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Epidemiological studies have identified many environmental agents that appear to significantly increase cancer risk in human populations. By analyzing tumor genomes from mice chronically exposed to 1 of 20 known or suspected human carcinogens, we reveal that most agents do not generate distinct mutational signatures or increase mutation burden, with most mutations, including driver mutations, resulting from tissue-specific endogenous processes. We identify signatures resulting from exposure to cobalt and vinylidene chloride and link distinct human signatures (SBS19 and SBS42) with 1,2,3-trichloropropane, a haloalkane and pollutant of drinking water, and find these and other signatures in human tumor genomes. We define the cross-species genomic landscape of tumors induced by an important compendium of agents with relevance to human health. A genomic analysis of tumors in mice caused by known or suspected carcinogens shows that most carcinogens do not generate distinct mutational signatures.

The roles of dichloromethane (DCM) and 1,2,3-trichloropropane (1,2,3-TCP) in occupational cholangiocarcinoma, first reported in 2012, remain elusive. This study aimed to determine the potential of 1,2-dichloropropane (1,2-DCP), DCM, and 1,2,3-TCP to induce DNA damage-a hallmark of carcinogenicity-in human cholangiocytes. Monocultures of human immortalized cholangiocytes (MMNK-1 cholangiocytes) and co-cultures of MMNK-1 cholangiocytes with human THP-1 monocyte-derived macrophages and monocytes were each exposed to 1,2-DCP, DCM or 1,2,3-TCP at 0, 0.1, and 0.4 mM for 24 hours. DNA double-strand break marker γ-H2AX-positive foci and γ-H2AX pan-nuclear staining-which is known to be induced during early or intermediate stages of apoptosis or under replicative stress/checkpoint abrogation in cholangiocytes-were counted in 100 and 200 cholangiocytes, respectively. Apoptosis was evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining. The increase in dense (≥55) γ-H2AX foci induced by all 3 chemical compounds was significantly greater in co-cultures with macrophages, but not with monocytes, than in monocultures. However, only 1,2-DCP decreased the number of γ-H2AX pan-nuclear-positive and TUNEL-positive cholangiocytes in co-cultures with macrophages, but not in monocultured cholangiocytes. Co-treatment with a pan-caspase inhibitor decreased the number of γ-H2AX pan-nuclear-positive cholangiocytes in each group by about 50%, suggesting that apoptotic signaling is involved, at least in part, in the induction of γ-H2AX pan-nuclear-positive cholangiocytes. Our study showed that co-culture with macrophages enhanced DNA double-strand breaks induced by all 3 tested chemical compounds, while only 1,2-DCP exhibited a proliferative effect in monocultures and anti-apoptotic effects in co-cultures with macrophages, which are key characteristics of carcinogens, thus distinguishing 1,2-DCP from DCM and 1,2,3-TCP.

Objectives The present study was conducted to investigate the relationship between occupational chemical exposure and incidence of cholangiocarcinoma among workers in the offset colour proof-printing section of a small printing company in Osaka, Japan. Methods We identified 51 men who had worked in the proof-printing room, and 11 men who had worked in the front room for at least 1 year between 1991 and 2006. We interviewed them about the chemicals they used, and estimated their levels of exposure to chemicals. We also investigated the medical records of 11 cholangiocarcinoma patients, and calculated the standardised mortality ratio (SMR) from 1991 to 2011. Results Workers used 1,2-dichloropropane (1,2-DCP) from approximately 1985 to 2006, and dichloromethane (DCM) from approximately 1985 to 1997/1998. Exposure concentrations were estimated to be 100–670 ppm for 1,2-DCP and 80–540 ppm for DCM among the proof-printing workers. All 11 patients were pathologically diagnosed with cholangiocarcinoma. Ages at diagnosis were 25–45 years, and ages at death were 27–46 years among the six deceased individuals. The primary cancer site was the intrahepatic bile duct for five patients, and the extrahepatic bile ducts for six. All patients were exposed to 1,2-DCP for 7–17 years and diagnosed with cholangiocarcinoma 7–20 years after their first exposure. Ten patients were also exposed to DCM for 1–13 years. The SMR for cholangiocarcinoma was 2900 (expected deaths: 0.00204, 95% CI 1100 to 6400) for all workers combined. Conclusions These findings suggest that 1,2-DCP and/or DCM may cause cholangiocarcinoma in humans.

In 2012, a social issue arose concerning a high incidence of cholangiocarcinoma (bile duct cancer) among printing workers. The cause was prolonged exposure to high concentrations of 1,2-dichloropropane that was included in the ink cleaning agent. Until then, it was not known that this substance could cause cancer in humans. The author was involved in this incident from the beginning. This article describes the course from the start of the investigation to the recognition of cholangiocarcinoma as an occupational disease. Furthermore, the article presents the pathological characteristics of occupational cholangiocarcinoma, as well as epidemiological analysis results.

Purpose 1,2,3-Trichloropropane (TCP) is a persistent groundwater pollutant and a suspected human carcinogen. It is also is an industrial chemical waste that has been formed in large amounts during epichlorohydrin manufacture. In view of the spread of TCP via groundwater and its toxicity, there is a need for cheap and efficient technologies for the cleanup of TCP-contaminated sites. In situ or on-site bioremediation of TCP is an option if biodegradation can be achieved and stimulated. This paper presents an overview of methods for the remediation of TCP-contaminated water with an emphasis on the possibilities of biodegradation. Conclusions Although TCP is a xenobiotic chlorinated compound of high chemical stability, a number of abiotic and biotic conversions have been demonstrated, including abiotic oxidative conversion in the presence of a strong oxidant and reductive conversion by zero-valent zinc. Biotransformations that have been observed include reductive dechlorination, monooxygenase-mediated cometabolism, and enzymatic hydrolysis. No natural organisms are known that can use TCP as a carbon source for growth under aerobic conditions, but anaerobically TCP may serve as electron acceptor. The application of biodegradation is hindered by low degradation rates and incomplete mineralization. Protein engineering and genetic modification can be used to obtain microorganisms with enhanced TCP degradation potential.

Recently, epidemiological studies revealed a positive relationship between an outbreak of occupational cholangiocarcinoma and exposure to organic solvents containing 1,2-dichloropropane (1,2-DCP). In 1,2-DCP-administered animal models, we previously found biliary excretion of potentially oncogenic metabolites consisting of glutathione- (GSH-) conjugated forms of 1,2-DCP (GS-DCPs); however, the GS-DCP production pathway remains unknown. To enhance the understanding of 1,2-DCP-related risks to human health, we examined the reactivity of GSH with 1,2-DCP in vitro and compared it to that with dichloromethane (DCM), the other putative substance responsible for occupational cholangiocarcinoma. Our results showed that 1,2-DCP was spontaneously conjugated with GSH, whereas this spontaneous reaction was hardly detected between DCM and GSH. Further analysis revealed that glutathione S-transferase theta 1 (GSTT1) exhibited less effect on the 1,2-DCP reaction as compared with that observed for DCM. Although GSTT1-mediated bioactivation of dihaloalkanes could be a plausible explanation for the production of reactive metabolites related to carcinogenesis based on previous studies, this catalytic pathway might not mainly contribute to 1,2-DCP-related occupational cholangiocarcinoma. Considering the higher catalytic activity of GSTT1 on DCM as compared with that on 1,2-DCP, our findings suggested differences in the activation processes associated with 1,2-DCP and DCM metabolism.

Dichloromethane (DCM) and 1,2-dichloropsropane (DCP) have various uses, including being solvents for paint removers. Photoinitiators are also used in a wide range of commercial applications such as printing. These chemicals have been shown to induce cytotoxic effects. In the present study, we evaluated the combined effects of DCM or DCP from paint removers and photoinitiators used in printing on normal human embryonic lung fibroblasts with the aim of preventing occupational injuries. We showed that DCP, 2,2-dimethoxy-2-phenylacetophenone (2,2-DMPAP), 2-ethylhexyl-4-(dimethylamino) benzoate (2-EHDAB), 1-hydroxycyclohexyl phenyl ketone (1-HCHPK), and methyl 2-benzoylbenzoate (MBB) induced cytotoxicity, whereas DCM and 2-isopropylthioxanthone (2-ITX) did not. In addition, 2-methyl-4′-(methylthio)-2-morpholinopropiophenone (MTMP) caused a slight increase in cytotoxicity. The combination of DCP and the four photoinitiators (2,2-DMPAP, 2-EHDAB, MBB, and MTMP) significantly induced cytotoxicity and also led to apoptosis. In conclusion, the combination of DCP and photoinitiators may increase the risk of respiratory diseases.

A blood sample from patient 2 was positive for 1,2,3-trichloropropane (TCP) (7.6 ng/ml; undetectable in the general population). [...]diagnoses of acute toxic leukoencephalopathy induced by toluene and TCP were established in the two workers.

CO boilers/direct heating systems used in greenhouses often lead to incomplete combustion, which results in the formation of hazardous gases, such as carbon monoxide (CO), nitroxide (NO ) and other hydrocarbons. In this study, strawberry plants that were grown on rockwool cubes were transferred to airtight bottles and treated with CO, NO , CH and C H gases for 1-48 hours. Oxidative damage due to hazardous gases was observed, as indicated by H O and [Formula: see text] determination. Photosynthetic pigments were reduced, and stomatal guard cells were damaged and remained closed compared to the control. The activity of other photosynthetic parameters was negatively related to hazardous gases. Reduction in the expression of multiprotein complexes was highly observed under hazardous gas treatments. This study highlighted that hazardous gases (CO, NO , CH and C H ) emitted due to incomplete combustion of CO fertilization units/or direct heating systems resulted in the formation of ROS in shoots and limited photosynthetic metabolism. We predicted that major steps must be incorporated to improve the efficiency of CO boiler/heating systems to decrease the emission of these hazardous gases and other hydrocarbons and to reduce the observed risks that are key to the reduction of crops.

The aim of this study was to investigate the protective effect of 3-alkynyl selenophene (3-ASP) on acute liver injury induced by carbon tetrachloride (CCl4) and 2-nitropropane (2-NP) in rats. On the first day of treatment, the animals received 3-ASP (25 mg/kg, p.o.). On the second day, the rats received CCl4 (1 mg/kg, i.p.) or 2-NP (100 mg/kg, p.o.). Twenty-four hours after CCl4 or 2-NP administration, the animals were euthanized, and their plasma and liver were removed for biochemical and histological analyses. The histological analysis revealed extensive injury in the liver of CCl4-exposed and 2-NP-exposed rats, which was attenuated by 3-ASP. 3-ASP significantly attenuated (1) the increase in plasmatic aspartate and alanine aminotransferase activities and lipid peroxidation levels induced by CCl4 and 2-NP; (2) the inhibition of δ-aminolevulinic dehydratase activity caused by 2-NP; and (3) the decrease in ascorbic acid (AA) levels and catalase (CAT) activity caused by CCl4. AA levels and CAT activity remained unaltered in the liver of rats exposed to 2-NP. The protective effect of 3-ASP on acute liver injury induced by CCl4 and 2-NP in rats was demonstrated.