BACKGROUND: Indoor air quality (IAQ) is an important determinant of human health. In Japan, IAQ guidelines have been established for 13 chemicals since 1997. Regarding ethylbenzene (EB), a previous guideline value of 3800 µg/m³ was established in 2000. However, the Ministry of Health, Labour, and Welfare decided to revise the value because of the publication of new hazard information after the establishment of the previous guideline value and the establishment of their respective IAQ guidelines by foreign organizations based on the new hazard information. This study conducted a detailed hazard assessment on EB and derived hazard assessment values to provide a toxicologically valid basis for revising the IAQ guideline value. METHODS: As it was defined that the IAQ guidelines would not exert adverse health effects on humans even if they inhaled the chemicals from indoor air over a lifetime, we investigated the general toxicity, developmental and reproductive toxicity, genotoxicity, and carcinogenicity of EB based on reliable hazard information cited in published assessment documents by domestic, foreign, or international risk assessment organizations. All the collected hazard information was examined, and we originally judged the no-observed adverse effect level and the lowest observed adverse effect level of each toxicity study. We then selected the most appropriate key study, an endpoint, and a point of departure and derived the hazard assessment values for each toxicity category. Finally, we selected a representative hazard assessment value for EB from the minimum hazard assessment value among general toxicity, developmental and reproductive toxicity, and carcinogenicity. RESULTS: Among the three toxicity categories, the minimum hazard assessment value was obtained from general toxicity, which was 0.0858 ppm (370 µg/m³) based on the loss of the outer hair cells in the organ of Corti in the cochlea observed in a 13-week repeated-dose inhalation toxicity study using rats. CONCLUSIONS It would be appropriate to adopt 0.0858 ppm (370 µg/m³) as a representative hazard assessment value to provide a basis for revising the IAQ guideline value for EB.
Japan ; Air Pollution, Indoor/adverse effects* ; Risk Assessment ; Humans ; Benzene Derivatives/toxicity* ; Guidelines as Topic ; Animals ; Air Pollutants/toxicity*

Objective: To investigate the protective effect of diallyl sulfide (DAS) , against benzene-induced genetic damage in rat. Methods: In September 2018, Sixty adult male adaptive feeding 5 days, were randomly divided into six groups according to their weight. Control groups, DAS control groups, benzene model groups, benzene+low DAS groups, benzene+middle DAS groups, benzene+High DAS group, 10 in each group. Rats in the DAS and DAS control group were orally given DAS at 40, 80, 160, 160 mg/kg, blank control and benzene model groups were given corn oil in the same volume. 2 h later, the rats in the benzene model and DAS treatment groups were given gavage administration of benzene (1.3 g/kg) mixed with corn oil (50%, V/V) , blank and DAS control groups were given corn oil in the same volume. Once a day, for 4 weeks. Samples were collected for subsequent testing. Results: Compared with the blank control group, In benzene treated rat, peripheral WBC count was reduced 65.06% (P=0.003) , lymphocyte ratiowas reduced (P=0.000) , micronucleus rate was increased (P=0.000) , Mean fluorescent intensity and relative fluorescence intensity of γH2AX in BMCs were increased 32.69%、32.64% (P=0.001、0.008) , Mean fluorescent intensity and relative fluorescence intensity of γH2AX in PBLs were increased 397.70%、396.26% (P=0.000、P=0.003) respectively. Compared with the benzene model group, the WBC count increased respectively (P=0.000、0.003、0.006) and the micronucleus rate decreased (P=0.000、0.000、0.000) in the DAS groups, Mean fluorescent intensity and relative fluorescence intensity ofγH2AX in BMCs were significantly reduced in the high DAS groups (P=0.000、0.000) , Mean fluorescent intensity and relative fluorescence intensity ofγH2AX in PBLs were significantly reduced in the low, middle, high DAS groups (P=0.000、0.000) . Conclusion: DAS can effectively suppress benzene induced genotoxic damage in rats.
4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid/analogs & derivatives* ; Allyl Compounds/pharmacology* ; Animals ; Benzene/toxicity* ; Corn Oil ; DNA Damage ; Male ; Rats ; Sulfides/pharmacology*

Benzene is classified as Group 1 carcinogen by IARC. It has been found that benzene induces hematotoxicity even in low dose exposure. The identification of key events during benzene induced hematotoxicty leads to adjustment of occupational exposure limits of benzene. In this review, we focus on the exposure, metabolism, target organs, key epigenetic changes, toxicty effects and end points of low-dose chronic benzene exposure induced hematotoxicity and finally discuss the perspectives on the future study of this area.
Benzene ; toxicity ; Carcinogens ; toxicity ; Epigenesis, Genetic ; Humans ; Occupational Exposure

Occupational diseases may be defined only medically or scientifically, and even then, their definition is not simple. However, compensable occupational diseases involve the additional layer of legal systems and social welfare policies as well. Their multifaceted nature makes determining the work-relatedness of these diseases more complex. Korea has established standards for the recognition of occupational diseases in Schedule 5 of the Enforcement Decree of the Labor Standards Act, and specific criteria for the recognition of occupational diseases are listed in Schedule 3 of the Enforcement Decree of the Industrial Accident Compensation Insurance Act. The new list of compensable occupational diseases comprises 13 articles as an open-ended system. The newly added articles pertain to lymphohematopoietic (Article 5) and infectious diseases (Article 9), as well as diseases of other target organs. Furthermore, the article on liver diseases (Article 8) has been partially revised. The new act has been changed to clarify the meaning as it has been presented in recent research. It is necessary to achieve agreement among concerned parties, including experts from the legal, medical, and social domains to resolve the issues of work-relatedness, causation, notion of aggravation, and so on for preparing a list and a process that are more reasonable.
Adult ; Benzene/toxicity ; Communicable Diseases/*economics ; Dimethylformamide/toxicity ; Drug-Induced Liver Injury/economics ; Female ; Hematologic Diseases/chemically induced/*economics ; Humans ; Lead/toxicity ; Liver Diseases/*economics ; Male ; Middle Aged ; Occupational Diseases/*economics ; Republic of Korea ; Trichloroethylene/toxicity ; Vinyl Chloride/toxicity ; Workers' Compensation/*economics

The legal scope and criteria for occupational cancer in Korea was out of date. The aim of this study was to review the current criteria for occupational cancer and amend the existent criteria on the basis of recent scientific evidence. The scientific evidence and the legal list of occupational cancer were analyzed to identify the causes of occupational cancer on a global scale. The relationship between compensated occupational cancer cases and carcinogen exposure in Korea was examined. The factors associated with specific causes and target cancers were determined to produce additional criteria. Five-hundred and nineteen cases of 2,468 were awarded compensation for occupational cancer including lung, malignant mesothelioma, lymphohematopoietic, and liver cancers from January 2000 to October 2012. Between 1996 and 2005, benzene accounted for 84.4% of cases, and between 1999 and 2005, asbestos was associated with 62.3% of cases. Fourteen novel causative agents and 12 additional target cancers were identified and the final guidelines were amended to include 23 causative agents and 21 target cancers. This amendment of the criteria for occupational cancer represents the widest change in Korean history and is expected to improve the understanding of occupational cancer by providing an up-to-date and accurate reference guide.
Asbestos/toxicity ; Benzene/toxicity ; Carcinogens/toxicity ; Female ; Humans ; Insurance, Health/*economics ; Middle Aged ; Neoplasms/chemically induced/*economics ; Occupational Diseases/*economics/mortality ; Occupational Exposure/*adverse effects ; Republic of Korea ; Workers' Compensation/*economics/legislation & jurisprudence/standards

OBJECTIVETo investigate the mechanism of genetic toxicity of gaseous benzene to mouse bone marrow cells and to provide an experimental basis for the discovery of early biomarkers among benzene-exposed population.

METHODSMale mice were randomly divided into control group and three benzene-exposed groups (6 mice per group). The control group was exposed to ambient air, and the three benzene-exposed groups were exposed to different concentrations of benzene (400, 800, and 1 600 mg/m(3)) for 15 days, 2 hours per day, in static inhalation chambers. At the end of the 15-day experimental period, the mice were killed. Bone marrow cells were separated from sacrificed mice, and superoxide dismutase (SOD) activity, glutathione peroxidase (GSH-Px) activity, myeloperoxidase (MPO) activity, and malondialdehyde (MDA) content were determined by biochemical methods. DNA damage was evaluated by micronucleus assay and single cell gel electrophoresis (SCGE). The expression of MPO protein was determined by immunocytochemistry.

RESULTSThe SOD activities in different dose groups (88.67 ± 13.58, 73.64 ± 4.50, and 67.63 ± 5.42 U/mg prot) were significantly decreased as compared with the control group (119.98±9.42 U/mg prot) (P<0.01). Moreover, the SOD activities in medium- and high-dose groups were significantly lower than that of the low-dose group (P < 0.05). The GSH-Px activities in medium- and high-dose groups (705.07 ± 93.75 and 674.77 ± 86.80 U/mg prot) were significantly decreased as compared with that of the control group (940.25 ± 82.63 U/mg prot) (P < 0.01), and the high-dose group had a significantly lower GSH-Px activity than the low-dose group (674.77 ± 86.80 U/mg prot vs 833.98 ± 130.64 U/mg prot, P < 0.05). The MDA content of low-, medium-, and high-dose groups (22.42±2.67, 22.38±3.02, and 27.66±2.89 nmol/mg prot) were significantly higher than that of the control group (12.35±1.58 nmol/mg prot) (P < 0.01), and MDA content was significantly higher in the high-dose group than in the medium- and low-dose groups (P < 0.05). The micronucleus assay showed that the micronucleus rates in different dose groups (4.67±0.82‰, 5.00±0.89‰, and 5.33±1.03‰) were significantly higher than that of the control group (2.50±0.55‰) (P < 0.01). The SCGE demonstrated that the DNA damage rates of medium- and high-dose groups (22.08% and 25.68%) were significantly higher than that of the control group (7.00%) (P < 0.01), and the DNA damage rate of high-dose group was significantly higher than that of the low-dose group (11.24%) (P < 0.05). MPO activity increased with the dose of benzene in all three benzene-treated groups (16.79±2.16, 19.46±2.28, and 22.53±2.76 U/g prot) and was significantly higher than that of the control group (12.89±0.74 U/g prot) (P < 0.01). The positive rates of MPO protein expression in low-, medium-, and high-dose groups (13.20±2.28%, 30.80±3.35%, and 40.20±1.92%) were significantly higher than that of the control group (6.60±1.14%) (P < 0.01). The MPO activity in high-dose group and the positive rates of MPO protein expression in medium- and high-dose groups were all significantly higher than those of the low-dose group (P < 0.01).

CONCLUSIONGaseous benzene exposure has toxic effect on genetics of mouse bone marrow cells. It leads to chromosome breakage and DNA damage, enhances the activity and protein expression of MPO, and induces lipid peroxidation. Lipid peroxidation damage is a potential mechanism by which gaseous benzene exerts toxic effect on mouse bone marrow cells.

Animals ; Apoptosis ; drug effects ; Benzene ; toxicity ; Bone Marrow Cells ; drug effects ; metabolism ; pathology ; DNA Damage ; Lipid Peroxidation ; drug effects ; Male ; Mice

OBJECTIVETo investigate the effect of ethylbenzene on the expression of heme oxygenase-1 (HO-1) intrarenal tissues.

METHODSForty male Sprague-Dawley rats were randomly and equally allocated to control group, low-dose exposure group, moderate-dose exposure group, and high-dose exposure group to inhale different doses of ethylbenzene (0, 433.5 mg/m(3) (100 ppm), 4335.0 mg/m(3) (1000 ppm), and 6500.0 mg/m(3) (1500 ppm)) for 6 h per day, 5 days per week, for 13 weeks. After the rat model of subchronic ethylbenzene exposure was established, the activities of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and catalase (CAT) in renal tissues were measured, and the mRNA and protein expression levels of HO-1 in renal tissues were measured by real-time PCR and Western blot.

RESULTSCompared with the control group, all exposure groups showed significantly decreased activities of GSH-Px and CAT in renal tissues and the moderate- and high-dose exposure groups showed significantly decreased activity of SOD in renal tissues (P < 0.05). All exposure groups showed significantly higher expression of HO-1 than the control group (P < 0.05). The high-dose exposure group showed significantly higher expression of HO-1 than the low- and moderate-dose exposure group (P < 0.05), and the moderate- and high-dose exposure group had significantly higher expression of HO-1 than the control group and low-dose exposure group (P < 0.05).

CONCLUSIONA certain dose of ethylbenzene can induce elevated expression of HO-1 and decreased antioxidant levels in rat renal tissues, thus leading to oxidative stress damage.

Animals ; Benzene Derivatives ; administration & dosage ; toxicity ; Catalase ; metabolism ; Glutathione Peroxidase ; metabolism ; Heme Oxygenase (Decyclizing) ; metabolism ; Inhalation Exposure ; Kidney ; enzymology ; Male ; Rats ; Rats, Sprague-Dawley ; Superoxide Dismutase ; metabolism

Benzene is an established leukotoxin and leukemogen in humans. We have previously reported that exposure of workers to benzene and to benzene metabolite hydroquinone in cultured cells induced DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to mediate the cellular response to DNA double strand break (DSB) caused by DNA-damaging metabolites. In this study, we used a new, small molecule, a selective inhibitor of DNA-PKcs, 2-(morpholin-4-yl)-benzo[h]chomen-4-one (NU7026), as a probe to analyze the molecular events and pathways in hydroquinone-induced DNA DSB repair and apoptosis. Inhibition of DNA-PKcs by NU7026 markedly potentiated the apoptotic and growth inhibitory effects of hydroquinone in proerythroid leukemic K562 cells in a dose-dependent manner. Treatment with NU7026 did not alter the production of reactive oxygen species and oxidative stress by hydroquinone but repressed the protein level of DNA-PKcs and blocked the induction of the kinase mRNA and protein expression by hydroquinone. Moreover, hydroquinone increased the phosphorylation of Akt to activate Akt, whereas co-treatment with NU7026 prevented the activation of Akt by hydroquinone. Lastly, hydroquinone and NU7026 exhibited synergistic effects on promoting apoptosis by increasing the protein levels of pro-apoptotic proteins Bax and caspase-3 but decreasing the protein expression of anti-apoptotic protein Bcl-2. Taken together, the findings reveal a central role of DNA-PKcs in hydroquinone-induced hematotoxicity in which it coordinates DNA DSB repair, cell cycle progression, and apoptosis to regulate the response to hydroquinone-induced DNA damage.
Apoptosis ; drug effects ; physiology ; Benzene ; toxicity ; Catalysis ; Chromones ; pharmacology ; DNA Damage ; drug effects ; genetics ; DNA Repair ; drug effects ; physiology ; DNA-Activated Protein Kinase ; antagonists & inhibitors ; metabolism ; Humans ; K562 Cells ; Morpholines ; pharmacology ; Protein Subunits

OBJECTIVETo evaluate the benzene exposure level and cytopenia among the benzene exposed workers in Shanghai, China and to analyze the influential factors for the health of benzene-exposed workers.

METHODSA total of 3314 benzene-exposed workers, who were from 85 benzene-related enterprises selected by stratified random sampling based on enterprise sizes and industries, were included in the study. The time-weighted average (TWA) concentration of benzene in each workshop was measured by individual sampling and fixed point sampling, and the benzene exposure level in workshop was evaluated accordingly. The occupational health examination results and health status of benzene-exposed workers were collected.

RESULTSThe median of TW A concentrations of benzene was 0.3 mg/m3. The TWA concentrations measured at 7 ( 1.4%) of the 504 sampling points were above the safety limit. Of the 7 points, 3 were from large enterprises, 2 from medium enterprises, and 2 from small enterprises; 3 were from shipbuilding industry, 1 from chemical industry, and 3 from light industry. Of the 3314 benzene-exposed workers, 451 ( 13.6%) had cytopenia, including 339 males ( 339/2548, 13.3%) and 112 females ( 112/766, 14.6% ). There were significant differences in the incidence rates of leukopenia and neutropenia among the benzene-exposed workers of different sexes and ages (P<0.05); there were significant differences in the incidence rate of cytopenia among the benzene-exposed workers of different ages and working years ( P<0.05 ); there were significant differences in the incidence of neutropenia among the benzene exposed workers of different working years ( P<0.05).

CONCLUSIONMonitoring and intervention measures should be enhanced to protect the benzene-exposed workers in the large enterprises in shipbuilding industry and medium and private enterprises in chemical industry from occupational hazards.

Adolescent ; Adult ; Benzene ; toxicity ; China ; epidemiology ; Female ; Humans ; Male ; Middle Aged ; Occupational Exposure ; Pancytopenia ; chemically induced ; epidemiology ; Young Adult

OBJECTIVETo study the oxidative damage and apoptosis of renal tubular epithelial cells (NRK-52e cell line) induced by ethylbenzene.

METHODSNRK-52e cells were exposed to 30, 60, 90, 120 μmol/L ethylbenzene for 24 hours. Cell viability were measured using MTT, the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT), the contents of malondialdehyde (MDA) and glutathione (GSH) were detected respectively. PI fluorescent staining assay was applied to detect percentage of apoptosis in ethylbenzene-treated groups.

RESULTSCompared with control group, cell outline became clear, cell diopter increased, cell became smaller and shrinkage, some cells broke in 60 μmol/L ethylbenzene-treated group. Plenty of cells died, suspension cells increased significantly in 90 μmol/L ethylbenzene-treated group. Compared with control group, cell viability the activities of SOD and CAT and the content of GSH were significantly decreased in 60 and 90 μmol/L ethylbenzene-treated groups (P<0.05). The MDA content were remarkably elevated in 90 μmol/L ethylbenzene-treated groups (P<0.05).

CONCLUSIONEthylbenzene can induce oxidative stress and apoptosis in NRK-52e cells (P<0.05).

Animals ; Apoptosis ; drug effects ; Benzene Derivatives ; toxicity ; Cell Line ; Epithelial Cells ; drug effects ; metabolism ; Kidney Tubules ; cytology ; Oxidation-Reduction ; Oxidative Stress ; drug effects ; Rats ; Reactive Oxygen Species ; metabolism