Toluene diisocyanate (TDI) is widely used in the production of flexible polyurethane foams, as well as in the formulation of polyurethane paints and coatings. The commercial material is generally a mixture of 2,4- and 2,6-TDI, the predominant mix being 80% 2,4 and 20% 2,6-TDI. The 2,4-isomer is considerably more reactive than the 2,6-TDI at ambient temperatures due to steric factors involving the positions of the isocyanate groups relative to the ring methyl group. Because of this difference in the reactivities of the isomers, it seemed probable that there might be an increase in the amount of 2,6-TDI offgased relative to the 2,4-isomer. Therfore a relative enrichment of the 2,6-TDI has been found in industrial atmospheres. Toluene diamines, which are metabolites of TDI, in urine have a linear relation with exposure to TDI, so that urianry TDA could be used as a biological index of the exposure to TDI. This study was conducted to investigate the distribution of TDI isomer in industrial atmospheres and to propose proper biological monitoring methods by identifying the relationships between the environmental TDI exposure and concentration of TDA in urine. Concentrations of 2,4-TDI and 2,6-TDI in air were 4.38microgram/m3 and 25.43microgram/m3, respectively. The Threshold Limited Value of 40microgram/m3 was exceeded for the 2,6-TDI in about 46.8% (22samples) of the samples, while the 2,4-TDI was not at all exceeded. The ratio between 2,4-TDI and 2,6-TDI varied in air samples in the range, of 2.4%:97.6%-51.0%:49.0%. There was an enrichment of 2,6-TDI in air relative to the 2,4-TDL Concentrations of 2,4-TDA and 2,6-TDA in urine were 1.31microgram/g creatinine and 4.16microgram/g creatinine, respectively. The ratio between 2, 4-TDA and 2,6-TDA varied in urine samples in the range of 1.4%:98.6%-99.9%:0.1%. There was an enrichment of 2,6-TDA in urine relative to the 2,4-TDA. No relation between the concerations of TDA isomer in urine and concerations of TDI isomer in air was found. Above results of this study, workers were more exposed to the 2,6-TDI relative to the 2,4-TDI in industrial atmospheres. Therefore, the establishment of TLV for 2,6-TDI should be considered. Also, the further studies on biological monitorigs of workers exposed to TDI should be continued.
Atmosphere ; Creatinine ; Diamines ; Environmental Monitoring ; Paint ; Polyurethanes ; Toluene 2,4-Diisocyanate* ; Toluene*

The prevalence studies on specific IgE to toluene diisocyanate (TDI)-human serum albumin (HSA) conjugate in TDI-induced asthma have shown variable results. In this study, we attempted to compare specific IgE bindings to TDI-HSA conjugate and its specificity using 3 different conjugates. Sera were collected from 20 TDI-induced asthma and 10 controls. Specific IgE were measured by ELISA using three TDI-HSA conjugates; two from Carnegie Mellon (CM; 98 and 99 CM conjugates) and one from Ajou University. To evaluate specificity and cross-reactivity, ELISA inhibition tests were applied. Positive and negative predictive values between Ajou conjugate and 98 CM conjugate were 75% and 100%. Those between Ajou and 99 CM were 100% and 93.8%. One patient showed an isolated positive response to the Ajou with negative responses to the other two conjugates. ELISA inhibition test using this patient's serum revealed the significant inhibitions by the Ajou and minimal inhibitions by the others. On the other hand, another patient showed an isolated positive response to 99 CM with negative responses to the others, and ELISA inhibition test showed significant inhibition by 99 CM with minimal inhibitions by the others. These results suggest that specific IgE bindings to a new antigenic determinant of TDI-HSA conjugate can be heterogeneous and differ from one individual to another.
Asthma/immunology ; Asthma/chemically induced* ; Enzyme-Linked Immunosorbent Assay ; Human ; IgE/biosynthesis* ; Serum Albumin/immunology* ; Toluene 2,4-Diisocyanate/immunology* ; Toluene 2,4-Diisocyanate/adverse effects

BACKGROUND: Toluene diisocyanate (TDI) can cause contact allergy and occupational asthma, but the mechanism underlying sensitization to this chemical compound remains controversal. Also the correlation of mast cell with contact hypersensitivity (CHS) and the role of mast cell in the TDI-induced CHS is unknown. This issue was investigated by administrating TDI on the skin of genetically mast cell-deficient WBB6F1/J-Kit(W)/ Kit(W-v) (W/W(V)) and congenic normal WBB6F1/J-Kit +/+ (+/+) mice. METHODS: To development of animal model of TDI-induced CHS and to investigate the correlation of mast cell with CHS and the role of mast cell in the TDI-induced CHS, W/W(V) and +/+ mice were sensitized with TDI on the back skin at day 1 and day 8, and then challenged with 1% TDI on the ear at day 15. At 1, 2, 4, 8, and 24 hours after 1% TDI challenge, the ear thicknesses were measured. It was investigated the histologic changes of dermis in the ear of W/W(V) and +/+ mice at 24 hours after 1% TDI challenge. RESULTS: TDI induced a significant ear swelling response in W/W(V) and +/+ mice. TDI induced the significant infiltrations of polymorphonuclear leukocytes and eosinophils in W/W(V) and +/+ mice, but not of mast cells in normal mice. And TDI increased a characteristic extent of mast cell degranulation in normal mice. There were no significant differences in the ear swelling and the infiltrations of polymorphonuclear leukocytes and eosinophils of normal versus W/W(V) mice, either at baseline or after TDI-induced CHS. CONCLUSION: From the above results, TDI can be used as a murine CHS model, and the mast cells may not be essential in TDI-induced CHS.
Animals ; Asthma, Occupational ; Dermatitis, Contact* ; Dermis ; Ear ; Eosinophils ; Hypersensitivity ; Mast Cells ; Mice ; Models, Animal ; Neutrophils ; Skin ; Toluene 2,4-Diisocyanate ; Toluene*

BACKGROUND: Toluene diisocyanate (TDI) can cause contact allergy and occupational asthma, but the mechanism underlying sensitization to this chemical compound remains controversal. Also the correlation of mast cell with contact hypersensitivity (CHS) and the role of mast cell in the TDI-induced CHS is unknown. This issue was investigated by administrating TDI on the skin of genetically mast cell-deficient WBB6F1/J-Kit(W)/ Kit(W-v) (W/W(V)) and congenic normal WBB6F1/J-Kit +/+ (+/+) mice. METHODS: To development of animal model of TDI-induced CHS and to investigate the correlation of mast cell with CHS and the role of mast cell in the TDI-induced CHS, W/W(V) and +/+ mice were sensitized with TDI on the back skin at day 1 and day 8, and then challenged with 1% TDI on the ear at day 15. At 1, 2, 4, 8, and 24 hours after 1% TDI challenge, the ear thicknesses were measured. It was investigated the histologic changes of dermis in the ear of W/W(V) and +/+ mice at 24 hours after 1% TDI challenge. RESULTS: TDI induced a significant ear swelling response in W/W(V) and +/+ mice. TDI induced the significant infiltrations of polymorphonuclear leukocytes and eosinophils in W/W(V) and +/+ mice, but not of mast cells in normal mice. And TDI increased a characteristic extent of mast cell degranulation in normal mice. There were no significant differences in the ear swelling and the infiltrations of polymorphonuclear leukocytes and eosinophils of normal versus W/W(V) mice, either at baseline or after TDI-induced CHS. CONCLUSION: From the above results, TDI can be used as a murine CHS model, and the mast cells may not be essential in TDI-induced CHS.
Animals ; Asthma, Occupational ; Dermatitis, Contact* ; Dermis ; Ear ; Eosinophils ; Hypersensitivity ; Mast Cells ; Mice ; Models, Animal ; Neutrophils ; Skin ; Toluene 2,4-Diisocyanate ; Toluene*

PURPOSE: Toluene diisocyanate (TDI) is a leading cause of occupational asthma (OA). Periostin is a matricellular protein implicated in type 2 immunity-driven asthma. Its pathogenic role in TDI-OA has not been completely elucidated. The present study was performed to investigate the role of periostin in TDI-OA. MATERIALS AND METHODS: Serum periostin levels were measured in subjects with TDI-OA, asymptomatic TDI-exposure controls (AECs), non-occupational asthmatics (NAs), and unexposed normal controls (NCs). To understand the mechanism by which TDI induces periostin production, primary small airway epithelial cells (SAECs) were cultured under stimulation of TDI and neutrophils from asthmatic patients. RESULTS: Fifty-three subjects with TDI-OA, 71 AECs, 67 NAs, and 83 NCs were enrolled. Serum periostin levels were significantly higher in TDI-OA subjects than in AECs (p=0.001), NAs (p < 0.001), and NCs (p < 0.001). In TDI-exposed subjects (TDI-OA and AEC), the PC20 methacholine levels were significantly lower in subjects with a higher periostin level than in those with a lower periostin level. TDI exposure did not increase periostin production directly by SAECs; however, periostin production increased significantly after co-culture with TDI and neutrophils, which was suppressed by an antioxidant. In addition, increased release of TGF-β1 was noted from SAECs when exposed to TDI and neutrophils, which was also suppressed by an antioxidant. CONCLUSION: These results suggest that an increased periostin level may contribute to the progression of airway inflammation to remodeling in TDI-exposed workers. A high serum periostin level is a potential serologic marker of the phenotype of TDI-OA.
Asthma ; Asthma, Occupational* ; Coculture Techniques ; Epithelial Cells ; Humans ; Inflammation ; Methacholine Chloride ; Neutrophils ; Phenotype ; Reactive Oxygen Species ; Toluene 2,4-Diisocyanate ; Toluene*

OBJECTIVE: To investigate the prevalence of airway hyperresponsiveness induced by isocyanate at one petrochemical industry complex in Yeochon, Korea. METHOD: Questionnaires, allergic skin prick test, toluene diisocyanate (TDI)-specific IgE, and non-specific airway hyperresponsiveness (AHR) were studied in 73 exposed workers and 27 control subjects. Methacholine challenge tests were done and bronc hial responsiveness (BR index) was defined as log (% fall of FEV1)/ log (last concentration of methacholine +10). RESULTS: Twenty-three workers (31.5% ) had respiratory symptoms, 21 had nasal symptoms, and eight had skin symptoms. Exposed workers with respiratory symptoms (n=22) had significantly higher BR index than those without them (0.82+/-0.06 vs 0.60+/-0.02, p<0.05). Exposed workers tended to have higher BR index than controls (0.67+/-0.03 vs 0.62+/-0.02). Three exposed workers had PC20 methacholine <2.0 mg/ml. There were no significant differences in atopy score between exposed workers and controls (p>0.05). Specific IgE antibodies were found in 19.7% of exposed workers. FEV, showed a significant negative correlation with BR index (r =-0.25, p<0.05). Poor correlation was noted between BR index and atopy, smoking status, or exposure duration. CONCLUSION: These findings suggest that workers exposed to isocyanates are at higher risk of airway hyperresponsiveness.
Antibodies ; Immunoglobulin E ; Isocyanates* ; Korea ; Methacholine Chloride ; Plants* ; Prevalence ; Skin ; Smoke ; Smoking ; Toluene 2,4-Diisocyanate ; Surveys and Questionnaires

OBJECTIVES: This study was carried out to estimate the prevalence of isocyanate-induced occupational asthma in toluene diisocyanate (TDI) exposed workers. METHODS: We examined 170 workers who had been directly exposed to TDI through a medical questionnaire, physical examination, and pulmonary function test. Based on screening examination, workers with suspected occupational asthma were selected for further evaluation such as methacholine and TDI challenge tests. RESULTS: Eleven (6.9%) among 170 workers complained of symptoms of occupational asthma, and 7 among these 11 symptomatic workers showed positive responses to the methacholine challenge test (4.1%). One spray painter was confirmed as having the TDI induced occupational asthma following a positive response to TDI challenge test. CONCLUSIONS: The prevalence of TDI-induced asthma was at 0.58% was lower than that for former studies (2-20%). Improved workplace environment, lower level of TDI exposure compared to the past, and the healthy workers effect may have contributed to this low rate of asthma prevalence in workers with TDI exposure.
Asthma ; Asthma, Occupational* ; Mass Screening ; Methacholine Chloride ; Physical Examination ; Prevalence* ; Questionnaires ; Respiratory Function Tests ; Toluene 2,4-Diisocyanate

Animals ; Dose-Response Relationship, Drug ; Female ; Male ; Rats ; Rats, Sprague-Dawley ; Toluene 2,4-Diisocyanate ; metabolism ; pharmacokinetics ; urine

OBJECTIVE: To explore the effect of transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) on toluene diisocyanate (TDI)-induced allergic airway inflammation in mice. METHODS: Thirty-two mice were randomly divided into AOO group, AOO+5Z-7-Oxozeaenol group, TDI group, and TDI+5Z-7-Oxozeaenol group. Another 32 mice were randomly divided into AOO group, TDI group, TDI +5Z-7-Oxozeaenol group, and TDI +5Z-7-Oxozeaenol + Necrostatin-1 group. TAK1 inhibitor (5Z-7-Oxozeaenol, 5 mg/kg) and/or RIPK1 inhibitor (Necrostatin-1, 5 mg/kg) were used before each challenge. Airway responsiveness, airway inflammation and airway remodeling were assessed after the treatments. We also examined the effect of TDI-human serum albumin (TDI-HSA) conjugate combined with TAK1 inhibitor on the viability of mouse mononuclear macrophages (RAW264.7) using CCK8 assay. The expressions of TAK1, mitogen-activated protein kinase (MAPK) and receptor interacting serine/threonine protease 1 (RIPK1) signal pathway in the treated cells were detected with Western blotting. The effects of RIPK1 inhibitor on the viability of RAW264.7 cells and airway inflammation of the mouse models of TDI-induced asthma were evaluated. RESULTS: TAK1 inhibitor aggravated TDI-induced airway inflammation, airway hyper responsiveness and airway remodeling in the mouse models (P < 0.05). Treatment with TAK1 inhibitor significantly decreased the viability of RAW264.7 cells, which was further decreased by co-treatment with TDI-HSA (P < 0.05). TAK1 inhibitor significantly decreased the level of TAK1 phosphorylation and activation of MAPK signal pathway induced by TDI-HSA (P < 0.05). Co-treatment with TAK1 inhibitor and TDI-HSA obviously increased the level of RIPK1 phosphorylation and caused persistent activation of caspase 8 (P < 0.05). RIPK1 inhibitor significantly inhibited the reduction of cell viability caused by TAK1 inhibitor and TDI-HSA (P < 0.05) and alleviated the aggravation of airway inflammation induced by TAK1 inhibitors in TDI-induced mouse models (P < 0.05). CONCLUSION Inhibition of TAK1 aggravates TDI-induced airway inflammation and hyperresponsiveness and may increase the death of macrophages by enhancing the activity of RIPK1 and causing persistent activation of caspase 8.
Animals ; Asthma/chemically induced* ; Inflammation ; Macrophages ; Mice ; Receptor-Interacting Protein Serine-Threonine Kinases ; Respiratory System ; Toluene 2,4-Diisocyanate/adverse effects*

BACKGROUND: There have been a few reports suggesting involvement of neutrophil as well as eosinophil in inducing bronchoconstriction aft,er inhalation of TDI. OBJECTIVE: In order to observe the source of chemokines in TDI-induced asthma, this investigation was designed to determine whether IL-8 and RANTES could be produced by human bronchial epithelial cells and whether dexamethasone had any effects on their production. Materials and METHODS: We cultured Beas-2B, a bronchial epithelial cell line, with five concentrations of TDI-human serum albumin (HSA) conjugate and compared them with those having no conjugate. The levels of IL-8 and RANTES in the supernatant were measured by ELISA. To evaluate the effect of pro-inflammatory cytokines, cells were incubated with peripheral blood mononuclear cell (PBMC) culture supernatant, which was derived from PBMC culture of a TDI -induced asthmatic subject under exposure to TDI-HSA conjugate, and then compared to those without PBMC supernatant addition. To evaluate the effect of dexamethasone, four concentrations of dexamethasone were pre-incubated and the same steps were repeated. RESULTS: There was significant production of IL-8 from bronchial epithelial cells with addition of TDI-HSA conjugate in a dose-dependent manner (p<0.05, respectively), which was significantly augmented with additions of PBMC supernatant (p<0.05, respectively) at each concentration. RANTES production was negligible, however, it increased significantly with addition of PBMC supernatant and TDI-HSA conjugate in a dose response manner(p<0.05, respectively). Compared to the untreated sample, pre-treatment of dexamethasone induced remarkable inhibitions of IL-8 and RANTES production. CONCLUSION: These results suggest that IL-8 and RANTES released from bronchial epithelial cells may contribute to neutrophil and eosinophil recruitment occurring in TDI-induced airway.
Asthma ; Bronchoconstriction ; Chemokine CCL5* ; Chemokines ; Cytokines ; Dexamethasone ; Enzyme-Linked Immunosorbent Assay ; Eosinophils ; Epithelial Cells* ; Humans ; Inhalation ; Interleukin-8 ; Neutrophils ; Serum Albumin ; Toluene 2,4-Diisocyanate* ; Toluene*