Objective: The aim of this study was to explore the ototoxicity of toluene in the early development of zebrafish embryos/larvae. Methods: Zebrafish were utilized to explore the ototoxicity of toluene. Locomotion analysis, immunofluorescence, and qPCR were used to understand the phenotypes and molecular mechanisms of toluene ototoxicity. Results: The results demonstrated that at 2 mmol/L, toluene induced zebrafish larvae death at 120 hours post fertilization (hpf) at a rate of 25.79% and inhibited the rate of hatching at 72 hpf. Furthermore, toluene exposure inhibited the distance travelled and average swimming velocity of zebrafish larvae while increasing the frequency of movements. As shown by fluorescence staining of hair cells, toluene inhibited the formation of lateral line neuromasts and middle line 1 (Ml Conclusion This study indicated that toluene may affect the development of both the inner ear and lateral line systems in zebrafish, while the lateral line system may be more sensitive to toluene than the inner ear.
Animals ; Ear, Inner/growth & development* ; Embryo, Nonmammalian/drug effects* ; Gene Expression Regulation, Developmental/drug effects* ; Hair Cells, Auditory/metabolism* ; Lateral Line System/growth & development* ; Locomotion/drug effects* ; Ototoxicity/physiopathology* ; Toluene/toxicity* ; Zebrafish

BACKGROUND: Plastic resins are complex chemicals that contain toluene diisocyanate (TDI) and/or trimellitic anhydride (TMA), which cause occupational allergies (OA), including respiratory allergies. Serum IgGs against TDI and TMA have been suggested as potential markers of the exposure status and as exploring cause of OA. Although TDI-specific IgG has been examined for suspected OA, TMA-specific IgG is not commonly evaluated in a urethane foam factory. This study therefore investigated both TDI- and TMA-specific IgGs in suspected OA patients and to evaluate the usefulness of the measurement of multiple chemical-specific IgG measurement for practical monitoring. METHODS: Blood samples were collected from two male workers who developed respiratory allergies supposedly caused by occupational exposure to TDI and/or TMA for the presence of TDI- and TMA-specific IgGs. In addition, blood samples from 75 male workers from a urethane foam factory, along with 87 male control subjects, were collected in 2014 and tested for the same IgGs in 2014. The presence and levels of TDI- and TMA-specific serum IgGs were measured using dot blot assays. RESULTS: We found that controls had mean concentrations of TDI- and TMA-specific IgGs of 0.98 and 2.10 μg/mL, respectively. In the two workers with respiratory allergies, the TDI-specific IgG concentrations were 15.6 and 9.51 μg/mL, and TMA-specific IgG concentrations were 4.56 and 14.4 μg/mL, which are clearly higher than those in controls. Mean concentrations of TDI- and TMA-specific IgGs in the factory workers were 1.89 and 2.41 μg/mL, respectively, and are significantly higher than those of the controls (P < 0.001 and P < 0.026 for TDI- and TMA-specific IgGs, respectively). CONCLUSION The workers suspected of OA showed an evidently high level of TDI- and TMA-specific IgG, and these levels in workers at the urethane foam factory were also significantly higher than those in controls. In conclusion, the measurement of TDI- and TMA-specific IgG among workers using plastic resins is helpful to monitor their exposure status.
Adult ; Air Pollutants, Occupational ; adverse effects ; immunology ; Environmental Monitoring ; Humans ; Immunoglobulin G ; blood ; immunology ; Japan ; Male ; Manufacturing and Industrial Facilities ; statistics & numerical data ; Middle Aged ; Occupational Diseases ; blood ; chemically induced ; Occupational Exposure ; adverse effects ; statistics & numerical data ; Phthalic Anhydrides ; immunology ; toxicity ; Respiratory Hypersensitivity ; blood ; chemically induced ; Toluene 2,4-Diisocyanate ; immunology ; toxicity ; Workforce

OBJECTIVES: We established a Wistar rat model of asthma caused by toluene diisocyanate (TDI) exposure, and investigated the relationship between TDI exposure concentrations and respiratory hypersensitivity, airway inflammation, and cytokine secretions in animals, to better understand the mechanism of TDI induced occupational asthma. METHODS: Wistar rats were exposed to two different concentrations of TDI vapor four hours a day for five consecutive days. Bronchoalveolar lavage (BAL) was performed, and differential leucocytes from the BAL fluid were analyzed. Lung histopathological examination was carried out to investigate the inflammatory status in the airways. Production of cytokines interleukin (IL)-4 and IL-5 productions in the BAL fluid in vivo was determined with enzyme-linked immunosorbent assay kits. RESULTS: The TDI-exposed rats exhibited greater airway hypersensitivity symptoms than the control rats. The BAL differential cell count and lung histopathological examination demonstrated that inflammation reactions were present in both the central and peripheral airways, characterized with marked infiltration of eosinophils in the TDI-exposed rats. The cytokine assay showed that IL-4 and IL-5 were predominantly produced in the BAL fluid in vivo. CONCLUSIONS: These findings imply that TDI exposure concentrations may greatly affect the occurrence and extent of inflammatory events and that Th2 type cytokines may play an important role in the immunopathogenesis of TDI-induced occupational respiratory hypersensitivity.
Animals ; Bronchoalveolar Lavage Fluid/chemistry/cytology ; Enzyme-Linked Immunosorbent Assay ; Eosinophils/cytology/immunology ; Female ; Gases/chemistry ; Hypersensitivity/pathology ; Interleukin-4/*analysis ; Interleukin-5/*analysis ; Lung/*drug effects/pathology/secretion ; Rats ; Rats, Wistar ; Toluene 2,4-Diisocyanate/*toxicity

Acidosis ; etiology ; Humans ; Kidney Diseases ; etiology ; Toluene ; toxicity

The development of a serological marker for early diagnosis of isocyanate-induced occupational asthma (isocyanate-OA) may improve clinical outcome. Our previous proteomic study found that expression of vitamin D-binding protein (VDBP) was upregulated in the patients with isocyanate-OA. In the present study, we evaluated the clinical relevance of VDBP as a serological marker in screening for isocyanate-OA among exposed workers and its role in the pathogenesis of isocyanate-OA. Three study groups including 61 patients with isocyanate-OA (group I), 180 asymptomatic exposed controls (AECs, group II), 58 unexposed healthy controls (NCs, group III) were enrolled in this study. The baseline serum VDBP level was significantly higher in group I compared with groups II and III. The sensitivity and specificity for predicting the phenotype of isocyanate-OA with VDBP were 69% and 81%, respectively. The group I subjects with high VDBP (> or = 311 microg/ml) had significantly lower PC20 methacholine levels than did subjects with low VDBP. The in vitro studies showed that TDI suppressed the uptake of VDBP into RLE-6TN cells, which was mediated by the downregulation of megalin, an endocytic receptor of the 25-hydroxycholecalciferol-VDBP complex. Furthermore, toluene diisocyanate (TDI) increased VEGF production and secretion from this epithelial cells by suppression of 1,25-dihydroxycholecalciferol [1,25(OH)2D3] production. The findings of this study suggest that the serum VDBP level may be used as a serological marker for the detection of isocyanate-OA among workers exposed to isocyanate. The TDI-induced VEGF production/secretion was reversed by 1,25(OH)2D3 treatment, which may provide a potential therapeutic strategy for patients with isocyanate-OA.
Adult ; Animals ; *Asthma/blood/chemically induced/pathology ; Cell Line ; Epithelial Cells ; Female ; Gene Expression/drug effects ; Humans ; Isocyanates/toxicity ; Male ; Middle Aged ; *Occupational Diseases/blood/chemically induced/pathology ; Rats ; Toluene 2,4-Diisocyanate/toxicity ; Vitamin D-Binding Protein/*blood

OBJECTIVES: Polycyclic aromatic hydrocarbons (PAH) and toluene have been reported to induce reactive oxygen species and oxidative stress. This study was performed to investigate the effects of low level exposure to PAHs or toluene on the lipid peroxidation level in elementary school children and the elderly in a rural area. METHODS: Forty seven elementary school children and 40 elderly people who were living in a rural area and not occupationally exposed to PAH or toluene were the subjects of this study. Information about active or passive smoking and diet was obtained using a self-administered questionnaire. The urinary 1-hydroxypyrene (1-OHP), 2-naphthol, hippuric acid and thiobarbituric acid reactive substance (TBARS) concentrations were measured, and these values were corrected with the urinary creatinine concentration. RESULTS: In school children, the geometric means of the urinary 1-OHP, 2-naphthol, hippuric acid and TBARS levels were 0.02 ymol/mol creatinine, 0.47 micron mol/mol creatinine, 0.14 g/g creatinine and 0.95 micron mol/g creatinine, respectively. Those values for the elderly were 0.07 micron mol/mol creatinine, 1.87 micron mol/mol creatinine, 0.11 g/g creatinine and 1.18 micron mol/g creatinine, respectively. The mean levels of urinary 1-OHP, 2-naphthol and TBARS were significantly higher in the elderly subjects than in the children. The urinary TBARS level was not correlated with the urinary 1-OHP, 2-naphthol and hippuric acid, but they were correlated with the age of the subjects. CONCLSIONS: These results suggest that low level inhalation exposure to PAH or toluene does not markedly increase lipid peroxidation, and age is a significant determinant of lipid peroxidation.
Child ; Environmental Exposure/*adverse effects ; Environmental Pollutants/*toxicity ; Female ; Humans ; Male ; Middle Aged ; Polycyclic Hydrocarbons, Aromatic/*toxicity ; *Rural Population ; Thiobarbituric Acid Reactive Substances/*analysis ; Toluene/*toxicity ; Urinalysis

BACKGROUND/AIMS: The current study was designed to determine whether the indoor air pollution in a hemodialysis room (HD) was different from that of other comparable areas in a hospital. METHODS: Five air monitor samplers were hung on the ceiling and placed on the table in both the HD and general ward nursing stations, respectively. In addition, five samplers were placed in the nurse's breathing zone of the HD and the general ward, respectively. Ten air monitor samplers were also placed on the edge of the bed in the HD, which represented the patient's breathing zone. The levels of benzene and toluene were analyzed by GC/MS. RESULTS: In the general ward, the toluene concentration was significantly higher in the nurse breathing zone than that for the ceiling or table samples (p=0.001). The benzene concentration was also significantly higher in the general ward nurse breathing zone than that in the HD (p=0.006). In addition, the benzene concentrations on the table were higher at the general ward as compared to the HD (p=0.028), but there was no significant difference between the ceiling, general ward station and HD. CONCLUSIONS: Both the benzene and toluene concentrations in the HD appear to be more affected by the outdoor atmospheric conditions than by any potential indoor internal sources.
Adult ; Aged ; Air Pollution, Indoor/*analysis ; Benzene/analysis/*toxicity ; *Environmental Monitoring ; Female ; Health Status Indicators ; Humans ; Kidney Failure, Chronic ; Korea ; Male ; Middle Aged ; *Renal Dialysis ; *Safety ; Toluene/analysis/*toxicity ; *Urban Population

Animals ; Female ; Injections, Intraventricular ; Male ; Maze Learning ; drug effects ; Memory ; drug effects ; Mice ; Mice, Inbred Strains ; Toluene ; administration & dosage ; toxicity

To evaluate the clinical significance of autoantibodies to three major epithelial cytokeratins (CK) -- CK8, CK18, and CK19 -- we compared 66 patients with toluene diisocyanate (TDI)-induced asthma (group I) with three control groups: 169 asymptomatic exposed subjects (group II), 64 patients with allergic asthma (group III), and 123 unexposed healthy subjects (group IV). Serum IgG, specific for human recombinant CKs, were measured by ELISA (enzyme linked immunosorbent assay), and ELISA inhibition tests were performed. The existence of these antibodies was confirmed by IgG immunoblot analysis. Anti-TDI-HSA (human serum albumin) IgE and IgG antibodies were measured by ELISA in the same set of the patients. The prevalence of CK8, CK18, and CK19 auotantibodies in group I was significantly higher than in the other three groups. Results of the ELISA inhibition test showed significant inhibition with the addition of three CKs in a dose-dependent manner. No significant association was found between CK autoantibodies and the prevalence of anti- TDI-HSA IgG and IgE antibodies. These results suggest that autoantibodies to CK18 and CK19 can be used as serologic markers for identifying patients with TDI-induced asthma among exposed workers.
Toluene 2,4-Diisocyanate/*toxicity ; Sensitivity and Specificity ; Occupational Diseases/chemically induced/*diagnosis ; Middle Aged ; Male ; Keratins/*immunology ; Keratin-8/immunology ; Keratin-19/immunology ; Keratin-18/immunology ; Immunoblotting ; Humans ; Female ; Enzyme-Linked Immunosorbent Assay ; Biological Markers/blood ; Autoantibodies/*blood ; Asthma/chemically induced/*diagnosis ; Adult

This investigation was designed to confirm IL-8 production from human bronchial epithelial cells with toluene diisocyanate (TDI) exposure and to examine the effects of pro-inflammatory cytokine and dexamethasone. We cultured Beas-2B, a bronchial epithelial cell line with TDI-HSA conjugate and compared with those without conjugate. IL-8 in the supernatant was measured by ELISA. To evaluate the effect of proinflammatory cytokines, peripheral blood mononuclear cells (PBMC) were collected from TDI- and non-TDI asthma patients, and were added to the epithelial cell culture. Dexamethasone or antibodies to TNF-alpha and IL-1beta were pre-incubated with PBMC supernatant. There was a significant production of IL-8 from bronchial epithelial cells with addition of TDI-HSA conjugate in a dose-dependent manner, which was significantly augmented with addition of PBMC supernatant. Higher production of IL-8 was noted with addition of PBMC supernatant from TDI-asthma patients than in those from non-TDI asthma patients. IL-1beta and IL-1beta/TFNalpha antibodies were able to suppress the IL-8 productions. Pre-treatment of dexamethasone induced dose-dependent inhibition of the IL-8 production. These results suggest that the IL-8 production from bronchial epithelial cells contribute to neutrophil recruitment occurring in TDIinduced airway inflammation. IL-1beta released from PBMC of TDI-induced asthma patients may be one of the pro-inflammatory cytokines to enhance IL-8 production.
Asthma/immunology ; Bronchi/*cytology/metabolism ; Cell Line ; Dexamethasone/pharmacology ; Epithelial Cells/cytology/*drug effects/*metabolism ; Glucocorticoids/pharmacology ; Human ; Interleukin-8/*metabolism ; Leukocytes, Mononuclear/cytology/metabolism ; Support, Non-U.S. Gov't ; Toluene 2,4-Diisocyanate/*toxicity