conjugated with glutathione in the liver, and that the glutathione-conjugated forms of 1,2-DCP, including a potential carcinogen that contains a chloride atom, were excreted into bile by the bile canalicular membrane transporter, ABCC2. These results may reflect a risk in the backfiring of biliary excretion as a connatural detoxification systems for xenobiotics. Our findings would contribute to uncover the latent mechanism by which the chronic exposure to 1,2-DCP increases cholangiocarcinoma risk and future understanding of cholangiocarcinoma biology.

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“…A recent report showed that inhalation of the solvent in mice and rats increased the incidence of Harderian gland adenoma and nasal cavity tumor, respectively 4,5) . By gavage administration, 1,2-DCP induced hepatocellular adenomas in mice but not in rats 6) .…”

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Assessment of the Genotoxicity of 1,2‐Dichloropropane and Dichloromethane after Individual and Co‐exposure by Inhalation in Mice

Suzuki

Yanagiba

Suda

et al. 2014

Journal of Occupational Health

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205Tetsuya SUZUKI, et al.: Genotoxicity of 1,2-dichloropropane and Dichloromethane effects were greatly enhanced by simultaneous exposure to DCM. (J Occup Health 2014; 56: 205-214) Key words: 1,2-Dichloropropane, Co-exposure, Dichloromethane, Genotoxicity, InhalationRecently, the occurrence of cholangiocarcinoma cases was reported among the employees and former employees of an offset printing company in Osaka, Japan 1) . So far, 11 cancer patients have been diagnosed among 62 workers conducting offset color proof printing in this factory, and this surely shows an extremely high incidence rate of this kind of cancer compared with the national average during the same period. In addition, the ages of the workers at diagnosis were 25−45 years, and this is obviously much younger that in the general population. Later, more cases were found in factories, including other offset printing companies, in a national survey sponsored by the occupational health authorities 2) . The occurrence of cholangiocarcinoma in this industry is therefore suspected to be related to some factors in the workplaces.1,2-Dichloropropane (1,2-DCP) and dichloromethane (DCM) were the substances suspected of causing the cancer, since they were used as the ink cleaners in a large amounts and can easily evaporate into the air, meaning that the workers were therefore exposed to these chlorinated organic solvents at high concentrations. Our colleagues carried out an experiment to reproduce the working environment of the proof-printing room of this company in Osaka and concluded that the exposure concentrations might have been as high as several hundreds ppm for either 1,2-DCP or DCM under the conditions of ordinary work amount 3) , and the latter solvent showed 2-3 fold higher concentration than the former solvent because of the difference in evaporation rate. Other components in the cleaner included 1,1,1-trichloroethane, petroleum- Occurrence of cholangiocarcinoma was recently reported at a high incidence rate among the employees working for an offset printing company in Osaka, Japan. 1,2-Dichloropropane (1,2-DCP) and dichloromethane (DCM) are suspected to be the causes of the cancer, as they had been used as ink cleaners in large amounts. However, it is not clear whether these chlorinated organic solvents played a role in the occurrence of cholangiocarcinoma or why the incidence rate is so high among the workers in this industry. To provide possible evidence for this severe occupational problem, we investigated the genotoxic effects of 1,2-DCP and DCM. Methods: Male B6C3F1 and gpt Delta C57BL/6J mice were exposed by inhalation to the individual solvents or both solvents at multiple concentrations including the levels that were possibly present in the workplaces. The genotoxicity was analyzed by Pig-a gene mutation and micronuclei assays in peripheral blood and gpt mutation and comet assays in the livers of mice after repeated inhalation of 1,2-DCP or/and DCM. Results: The Pig-a mutant frequencies and micronuclei incidences were not significantl...

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Subchronic toxicity and carcinogenicity studies of 1,2-dichloropropane inhalation to mice

Cited by 24 publications

References 17 publications

Relationship between cumulative exposure to 1,2-dichloropropane and incidence risk of cholangiocarcinoma among offset printing workers

Relationship between cumulative exposure to 1,2-dichloropropane and incidence risk of cholangiocarcinoma among offset printing workers

Halogenated hydrocarbon solvent-related cholangiocarcinoma risk: biliary excretion of glutathione conjugates of 1,2-dichloropropane evidenced by untargeted metabolomics analysis

Assessment of the Genotoxicity of 1,2‐Dichloropropane and Dichloromethane after Individual and Co‐exposure by Inhalation in Mice

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