Biochemical effects of three carcinogenic chlorinated methanes in rat liver

Kitchin, Kirk T.; Brown, Jerry L.

doi:10.1002/tcm.1770090108

Cited by 17 publications

(11 citation statements)

References 17 publications

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“…From data presented in this paper as well as other similiar studies of DDT and DDE [29], chlorinated methanes [37] and lY2-dibromoethane [23], we can conclude that for halogenated hydrocarbons this biochemical assay system is a good predictor of promotion of carcinogenesis. In contrast, in three different studies using short-term mutagenicity tests only 0%, 0%, and 9% of carcinogenic halogenated hydrocarbons gave a positive response [38-401.…”

Section: Discussionsupporting

confidence: 57%

Biochemical studies of promoters of carcinogenesis in rat liver

Kitchin

Brown

1989

Teratog Carcinog Mutagen

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Adult female rats were orally dosed with 1/5 to 3/5 the published LD50 of either promoters or putative promoters of carcinogenesis [hexachlorobenzene (HCB), alpha-hexachlorocyclohexane (alpha-HCH), kepone and toxaphene] or noncarcinogens [coumaphos, EDTA, caprolactam, 8-hydroxyquinoline, titanium (IV) oxide, sodium diethyldithiocarbamate (DEDTC), and sucrose] at 21 and 4 h before sacrifice. The promoters selected in this study were all of the halogenated hydrocarbon class. At doses of 1/5 to 3/5 the LD50, all four promoters or putative promoters induced rat hepatic ODC activity. The seven noncarcinogens produced several biochemical effects at doses of 1/5 the LD50: increased serum alanine aminotransferase activity (SGPT) (caprolactam and DEDTC), decreased hepatic cytochrome P-450 content (DEDTC), and increased hepatic ODC activity (8-hydroxyquinoline and DEDTC). None of the seven noncarcinogens caused hepatic DNA damage or coordinate induction of hepatic ODC and cytochrome P-450. The results support the interpretation that several of these biochemical parameters are useful in distinguishing potential tumor promoters and noncarcinogens.

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Section: Discussionsupporting

confidence: 57%

Biochemical studies of promoters of carcinogenesis in rat liver

Kitchin

Brown

1989

Teratog Carcinog Mutagen

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“…Genotoxicity is one of the important steps with relevance to cancer development. DCM exhibited genotoxic effects in bacteria 14) and mammalian cells 15) and induced DNA damage in the liver and lung in mice and rats 16,17) . While chromosome aberration and micronucleus tests in bone marrow cells 14,18) and the unscheduled DNA synthesis (UDS) assay in hepatocytes showed negative results in mice and rats administered DCM via gavage 19) , DCM inhalation induced chromosome aberration in bone marrow and pulmonary cells and micronuclei (MNs) in peripheral blood erythrocytes 20) .…”

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confidence: 99%

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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“…[29] 1,2-dibromoethane; [26] p,p'-DDE, p,p'DDT; [27] 2,4dichlorophenoxyacetic acid, 2,4,5-trichlorophenol, 2,4,6-trichlorophenol; [28] carbon tetrachloride, chloroform, methylene chloride; [25] kepone, a-hexachlorocyclohexane, toxaphene, hexachlorobenzene;…”

Section: Summary Of Nine Predictors Of Cancer and Cancer Bioassay Datmentioning

confidence: 99%

Predicting rodent carcinogenicity of halogenated hydrocarbons by in vivo biochemical parameters

Kitchin

Brown

Kulkarni

1993

Teratog Carcinog Mutagen

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Forty halogenated hydrocarbons of known rodent carcinogenicity (24 carcinogens, 16 noncarcinogens), including many promoters of carcinogenesis, nongenotoxic carcinogens, and hepatocarcinogens, were selected for study. The chemicals were administered by gavage in two dose levels to female Sprague-Dawley rats. The effects of these 40 chemicals on four biochemical assays [hepatic DNA damage by alkaline elution (DD), hepatic ornithine decarboxylase activity (ODC), serum alanine aminotransferase activity (ALT), and hepatic cytochrome P-450 content (P450)] were determined. Composite predictive parameters are defined as follows: CP = [ODC and P450], CT = [ALT and ODC], and TS = [DD or CP or CT]. The operational characteristics of TS for predicting rodent cancer were sensitivity 58%, specificity 81%, positive predictivity 82%, negative predictivity 57%, and concordance 68%. The concordance for the Ames test (45%) and structural alerts (SA; 46%) was much lower. TS also outperformed the Ames test and SA in producing fewer false positives (the specificity of TS was 81% vs. only 63% for the Ames test and 57% for SA). For predicting the carcinogenicity of the most difficult halogenated hydrocarbons (Ames and SA negative chemicals), TS was capable of successfully predicting the carcinogenicity of 8 (carbon tetrachloride, chloroform, alpha-hexachlorocyclohexane, kepone, mirex, monuron, p,p'-DDE, and 2,4,6-trichlorophenol) out of 16 of these non-DNA-reactive halogenated hydrocarbon carcinogens. All 8 of these halogenated hydrocarbons were positive in either CP or CT. This evidence shows that nongenotoxic carcinogenesis is best predicted by nongenotoxic parameters such as CP or CT (components of the predictor TS).

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Biochemical effects of three carcinogenic chlorinated methanes in rat liver

Cited by 17 publications

References 17 publications

Biochemical studies of promoters of carcinogenesis in rat liver

Biochemical studies of promoters of carcinogenesis in rat liver

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

Predicting rodent carcinogenicity of halogenated hydrocarbons by in vivo biochemical parameters

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