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

Abstract

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...

Lack of in vivo mutagenicity of 1,2-dichloropropane and dichloromethane in the livers of gpt delta rats administered singly or in combination

“…Therefore, at higher concentrations, the CYP pathway becomes saturated, and the GST pathway begins to become predominant in 1,2‐DCP metabolism, possibly involving the production of a reactive episulfonium ion, which may form DNA adducts and induce genotoxicity (Kim & Guengerich, ; Zoetemelk et al ., ). From the results of a previous report, simultaneous exposure to 1,2‐DCP and DCM results in saturation of the CYP pathway, and the GST pathway begins to become the predominant metabolic route, suggesting that the genotoxicity of 1,2‐DCP is enhanced by DCM (Suzuki et al ., ). In the present study, the gene and protein expression levels of CYP2E1 and GSTT1 were not affected by exposure to the test chemicals, suggesting that the CYP pathway was not saturated and that the GST pathway did not begin to become predominant.…”

“…Additionally, significant increases in the frequencies of sister chromatid exchange and chromosome aberrations have been observed in the lungs, peripheral blood lymphocytes and bone marrow cells of B6C3F1 male mice that inhaled DCM (Allen et al ., ). In studies examining the in vivo genotoxic effects of 1,2‐DCP, inhalation of 1,2‐DCP but not DCM was shown to increase DNA damage measured by comet assays in the livers of C57BL/6 J mice bearing a reporter gene; furthermore, co‐exposure by inhalation of 1,2‐DCP and DCM was shown to increase the mutation frequency (MF) of the reporter gene in the liver compared with that of exposure to 1,2‐DCP alone (Suzuki et al ., ). These data indicated that the genotoxic effects of 1,2‐DCP are enhanced by DCM.…”

Comparison of Clinical Characteristics between Occupational and Sporadic Young-Onset Cholangiocarcinoma

“…The characteristic findings in patients with occupational cholangiocarcinoma include regional dilatation of the intrahepatic bile ducts related to chronic bile duct injury, precancerous lesions including biliary intraepithelial neoplasia, and early cancerous lesions (Kaneko et al, 2014;Sato et al, 2014;Suzuki et al, 2014;Tomimaru et al, 2015). In contrast, regional dilatation of the intrahepatic bile ducts was not observed by diagnostic imaging in the sporadic group.…”

Distribution of 1,2-dichloropropane in blood and other tissues of rats after oral administration

“…DCP from this bolus is being constantly eliminated from the rat's body by metabolism and excre- tion. After the Cmax, the higher concentrations of DCP in the liver and kidney could affect elimination of DCP by metabolism (Timchalk et al, 1991;Hutson et al, 1971;Jones and Gibson, 1980;Bartels and Timchalk, 1990;Suzuki et al, 2014) and excretion (Timchalk et al, 1991;Hutson et al, 1971;Jones and Gibson, 1980), and DCP concentration in the lung is expected to decrease due to exhalation (Timchalk et al, 1991;Hutson et al, 1971). After Cmax, elimination of DCP from the rat's body by metabolism and excretion results in time-course changes of DCP concentration in the tissues (Figs.…”