1,2-Dichloroethane causes anxiety and cognitive dysfunction in mice by disturbing GABA metabolism and inhibiting the cAMP-PKA-CREB signaling pathway.

1,2-Dichloroethane (1,2-DCE) is a powerfully toxic neurotoxin, which is a common environmental pollutant. Studies have indicated that 1,2-DCE long-term exposure can result in adverse effects. Nevertheless, the precise mechanism remains unknown. In this study, behavioral results revealed that 1,2-DCE long-term exposure could cause anxiety and learning and memory ability impairment in mice. The contents of γ-aminobutyric acid (GABA) and glutamine (Gln) in mice's prefrontal cortex decreased, whereas that of glutamate (Glu) increased. With the increase in dose, the activities of glutamate decarboxylase (GAD) decreased and those of GABA transaminase (GABA-T) increased. The protein and mRNA expressions of GABA transporter-3 (GAT-3), vesicular GABA transporter (VGAT), GABA A receptor α2 (GABAARα2), GABAARγ2, K-Cl cotransporter isoform 2 (KCC2), GABA B receptor 1 (GABABR1), GABABR2, protein kinase A (PKA), cAMP-response element binding protein (CREB), p-CREB, brain-derived neurotrophic factor (BDNF), c-fos, c-Jun and the protein of glutamate dehydrogenase (GDH) and PKA-C were decreased, while the expression levels of GABA transporter-1 (GAT-1) and Na-K-2Cl cotransporter isoform 1 (NKCC1) were increased. However, there was no significant change in the protein content of succinic semialdehyde dehydrogenase (SSADH). The expressions of adenylate cyclase (AC) and cyclic adenosine monophosphate (cAMP) contents were also reduced. In conclusion, the results of this study show that exposure to 1,2-DCE could lead to anxiety and cognitive impairment in mice, which may be related to the disturbance of GABA metabolism and its receptors along with the cAMP-PKA-CREB pathway.

Investigation of potential early key events and mode of action for 1,2-dichloroethane-induced mammary tumors in female rats.

1,2-dichloroethane (DCE or EDC) is a chlorinated hydrocarbon used as a chemical intermediate, including in the synthesis of polyvinyl chloride. Although DCE has induced tumors in both rats and mice, the overall weight-of-evidence suggests a lack of in vivo mutagenicity. The present study was conducted to explore a potential mode of action further for tumor formation in rat mammary tissue. Fischer 344 rats were exposed to target concentrations of 0 or 200 ppm of DCE vapors (6 hours/day, 7 days/week) for at least 28 days; 200 ppm represents a concentration of ~20% higher than that reported to induce mammary tumors. Endpoints examined included DNA damage (via Comet assay), glutathione (reduced, oxidized and conjugated), tissue DNA adducts, cell proliferation and serum prolactin levels. Exposure to DCE did not alter serum prolactin levels with consistent estrous stage, did not cause cell proliferation in mammary epithelial cells, nor result in histopathological alterations in the mammary gland. DNA adducts were identified, including the N7 -guanylethyl glutathione adduct, with higher adduct levels measured in liver (nontumorigenic target) compared with mammary tissue isolated from the same rats; no known mutagenic adducts were identified. DCE did not increase the Comet assay response in mammary epithelial cells, whereas DNA damage in the positive control (N-nitroso-N-methylurea) was significantly increased. Although the result of this study did not identify a specific mode of action for DCE-induced mammary tumors in rats, the lack of any exposure-related genotoxic responses further contributes to the weight-of-evidence suggesting that DCE is a nongenotoxic carcinogen.

1,2-Dichloroethane induces cerebellum granular cell apoptosis via mitochondrial pathway in vitro and in vivo.

1,2-Dichloroethane (1,2-DCE) is a widely used chlorinated organic toxicant, but little is known about the cerebellar dysfunction induced by excessive exposure to it. To uncover 1,2-DCE-induced neurotoxicity in cerebellar granular cells (CGCs), and to investigate the underlying mechanisms, we explored this, both in vitro and in vivo. Our findings showed significant cell viability inhibition in human CGCs (HCGCs) treated with 1,2-DCE. Flow cytometry and mitochondrial membrane potential analyses discovered an increase in apoptotic-mediated cell death in HCGCs after 1,2-DCE treatment. This HCGC apoptosis was involved in the increases of protein expression in Cytochrome c, Caspase-3, Bad, Bim, transformation related protein 53, Caspase-8, tumor necrosis factor-α, and Survivin. Quantitative real-time PCR (qPCR) and western blot confirmed the increases in Cytochrome c, Caspase-3, cleaved Caspase-3, and Bad in HCGCs after 1,2-DCE treatment. Bax inhibitor peptide V5 rescued 1,2-DCE-induced HCGC apoptosis. Furthermore, 80 CD-1 male mice were exposed to 1,2-DCE by inhalation at 0, 100, 350, and 700 mg/m3 for 6 h/day for 4 weeks. An open field test found abnormal neurobehavioral changes in the mice exposed to 1,2-DCE. Histopathological examination showed significantly shrunken and hypereosinophilic cytoplasm with nuclear pyknosis in mouse CGCs from the 700 mg/m3 1,2-DCE group. TdT-mediated dUTP nick-end labeling assay verified significant increases in apoptotic positive cells in the mouse CGCs after 1,2-DCE exposure. We confirmed the increases in the expressions of Cytochrome c, Caspase-3, cleaved Caspase-3 and Bad in the mice exposed to 1,2-DCE. These findings suggest that 1,2-DCE exposure can induce CGC apoptosis and cerebellar dysfunction, at least in part, through mitochondrial pathway.

LncRNA-241 inhibits 1,2-Dichloroethane-induced hepatic apoptosis.

Chlorinated organic chemical 1,2-dichloroethane (1,2-DCE) is used widely in industrial production processes, and excessive exposure may lead to liver damage. The mechanisms underlying 1,2-DCE-induced hepatotoxicity are not fully understood. Numerous studies have demonstrated that long-non-coding RNAs (lncRNAs) play a pivotal role in the chemical-induced toxicity. To explore whether aberrant lncRNA expression is involved in hepatotoxicity mediated by 1,2-DCE exposure, we detected alterations of lncRNA expression profiling in a mouse model of 1,2-DCE-induced hepatotoxicity by microarray chip. Bioinformatic analysis indicated that a down-regulated lncRNA (lncRNA241) after 1,2-DCE exposure might be involved in 1,2-DCE-induced hepatotoxicity. We treated AML12 cells with 1,2-DCE and its metabolite 2-chloroacetic acid (2-CA) for 48 h, and the results revealed that it was 2-CA rather than primary form (1,2-DCE) that resulted in the decline of lncRNA241 expression in hepatocytes. In vitro intervention studies revealed that the repression of lncRNA241 expression after 2-CA exposure led to the down-regulation of anti-apoptosis-associated factor insulin growth factor-1 (Igf1) at mRNA and protein levels through modulation of their common target mmu-miR-451a, which promoted hepatic apoptosis. This study provides valuable insight into the role of lncRNAs in response to hepatocyte apoptosis induced by 1,2-DCE.

The clinical and pathological features of toxic encephalopathy caused by occupational 1,2-dichloroethane exposure.

To understand the clinical and pathological features of 1,2-dichloroethane (DCE) toxic encephalopathy.The cases of 4 patients who were admitted to Xiangya hospital between January 8, 2008 and November 8, 2012 with diagnoses of DCE toxic encephalopathy were examined. We recorded data on gender, age of onset, exposure time to DCE, symptom onset to admission interval, symptom onset to worst symptom experience interval, and clinical manifestations, as well as cranial magnetic resonance imaging (MRI) and brain biopsy pathology results.All 4 patients had a history of DCE exposure and presented with symptoms of intracranial hypertension. Cranial MRI revealed extensive brain edema throughout the subcortical white matter, the bilateral globus pallidus, and the cerebellar dentate nuclei. The brain biopsy confirmed severe cerebral edema, including peripherovascular edema, with swelling of various cell types, with extensive glial cell necrosis. After treatment with steroids and mannitol (3-10 weeks), all 4 patients recovered, partially or completely.Severe brain edema and extensive glial cell necrosis were the main pathological features observed in the present cases, with a likely etiology of DCE toxicity. Early, prompt, and long-term treatment with dehydrating agents and glucocorticoids was an effective treatment for this condition.

Toxic effects of combined treatment of 1,2-dichloroethane and ethanol on mouse brain and the related mechanisms.

The aim of this study was to explore the mechanisms of brain damage induced by the combined treatment of mice with 1,2-dichloroethane (1,2-DCE) and ethanol. Mice were divided into control group; 1,2-DCE-intoxicated group; ethanol-treated group; and low-, medium-, and high-dose combined treatment groups. Histological observations along with brain organ coefficients and water content were used to measure the brain damage directly and indirectly. The levels of nonprotein sulfhydryls, malondialdehyde (MDA), and superoxide dismutase activity were used as parameters to evaluate oxidative stress in the brain. Protein and messenger RNA (mRNA) levels of cytochrome P450 2E1 (CYP2E1), zonula occludens-1 (occludin and zo-1), aquaporin-4 (AQP4), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase (HO)-1, and the γ-glutamyl cysteine synthetase catalytic and modulatory subunits (γ-GCSc, GR, and γ-GCSm) in the brain were examined by Western blot analysis and quantitative polymerase chain reaction analysis, respectively. Effects of the combined treatment of 1,2-DCE and ethanol were evaluated by analysis of variance with a factorial design. The results suggested that combined exposure to ethanol and 1,2-DCE synergistically increased CYP2E1 protein and mRNA levels, accelerated the metabolism of ethanol and 1,2-DCE in the brain tissue, induced high production of reactive oxygen species (ROS), and increased MDA levels, thereby damaging the blood-brain barrier and causing obvious pathological changes in brain tissue. However, the increased level of ROS activated the Nrf2 signal transduction pathway, promoting the expression of HO-1 and glutathione-related antioxidant enzymes in the brain to protect the cells from oxidative damage.

1,2-Dichloroethane-induced hepatotoxicity and apoptosis by inhibition of ERK 1/2 pathways.

1,2-Dichloroethane (DCE) is a ubiquitous occupational environmental contaminant. Subacute exposure to DCE can cause severe toxic encephalopathy and has obvious toxic effects on the liver. However, the toxicity of DCE on the liver and its molecular mechanism remain elusive. In the present study, we established a DCE-exposed animal model by inhalation in SD rats and used HepG2 cells in in vitro tests. The DCE-exposed groups showed hepatic dysfunction relative to the control group. Moreover, apoptotic cells and decreased phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) were found in liver tissue of rats in 3 DCE-exposed groups. In vitro tests showed that short-term exposure to DCE induced apoptosis in HepG2 cells. Furthermore, the incubation of cells with DCE significantly decreased the phosphorylation of ERK1/2 in a concentration-dependent manner. Additionally, incubating HepG2 cells with epidermal growth factor, an ERK1/2 activator, significantly increased apoptosis in HepG2 cells. In conclusion, our results suggest that DCE induces apoptosis in HepG2 cells by inhibiting ERK1/2 pathways.

Aberrant expression of miR-451a contributes to 1,2-dichloroethane-induced hepatic glycerol gluconeogenesis disorder by inhibiting glycerol kinase expression in NIH Swiss mice.

The identification of aberrant microRNA (miRNA) expression during chemical-induced hepatic dysfunction will lead to a better understanding of the substantial role of miRNAs in liver diseases. 1,2-Dichloroethane (1,2-DCE), a chlorinated organic toxicant, can lead to hepatic abnormalities in occupationally exposed populations. To explore whether aberrant miRNA expression is involved in liver abnormalities mediated by 1,2-DCE exposure, we examined alterations in miRNA expression patterns in the livers of NIH Swiss mice after dynamic inhalation exposure to 350 or 700 mg m-3 1,2-DCE for 28 days. Using a microarray chip, we discovered that only mmumiR-451a was significantly upregulated in the liver tissue of mice exposed to 700 mg m-3 1,2-DCE; this finding was validated by quantitative real-time polymerase chain reaction. In vitro study revealed that it was metabolite 2-chloroacetic acid, not 1,2-DCE that resulted in the upregulation of mmu-miR-451a in the mouse AML12 cell line. Furthermore, our data showed that the upregulation of mmu-miR-451a induced by 2-chloroacetic acid could suppress the expression of glycerol kinase and lead to the inhibition of glycerol gluconeogenesis in mouse liver tissue and AML12 cells. These observations provide evidence that hepatic mmu-miR-451a responds to 1,2-DCE exposure and might induce glucose metabolism disorders by suppressing the glycerol gluconeogenesis process.

1,2-Dichloroethane Induces Reproductive Toxicity Mediated by the CREM/CREB Signaling Pathway in Male NIH Swiss Mice.

1,2-Dichloroethane (1,2-DCE) is a widely used chlorinated organic toxicant but little is known about the reproductive disorders induced by its excessive exposure. To reveal 1,2-DCE-induced male reproductive toxicity and to elucidate the underlying mechanisms, we exposed male National Institutes of Health Swiss mice to 1,2-DCE by inhalation at 0, 100, 350, and 700 mg/m3 for 6 h/day, for 1 and 4 weeks. Our findings showed a significant decrease in body weight with increased testis/body weight ratio, reduced sperm concentration and induced malformation of spermatozoa, and vacuolar degeneration of germ cells in the seminiferous tubules of testes in mice exposed to 1,2-DCE. Cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB) and cAMP-response element modulator (CREM) were significantly inhibited by 1,2-DCE. This is consistent with the declines in the transducer of regulated CREB activity 1 and activator of CREM in testis, which results in the decrease in lactate dehydrogenase C and testis-specific kinase 1 in the testes. Moreover, the activation of p53 and Bax with the inhibition of Bcl-2 might be the reason for the upregulation of caspase-3 in the apoptosis, as detected by TdT-mediated dUTP nick-end labeling assay in the testes induced by 1,2-DCE. Finally, elevated testosterone levels were found along with increased levels of gonadotropin-releasing hormone, cAMP, luteinizing hormone (LH), and LH receptors in the testes. These findings suggest that 1,2-DCE inhibits CREM/CREB signaling cascade and subsequently induces apoptosis associated with p53 activation and mitochondrial dysfunction. This also results in induced malformation of spermatozoa, reduced sperm concentration, and pathological impairment of the testes.

Lung Tumor Induction by 26-week Dermal Application of 1,2-Dichloroethane in CB6F1-Tg rasH2 Mice.

Short-term alternatives to traditional 2-year carcinogenic studies in rodents are being actively pursued. Recently, a 26-week short-term carcinogenicity study using CB6F1-Tg rasH2@Jcl (rasH2) mice has become a worldwide standard for the evaluation of chemical carcinogenesis. However, an acceptable short-term carcinogenic study model for dermally applied products is still lacking. To investigate the suitability of using the rasH2 mouse to test carcinogenic potential, 1,2-dichloroethane (1,2-DCE) was dermally applied to rasH2 mice: 1,2-DCE is a known carcinogen that causes lung bronchiolo-alveolar adenomas and adenocarcinomas when administered topically, orally, or by inhalation exposure; 1,2-DCE at a dose level of 126 mg/mouse in 200 µl acetone or acetone alone (vehicle control) was applied to the dorsal skin of 10 mice of each sex 3 times a week for 26 weeks. As a positive control, 10 mice of each sex received a single intraperitoneal injection of 75 mg/kg of N-methyl- N-nitrosourea. Bronchiolo-alveolar adenomas and adenocarcinomas were significantly increased in 1,2-DCE-treated rasH2 mice of both sexes, and bronchiolo-alveolar hyperplasias were significantly increased in female mice. Overall, almost all mice of each sex developed adenomas and/or adenocarcinomas with 100% of female rasH2 mice developing bronchiolo-alveolar adenocarcinomas.

1,2-Dichloroethane impairs glucose and lipid homeostasis in the livers of NIH Swiss mice.

Excessive exposure to 1,2-Dichloroethane (1,2-DCE), a chlorinated organic toxicant, can lead to liver dysfunction. To fully explore the mechanism of 1,2-DCE-induced hepatic abnormalities, 30 male National Institutes of Health (NIH) Swiss mice were exposed to 0, 350, or 700mg/m3 of 1,2-DCE, via inhalation, 6h/day for 28days. Increased liver/body weight ratios, as well as serum AST and serum ALT activity were observed in the 350 and 700mg/m3 1,2-DCE exposure group mice, compared with the control group mice. In addition, decreased body weights were observed in mice exposed to 700mg/m3 1,2-DCE, compared with control mice. Exposure to 350 and 700mg/m3 1,2-DCE also led to significant accumulation of hepatic glycogen, free fatty acids (FFA) and triglycerides, elevation of blood triglyceride and FFA levels, and decreases in blood glucose levels. Results from microarray analysis indicated that the decreases in glucose-6-phosphatase catalytic subunit (G6PC) and liver glycogen phosphorylase (PYGL) expression, mediated by the activation of AKT serine/threonine kinase 1 (Akt1), might be responsible for the hepatic glycogen accumulation and steatosis. Further in vitro study demonstrated that 2-chloroacetic acid (1,2-DCE metabolite), rather than 1,2-DCE, up-regulated Akt1 phosphorylation and suppressed G6PC and PYGL expression, resulting in hepatocellular glycogen accumulation. These results suggest that hepatic glucose and lipid homeostasis are impaired by 1,2-DCE exposure via down-regulation of PYGL and G6PC expression, which may be primarily mediated by the 2-chloroacetic acid-activated Akt1 pathway.

Alteration in mitochondrial function and glutamate metabolism affected by 2-chloroethanol in primary cultured astrocytes.

The aim of this study was to explore the mechanisms that contribute to 1,2-dichloroethane (1,2-DCE) induced brain edema by focusing on alteration of mitochondrial function and glutamate metabolism in primary cultured astrocytes induced by 2-chloroethanol (2-CE), a metabolite of 1,2-DCE in vivo. The cells were exposed to different levels of 2-CE in the media for 24h. Mitochondrial function was evaluated by its membrane potential and intracellular contents of ATP, lactic acid and reactive oxygen species (ROS). Glutamate metabolism was indicated by expression of glutamine synthase (GS), glutamate-aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1) at both protein and gene levels. Compared to the control group, exposure to 2-CE could cause a dose dependent damage in astrocytes, indicated by decreased cell viability and morphological changes, and supported by decreased levels of nonprotein sulfhydryl (NPSH) and inhibited activities of Na+/K+-ATPase and Ca2+-ATPase in the cells. The present study also revealed both mitochondrial function and glutamate metabolism in astrocytes were significantly disturbed by 2-CE. Of which, mitochondrial function was much vulnerable to the effects of 2-CE. In conclusion, our findings suggested that mitochondrial dysfunction and glutamate metabolism disorder could contribute to 2-CE-induced cytotoxicity in astrocytes, which might be related to 1,2-DCE-induced brain edema.

Development of an inhalation unit risk factor for ethylene dichloride.

The Texas Commission on Environmental Quality (TCEQ) conducts up-to-date carcinogenic assessments for chemicals emitted in Texas. An inhalation unit risk factor (URF) was developed for ethylene dichloride (EDC, CAS 107-06-2) based on tumorigenicity results observed in a 2-year animal inhalation study conducted by Nagano et al. More specifically, the incidence of combined mammary gland tumors (adenomas, fibroadenomas, adenocarcinomas) in female rats demonstrated a statistically significant dose-response relationship, was amenable to benchmark concentration (BMC) modeling, was ultimately determined to be the most sensitive tumorigenic effect in the most sensitive species and sex, and was utilized as the carcinogenic endpoint for the development of the URF. The 95% lower confidence limit of the BMC at the 10% excess risk level (BMCL10 of 40.1 ppm) was determined for calculation of the URF. The resulting URF based on increased incidence of combined mammary gland tumors in female rats is 1.4E-02 per ppm (3.4E-03 per mg/m(3)). The lifetime air concentration corresponding to a no significant excess risk level of 1 in 100 000 is 0.71 ppb (2.9 µg/m(3)), which is considered sufficiently health-protective for use in protecting the general public against the potential carcinogenic effects of chronic exposure to EDC in ambient air.

Genotoxicity and immunotoxic effects of 1,2-dichloroethane in Wistar rats.

Dichloroethane is widely used as a solvent, degreasing agent and in a variety of commercial products, and is known for being a ubiquitous contaminant in the environment. Important sources principally include the emissions from industrial processes, improper consumption, storage, and disposal methods. In view of the fact that the mechanism of its genotoxicity has not been satisfactorily elucidated, the acute in vivo toxicological impact is assessed in Rattus norvegicus. A systematic investigation has been made involving the use of conventional methods along with molecular and flow cytometric approaches. The micronucleus and chromosomal aberration frequencies were significantly elevated in bone marrow cells exposed to three concentrations at multiple treatment durations indicating positive time- and dose-response relationships. The mitotic index significantly decreased in similar concentrations in contrast to normal control. Separate studies were performed on blood cells for comet assay. It revealed dichloroethane-induced DNA damage in all exposures readily explainable in a dose- and time-dependent manner. Recent molecular techniques were further employed using leukocytes for the cell apoptosis/cycle and mitochondrial membrane potential employing propidium iodide staining and rhodamine-123, respectively. The effect on mitochondrial membrane permeability, cell cycle phases, and the DNA damage was analyzed through flow cytometry. These indicators revealed dichloroethane treatment decreased the mitochondrial membrane potential, affected the cell cycle, and confirmed the DNA damage, leading to apoptosis of the cells of the immune system responsible for immunotoxic effects of dichloroethane on rat leukocytes.

Toxicity of industrially relevant chlorinated organic solvents in vitro.

The cytotoxic effects of 4 industrially important chlorinated organic solvents, dichloromethane (DCM), 1,2-dichloroethane (DCE), trichloroethylene (TCE), and tetrachloroethylene (PERC) in vitro, were investigated. Jurkat T cells were exposed to the solvents individually for 72 hours and changes in reactive oxygen species (ROS) formation, cell proliferation, intracellular free calcium concentration ([Ca(2+)]), and caspase-3 activity were measured. There was a concentration-dependent increase in the ROS formation and intracellular free [Ca(2+)] following exposure to each of the solvents. This was accompanied by a decrease in the cell proliferation. Solvent potency decreased in the following order: PERC > TCE > DCM > DCE. Caspase-3 activity was increased in a concentration-dependent manner by TCE and PERC but was not significantly altered by DCM or DCE. n-Acetyl-l-cysteine pretreatment showed that changes in the intracellular free [Ca(2+)] and caspase-3 activity were independent of ROS formation. However, increased ROS formation did play a causal role in the decreased cell proliferation observed.

[The effects of 1,2-dichloroethane on the cellular proliferation, cellular cycle and apoptosis of SW620 cells in vitro].

OBJECTIVE: To explore the effects of 1,2-dichloroethane (1,2-DCE) on the cellular proliferation, cellular cycle and apoptosis of SW620 cells in vitro. METHODS: SW620 cells were exposed to 1,2-DCE at different concentrations for 0.5 and 1 h. MTT assay was used to detect the relative number and relative viability, the low cytometry (FCM) assay was utilized to measure the cell cycle and apoptosis. RESULTS: The results of MTT assay showed that the cellular relative viability decreased with the 1,2-DCE's dose and exposure time. Compared with the DMSO group, the relative cellular viability of cells exposed to 1,2-DCE at the doses of 75, 100, 125, 150, 175, 200 µmol/L for 1 h decreased (P<0.05 or P<0.01). Compared with the groups exposed to 1,2-DCE for 0.5 h, the relative cellular viability of cells exposed to 175 µmol/L 1,2-DCE for 1 h decreased significantly (P<0.01). IC(50) of cellular proliferation in cells exposed to 1,2-DCE for 0.5 h was 89.41 µmol/L, and 95% confidence interval was 85.23 to 93.79 µmol/L. IC(50) of cellular proliferation in cells exposed to 1,2-DCE for 1 h was 87.68 µmol/L, and 95% confidence interval was 83.71 to 91.82 µmol/L. The results of FCM indicated that compared with the control group, the G(0)/G(1) phase in groups exposed to 1,2-DCE at the doses of 25, 50, 100, 150 and 200 µmol/L for 1 h decreased significantly (P<0.05 or P<0.01), the S phase in groups exposed to 1,2-DCE at the doses of 25, 50 and 100 µmol/L for 1 h reduced significantly (P<0.05 or P < 0.01), the G(2)/M phase in groups exposed to 1,2-DCE at the doses of 25, 50, 100, 150 and 200 µmol/L for 1 h increased significantly (P<0.05 or P<0.01). However, 1,2-DCE could not induce apoptosis of SW620 cells. CONCLUSION: 1,2-DCE could inhibit the proliferation of SW620 cells, and arrest SW620 cells at G(2)/M phase, but could not induce the apoptosis of SW620 cells in vitro.

A review of the genotoxicity of 1,2-dichloroethane (EDC).

1,2-Dichloroethane (EDC, CAS#107-06-2) is a high production volume halogenated aliphatic hydrocarbon that is used mainly in the manufacture of vinyl chloride. EDC has been found in ambient and residential air samples, as well as in groundwater, surface water and drinking water. EDC has been well-studied in a variety of genotoxicity assays, and appears to involve the metabolic activation of the parent compound. We critically evaluated the genotoxicity data of EDC and its metabolites as part of an evaluation of carcinogenic mechanisms of action of EDC. EDC is genotoxic in multiple test systems via multiple routes of exposure. EDC has been shown to induce DNA adduct formation, gene mutations and chromosomal aberrations in the presence of key activation enzymes (including CYP450s and/or GSTs) in laboratory animal and in vitro studies. EDC was negative for clastogenesis as measured by the micronucleus assay in mice. In general, an increased level of DNA damage is observed related to the GSH-dependent bioactivation of EDC. Increased chromosomal aberrations with increased CYP450 expression were suggestive of a role for the oxidative metabolites of EDC in inducing chromosomal damage. Taken together, these studies demonstrate that EDC exposure, in the presence of key enzymes (including CYP450s and/or GSTs), leads to DNA adduct formation, gene mutations and chromosomal aberrations.

[Carcinogenic hazard of chloroform and other drinking water chlorination by-products].

The paper presents the results of studying the carcinogenic effect of chloroform and its combination with carbon tetrachloride, 1,2-dichloroethane, trichloroethylene during chronic oral administration to F1(CBAxC57Bl6) mice. There is a relationship between the manifestation of carcinogenesis to the dose of chloroform and a combination of chemicals, as well as its enhancement upon exposure to the combination as compared with acute administration of chloroform. Exposure to a combination of substances at the level of their maximum permissible concentrations does not affect carcinogenesis. The possible mechanisms of the specific features of carcinogenesis in this experiment are discussed.

Analysis of DNA adducts formed in vivo in rats and mice from 1,2-dibromoethane, 1,2-dichloroethane, dibromomethane, and dichloromethane using HPLC/accelerator mass spectrometry and relevance to risk estimates.

Dihaloalkanes are of toxicological interest because of their high-volume use in industry and their abilities to cause tumors in rodents, particularly dichloromethane and 1,2-dichloroethane. The brominated analogues are not used as extensively but are known to produce more toxicity in some systems. Rats and mice were treated i.p. with (14)C-dichloromethane, -dibromomethane, -1,2-dichloroethane, or -1,2-dibromoethane [5 mg (kg body weight)(-1)], and livers and kidneys were collected to rapidly isolate DNA. The DNA was digested using a procedure designed to minimize processing time, because some of the potential dihalomethane-derived DNA-glutathione (GSH) adducts are known to be unstable, and the HPLC fractions corresponding to major adduct standards were separated and analyzed for (14)C using accelerator mass spectrometry. The level of liver or kidney S-[2-(N(7)-guanyl)ethyl]GSH in rats treated with 1,2-dibromoethane was approximately 1 adduct/10(5) DNA bases; in male or female mice, the level was approximately one-half of this. The levels of 1,2-dichloroethane adducts were 10-50-fold lower. None of four known (in vitro) GSH-DNA adducts was detected at a level of >2/10(8) DNA bases from dibromomethane or dichloromethane. These results provide parameters for risk assessment of these compounds: DNA binding occurs with 1,2-dichloroethane but is considerably less than from 1,2-dibromoethane in vivo, and low exposure to dihalomethanes does not produce appreciable DNA adduct levels in rat or mouse liver and kidney of the doses used. The results may be used to address issues in human risk assessment.