To Toluene Diisocyanate Research Articles

HMGB1 inhibition reduces TDI-induced occupational asthma through ROS/AMPK/autophagy pathway

Exposure to toluene diisocyanate (TDI) can cause pulmonary diseases such as asthma. Inhibition of high mobility group box 1 protein (HMGB1) has been found to be protective against the toxic effects of TDI on human bronchial epithelial (HBE) cells. Here, we evaluated the in vivo positive roles of HMGB1 in the TDI-caused asthma mice and explored its underlying mechanisms in HBE cells. We found that suppression of HMGB1 obviously alleviated airway inflammation, airway hyperresponsiveness, and airway remodeling in the lung tissue of the asthma mice. The in vitro results showed that inhibition of HMGB1 ameliorated TDI-induced reactive oxygen species (ROS) release, inflammatory response, and activation of autophagy in HBE cells. At the molecular level, inhibition of HMGB1 decreased the expressions of HMGB1, Toll-like receptor 4, Vimentin and matrix metalloproteinase-9 proteins, activated NF-κB and NOD-like receptor protein 3 (NLRP3) inflammasome, and increased E-cadherin expression. Importantly, activation of autophagy could lead to the overactivation of NLRP3 inflammasome in TDI-induced asthma. These results suggest that inhibition of HMGB1 can alleviate TDI-induced asthma through ROS/AMPK/autophagy pathways, which may provide valuable evidence for the pathogenesis and therapeutic targets of TDI-induced asthma.

RAGE mediates airway inflammation via the HDAC1 pathway in a toluene diisocyanate-induced murine asthma model

BackgroundExposure to toluene diisocyanate (TDI) is a significant pathogenic factor for asthma. We previously reported that the receptor for advanced glycation end products (RAGE) plays a key role in TDI-induced asthma. Histone deacetylase (HDAC) has been reported to be important in asthmatic pathogenesis. However, its effect on TDI-induced asthma is not known. The aim of this study was to determine the role of RAGE and HDAC in regulating airway inflammation using a TDI-induced murine asthma model.MethodsBALB/c mice were sensitized and challenged with TDI to establish an asthma model. FPS-ZM1 (RAGE inhibitor), JNJ-26482585 and romidepsin (HDAC inhibitors) were administered intraperitoneally before each challenge. In vitro, the human bronchial epithelial cell line 16HBE was stimulated with TDI-human serum albumin (TDI-HSA). RAGE knockdown cells were constructed and evaluated, and MK2006 (AKT inhibitor) was also used in the experiments.ResultsIn TDI-induced asthmatic mice, the expression of RAGE, HDAC1, and p-AKT/t-AKT was upregulated, and these expressions were attenuated by FPS-ZM1. Airway reactivity, Th2 cytokine levels in lymph supernatant, IgE, airway inflammation, and goblet cell metaplasia were significantly increased in the TDI-induced asthmatic mice. These increases were suppressed by JNJ-26482585 and romidepsin. In addition, JNJ-26482585 and romidepsin ameliorated the redistribution of E-cadherin and β-catenin in TDI-induced asthma. In TDI-HSA-stimulated 16HBE cells, knockdown of RAGE attenuated the upregulation of HDAC1 and phospho-AKT (p-AKT). Treatment with the AKT inhibitor MK2006 suppressed TDI-induced HDAC1 expression.ConclusionsThese findings indicate that RAGE modulates HDAC1 expression via the PI3K/AKT pathway, and that inhibition of HDAC prevents TDI-induced airway inflammation.

Analysis of the relationship between the changes of lung function and serum proinflammatory cytokines in workers occupationally exposed to toluene diisocyanate

Objective: To analyze the correlation between the changes of lung function and serum proinflammatory cytokines in workers occupationally exposed to toluene diisocyanate (TDI), and to explore the evaluation index of respiratory toxicity of TDI. Methods: In October 2014, 61 male workers engaged in TDI synthesis process, purification process, packaging process and the above production process in a TDI factory in western China were selected as TDI exposure group; 62 male enterprise managers who were not exposed to TDI and other known allergenic chemicals were selected as control group, which were matched at the age of workers in exposure group. The questionnaire survey obtained information such as gender, length of service, age, occupational history, exposed length of service and so on. The lung function indexes [forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), FEV1/FVC] and serum levels of interleukin (IL)-1 β, IL-6, IL-8, tumor necrosis factor (TNF)-α, macrophage inflammatory factor-1 β, monocyte chemoattractant factor-1 and vascular endothelial growth factor were measured. The urine was collected after the weekend shift, and the concentration of (TDA), the metabolite of TDI, was determined as the index of internal exposure. Spearman rank correlation was used to analyze the correlation between cytokines and lung function indexes, and multivariate linear regression was used to analyze the changes of lung function indexes and cytokines with TDI exposure concentration and time. Results: The median age (P5-P95) of the exposed group and the control group was 36.5 (24.0-51.0) and 38.0 (24.0-50.0) years, respectively. In the exposed group, the median length of service (P5-P95) was 6.94 (0.97-26.33) years, and the median concentration of TDA in urine was 15.56 (2.28-112.16) ng/ml. The three indexes of lung function, FVC, FEV1, FEV1/FVC and the levels of serum IL-8 and TNF-α were significantly lower than those in the control group (P<0.01). With the increase of exposure concentration and exposure time, the level of serum TNF-α, FVC and FEV1 decreased, and showed a good dose-effect and time-effect relationship (all Ptrend values< 0.05). Serum IL-8 and TNF-α were positively correlated with FVC, FEV1 and FEV1/FVC (all P values<0.01). Conclusion: The levels of serum inflammatory factors IL-8 and TNF-α in worker exposed to TDI are related to lung function indexes, which can be used as early evaluation indexes of respiratory toxicity induced by TDI.

Effect of occupational exposure to toluene diisocyanate on workers' health

To investigate the effect of occupational exposure to toluene diisocyanate (TDI) on the workers' health. A total of 76 workers exposed to TDI (exposure group) and 64 management staff members (control group) were selected from a factory as the study subjects. Area sampling was performed for the place with exposure to TDI according to the method in GBZ 159-2004 Specifications of air sampling for hazardous substances monitoring in the workplace, and gas chromatography was applied to measure the concentration of TDI in workplace air. The workers' personal information was collected with questionnaire, pulmonary ventilation function was determined with a portable spirometer, hematological parameters were analyzed by automatic blood analyzer and blood chemistry analyzer, and the indicators of oxidative damage and energy metabolism were measured by the reagent kit provided by Nanjing Jiancheng Bioengineering Institute. SPSS 17 software was applied for statistical analysis. The exposure group had significantly lower forced vital capacity (FVC), forced expiratory volume in 1 second(FEV1.0), and FEV1.0/FVC ratio than the control group (P <0.05). Compared with the control group, the exposure group had significantly higher red blood cell count, platelet distribution width, mean platelet volume, lymphocyte count, and neutrophil count(P<0.01), and significantly lower activities of lactate dehydrogenase(LDH), superoxide dismutase, and succinodehydrogenase (SDH)(P <0.01). In the exposure group, the length of exposure was negatively correlated with the activities of SDH and LDH in the serum (r=-0.319, P <0.05; r=-0.239, P <0.05), and the length of exposure was not found to be correlated with the activity of SOD and pulmonary function indices. TDI can induce inflammatory response and lung ventilation function impairment in workers exposed to TDI, as well as oxidative stress and imbalance of energy metabolism. Therefore, it can cause damage to workers' health, and protective measures should be enhanced.

Occupational exposure to diisocyanates in polyurethane foam factory workers.

The aim of the study was to evaluate health effects of occupational exposure to diisocyanates (DIC) among polyurethane foam products factory workers. Thirty workers had a physical examination, skin prick tests with common allergens, allergen-specific immunoglobulin E (IgE) antibodies to diisocyanates and pulmonary function tests. Concentrations of selected isocyanates in the workplace air samples as well as concentration of their metabolites in the urine samples collected from the workers of the plant were determined. The most frequent work-related symptoms reported by the examined subjects were rhinitis and skin symptoms. Sensitization to at least 1 common allergen was noted in 26.7% of the subjects. Spirometry changes of bronchial obstruction of a mild degree was observed in 5 workers. The specific IgE antibodies to toluene diisocyanate (TDI) and 4,4'-methylenebis(phenyl isocyanate) (MDI) were not detected in any of the patients' serum. Cellular profiles of the collected induced sputum (ISP) did not reveal any abnormalities. Air concentrations of TDI isomers ranged 0.2-58.9 μg/m3 and in 7 cases they exceeded the Combined Exposure Index (CEI) value for those compounds. Concentrations of TDI metabolites in post-shift urine samples were significantly higher than in the case of pre-shift urine samples and in 6 cases they exceeded the British Biological Monitoring Guidance Value (BMGV - 1 μmol amine/mol creatinine). We didn't find a correlation between urinary concentrations of TDI, concentrations in the air and concentrations of toluenediamine (TDA) in the post shift urine samples. Lack of such a correlation may be an effect of the respiratory protective equipment use. Determination of specific IgE in serum is not sensitive enough to serve as a biomarker. Estimation of concentrations of diisocyanate metabolites in urine samples and the presence of work-related allergic symptoms seem to be an adequate method for occupational exposure monitoring of DIC, which may help to determine workers at risk as well as to recognize hazardous workplaces.

Risk assessment for consumer exposure to toluene diisocyanate (TDI) derived from polyurethane flexible foam

Polyurethanes (PU) are polymers made from diisocyanates and polyols for a variety of consumer products. It has been suggested that PU foam may contain trace amounts of residual toluene diisocyanate (TDI) monomers and present a health risk. To address this concern, the exposure scenario and health risks posed by sleeping on a PU foam mattress were evaluated. Toxicity benchmarks for key non-cancer endpoints (i.e., irritation, sensitization, respiratory tract effects) were determined by dividing points of departure by uncertainty factors. The cancer benchmark was derived using the USEPA Benchmark Dose Software. Results of previous migration and emission data of TDI from PU foam were combined with conservative exposure factors to calculate upper-bound dermal and inhalation exposures to TDI as well as a lifetime average daily dose to TDI from dermal exposure. For each non-cancer endpoint, the toxicity benchmark was divided by the calculated exposure to determine the margin of safety (MOS), which ranged from 200 (respiratory tract) to 3×106 (irritation). Although available data indicate TDI is not carcinogenic, a theoretical excess cancer risk (1×10−7) was calculated. We conclude from this assessment that sleeping on a PU foam mattress does not pose TDI-related health risks to consumers.

Vapor conjugation of toluene diisocyanate to specific lysines of human albumin

Exposure to toluene diisocyanate (TDI), an industrially important crosslinking agent used in the production of polyurethane products, can cause asthma in sensitive workers. Albumin has been identified as a major reaction target for TDI in vivo, and TDI–albumin reaction products have been proposed to serve as exposure biomarkers and to act as asthmagens, yet they remain incompletely characterized. In the current study, we used a multiplexed tandem mass spectrometry (MS/MS) approach to identify the sites of albumin conjugation by TDI vapors, modeling the air/liquid interface of the lung. Vapor phase TDI was found to react with human albumin in a dose-dependent manner, with up to 18 potential sites of conjugation, the most susceptible being Lys351 and the dilysine site Lys413–414. Sites of vapor TDI conjugation to albumin were quantitatively limited compared with those recently described for liquid phase TDI, especially in domains IIA and IIIB of albumin. We hypothesize that the orientation of albumin at the air/liquid interface plays an important role in vapor TDI conjugation and, thus, could influence biological responses to exposure and the development of in vitro assays for exposure and immune sensitivity.

How long do the systemic and ventilatory responses to toluene diisocyanate persist in dermally sensitized mice?

Years after removal from exposure, workers with occupational asthma still show respiratory symptoms and airway hyperresponsiveness on re-exposure to the offending agent. We investigated the persistence of the respiratory responsiveness to toluene diisocyanate (TDI) in a mouse model. BALB/C mice received dermal applications of TDI on days 1 and 8, and a single intranasal instillation of TDI on day 10, 15, 20, 25, 30, 40, 50, 60, or 90. After instillation, early (1 hour) changes in ventilatory function and methacholine responsiveness (22 hours) were assessed. Cell counts and macrophage inflammatory protein 2 were measured in bronchoalveolar lavage. Total serum IgE, IgG(1), and IgG(2a) were quantified. Lymphocyte subpopulations were assessed in auricular and cervical lymph nodes, and release of IL-4 and IFN-gamma by these lymph node cells was measured. Toluene diisocyanate-treated mice showed immediate ventilatory changes, increased methacholine reactivity, and an influx of neutrophils and macrophage inflammatory protein 2 in bronchoalveolar lavage as long as 50 days after initial treatment. These mice also showed a relative increase in CD19(+) cells and a decrease in CD4(+) and CD8(+) cells in auricular lymph nodes. Increased release of IL-4 and IFN-gamma in auricular lymph node cells was observed only until 20 days after sensitization. Total serum IgE, IgG(1), and IgG(2a) remained significantly elevated in TDI-sensitized mice until 90 days after dermal sensitization. Ventilatory and lung inflammatory responses decrease with increasing delay between sensitization and challenge, despite persistent humoral signs of sensitization.

Underestimation of toluene diisocyanate concentration using long-term sampling with 1-(2-methoxyphenyl) piperazine impregnated filters

Occupational exposure to toluene diisocyanate (TDI) is a known occupational hazard and the occupational exposure limits in air are very low. One of the most common methods to monitor exposure to isocyanates is to sample air through filters impregnated with 1-(2-methoxyphenyl) piperazine (2MP). In one earlier field study it was found that long-term sampling with 2MP-filters underestimated the exposure compared with consecutive short-term samples of TDI. The aim of this study was to confirm that finding in a controlled atmosphere in the laboratory. A test atmosphere of 2,4-TDI or 2,6-TDI was generated in a small test chamber and parallel long-term samples and consecutive short-term samples were collected. A total of 159 filters were exposed. The long-term samples collected significantly lower amounts of TDI than the sum of the short-term samples. For a 4-h sampling, the air levels were calculated to underestimate the exposure for 2,4-TDI by a factor of 1.4 and for 2,6-TDI by a of factor 1.3. The calculated underestimation was lower than earlier reported.

Eye and airway symptoms in low occupational exposure to toluene diisocyanate

Exposure to diisocyanates is a well known occupational hazard. The objective of this study was to determine the possibility of an association between low exposure to toluene diisocyanate (TDI) (airborne isocyanates and biomarkers of isocyanates in plasma and urine) and symptoms of the eyes and upper and lower airways. Altogether 136 workers occupationally exposed to TDI and 118 unexposed employees were studied. A physician compiled thorough medical and occupational histories and registered symptoms, total and work-related, of the eyes, nose, and lower airways. The exposure was assessed with personal air measurements and with biomarkers of exposure in plasma and urine. The average exposure in the ambient air at the workplace of the exposed participants was below 1 ppb. Compared with the unexposed group, the exposed workers reported more total symptoms of the eyes and lower airways, as well as nose bleeding. A similar pattern, with even higher odds ratios, was observed for work-related symptoms. However, only eye symptoms proved to be significantly associated with the exposure, notably with all of the exposure measures. The risk was more pronounced for exposure to 2,4-TDI than for exposure to 2,6-TDI. Even very low exposure to TDI is related to negative health effects on exposed workers. Clear dose-response relationships were observed between three different measures of exposure and symptoms of the eyes.

Rechallenging subjects with occupational asthma due to toluene diisocyanate (TDI), after long-term removal from exposure

Aims of this study were to define (1) whether toluene diisocyanate (TDI) bronchial hyper-responsiveness persists in subjects with occupational asthma after long-term cessation of exposure; (2) whether evolution of specific bronchial TDI sensitization and symptoms and functional abnormalities of asthma were coincident, and (3) the determinants at the time of diagnosis of patients' outcome. Twenty-five nonatopic spray painters with occupational asthma due to TDI were re-examined 58 +/- 7 (46-73) months after removal from exposure. On both examinations, the severity of asthmatic symptoms and the need for antiasthma treatment over the past 12 months were graded and lung function tests, measurement of airway responsiveness to methacholine (PD(20)), circulating total IgE and TDI-HSA specific IgE, skin tests with common inhalant allergens and specific bronchial challenge with TDI were carried out. Seven subjects were still TDI-reactors and 18 lost reactivity to it. All persistent reactors had still asthma and their symptom score, medication score, FEV(1), PD(20) and serum IgE were unchanged between assessments. In the 18 subjects no longer responsive to TDI, 8 had still features of asthma: their symptom and medication score had improved significantly, but FEV(1), PD(20) and serum IgE had not significantly changed; the other ten patients no longer reactors to TDI were also asymptomatic and their PD(20) had become normal. The duration of symptomatic exposure to TDI was the only feature at diagnosis that differentiated patients with persistent TDI airway hyper-responsiveness and asthma from those who were no longer responsive to TDI but still asthmatic and those who were no longer responsive to TDI and no longer asthmatic (4 +/- 1.6; 2.1 +/- 0.8; 0.6 +/- 0.3 years, respectively; p < 0.001). our study demonstrates that airway sensitization to TDI and symptoms and functional airway abnormalities of asthma can persist for years after cessation of exposure and may have different outcome. If avoidance of the offending agent takes place within few months after the development of symptoms, remission of asthma and of TDI bronchial hyper-responsiveness can occur, whereas waiting for years makes it too late to cure asthma and, in the end, to reverse specific sensitization.

Immunologic Changes in Human Albumin Exposed to Toluene Diisocyanate (TDI) Vapor: Differences Compared with Liquid TDI Exposure and Association with IgE/IgG Binding and TDI Asthma

Immunologic Changes in Human Albumin Exposed to Toluene Diisocyanate (TDI) Vapor: Differences Compared with Liquid TDI Exposure and Association with IgE/IgG Binding and TDI Asthma

Dexamethasone Suppresses Histamine Synthesis by Repressing both Transcription and Activity of HDC in Allergic Rats

Histamine synthesized by histidine decarboxylase (HDC) from L-histidine is a major chemical mediator in the development of nasal allergy which is characterized by nasal hypersensitivity. However the regulatory mechanism of histamine synthesis by HDC remains to be elucidated. The objectives of the present study were to examine the changes of histamine content, HDC activity and HDC mRNA expression in the nasal mucosa of allergy model rats sensitized by the exposure to toluene diisocyanate (TDI) and to investigate the effect of dexamethasone on the above mentioned allergic parameters. Rats were sensitized and provocated by TDI and the nasal allergy-like behaviors were scored during a 10 minute period after provocation. Histamine content and HDC activity in the nasal mucosa were determined using fluorometric high performance liquid chromatography. The expression of HDC mRNA in nasal mucosa was determined using real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). In TDI-sensitized rats, nasal allergy-like behaviors such as sneezing and watery rhinorrhea were induced. Histamine content, HDC activity and HDC mRNA expression in nasal mucosa were also significantly increased after TDI provocation. Pretreatment with dexamethasone significantly suppressed nasal allergy-like behaviors, up-regulation of histamine content, HDC activity and HDC mRNA induced by TDI in TDI-sensitized rats. These findings indicate that increased synthesis of histamine through up-regulation of HDC gene expression and HDC activity in nasal mucosa plays an important role in the development of nasal hypersensitivity. Repression of HDC gene expression and HDC activity by dexamethasone may underlie its therapeutic effect in the treatment of allergy.

Improvement in the GC–MS method for determining urinary toluene-diamine and its application to the biological monitoring of workers exposed to toluene-diisocyanate

To develop a simple and sensitive GC-MS method for determining toluene-diamine (TDA) in urine and to apply the method for biological monitoring of workers exposed to toluene-diisocyanate (TDI). After acid hydrolysis of 0.1 ml of urine, diluted tenfold with water, for 1.5 h, the free TDA formed was extracted with dichloromethane, and the heptafluorobutyric anhydride derivative was determined by GC-MS. We applied the method to the biological monitoring of 18 workers who were using an 80:20 mixture of 2,4-TDI and 2,6-TDI. 2,6-TDA and 2,4-TDA were simply determined in 7 min by GC-MS. TDA levels in post-shift urine were well correlated with personal exposure levels of TDI. The correlation was improved by correction with creatinine or specific gravity in the 2,6-isomer, but not in the 2,4-isomer because of low exposure levels. From the correlation equation, the 2,6-TDA level (corrected with creatinine), corresponding to the TDI level of 5 ppb, was calculated to be 31.6 mug/g Cre. TDAs in pre-shift urine also correlated significantly with the personal exposure levels of TDIs, although the slope of the correlations for pre-shift samples was 60%-70% of those for post-shift samples. The correlation between 2,4-TDA and 2,6-TDA levels was significant, although the levels of the 2,4-isomer were less than one-tenth of the 2,6-isomers in both air (personal exposure) and urine. The present method is simple and practicable and can be useful for biological monitoring of TDI workers.

Airway inflammatory and immunological events in a rat model exposed to toluene diisocyanate

To investigate the inflammatory and immunological events in the airway induced by a short period of repeated exposure to toluene diisocyanate (TDI), an animal model was established, which resembled the industrial field exposure. After whole body exposure of Wistar rats to 0.38 and 1.20 ppm TDI vapor 4 h a day for five consecutive days in a glass chamber, bronchoalveolar lavage (BAL) was performed. BAL fluid cellular and cytokine contents were then determined. Histopathological examinations were also carried out on the lungs. The TDI vapor exposure resulted in airway symptoms similar to those in occupational asthma. BAL fluid cellular analysis and lung histophathological examination revealed that inflammatory response was characterized by marked eosinophil infiltration of the airways. The cytokine assay revealed significant production of IL-4 in the airways of the TDI exposed rats as compared to the control rats. These findings indicated that a short period of repeated exposure to TDI vapor may cause respiratory hypersensitivity in which airway inflammatory and immunological events represented by eosinophil infiltration and Th2 cytokines may play an important role. Also, this animal model may be suitable for exploring the mechanism underlying TDI-induced occupational asthma.

Effect of Glucocorticoid on Upregulation of Histamine H1 Receptor mRNA in Nasal Mucosa of Rats Sensitized by Exposure to Toluene Diisocyanate

Objective—Histamine is a major chemical mediator in the development of nasal allergy, which is characterized by nasal hypersensitivity. In this study, we used rats sensitized by exposure to toluene diisocyanate (TDI) as an animal model of nasal hypersensitivity and examined changes in expression of histamine H1 receptor (H1R) in the nasal mucosa. The effect of glucocorticoid on upregulation of H1R in nasal mucosa induced by TDI was also examined.Material and Methods—In rats sensitized by exposure to TDI, nasal allergy-like behavior was scored during a 10-min period after TDI provocation. The expression of H1R in the nasal mucosa was determined by means of a real-time quantitative reverse transcriptase polymerase chain reaction and a [3H]mepyramine binding assay.Results—In TDI-sensitized rats, nasal allergy-like behavior, such as sneezing and watery rhinorrhea, was induced after intranasal application of TDI and nasal hypersensitivity to histamine was significantly increased. The level of H1R mRNA expression and the specific binding of [3H]mepyramine in the nasal mucosa were significantly increased after intranasal application of TDI in TDI-sensitized rats. Pretreatment with dexamethasone significantly reduced both nasal allergy-like behavior and the upregulation of H1R induced by TDI in the rats.Conclusion—As shown in TDI-sensitized rats, our findings suggest that the upregulation of H1R in the nasal mucosa is one of the mechanisms responsible for nasal hypersensitivity behavior and nasal hypersensitivity to histamine and that the therapeutic effects of dexamethasone are, in part, due to its inhibitory action on the upregulation of H1R.

Cancer incidence and mortality of isocyanate exposed workers from the Swedish polyurethane foam industry: updated findings 1959–98

Aims: To assess whether cancer incidence and mortality in chronic obstructive lung diseases were increased in the Swedish polyurethane foam industry cohort, updated with 11 more years of follow up....

A 17-year epidemiological study on changes in lung function in toluene diisocyanate foam workers.

To determine whether longitudinal declines in ventilatory capacity and the occurrence of respiratory symptoms in workers manufacturing polyurethane foam were related to toluene diisocyanate (TDI) exposure. A population of workers from 12 UK factories was studied between 1981 and 1986 [8]. A survivor cohort of 251, of whom 217 were in the 1981-1986 study, was examined again in 1997-1998. Modified British Medical Research Council respiratory questionnaires and lung function measurements were completed for each of the 251 subjects at the beginning and end of the 17-year study period. Mean TDI exposures for all jobs in which subjects were employed were assessed and related to their occupational histories. The annual declines in 1-second forced expiratory volume (FEV(1)) and forced vital capacity (FVC) were not related to TDI exposure, and were typical of those measured in other populations not exposed to TDI. Over the study period the cold-foam handling group ( n=26) showed an increase in breathlessness and a significant excess decline in FVC; the exposed group ( n=175) showed an increase in wheezing (mainly smokers), whilst the low-exposure group ( n=50) showed a decrease in chest illness. Smoking and an increase in body weight both caused excess declines in FEV(1). This study does not provide evidence that there was any TDI-related decline in FEV(1) or in FVC over a 17-year period in workers exposed to TDI at the levels prevailing in the UK factories that manufactured flexible polyurethane foam.

Exposure to toluene diisocyanate (TDI) induces IL-8 production from bronchial epithelial cells: effect of pro-inflammatory cytokines.

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/TNF alpha 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 TDI-induced 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.

Evaluation of self-reported skin problems among workers exposed to toluene diisocyanate (TDI) at a foam manufacturing facility.

Toluene diisocyanate, or TDI (CAS 584-84-9) is a well-known asthmagen and respiratory irritant. TDI is also known for its ability to irritate the skin and mucous membranes. To further investigate the dermal effects of TDI, NIOSH investigators conducted a cross-sectional study at a flexible foam manufacturing plant. A total of 114 workers participated in the study. Participants completed a medical questionnaire, provided blood for antibody testing to TDI and other allergens, and a subset of participants reporting skin symptoms underwent skin patch testing to a standard diisocyanate panel. Production line workers were more than twice as likely to report skin problems as those working in nonproduction areas (PRR = 2.66; 95% CI = 1.14-16.32; P = 0.02). Age, gender and duration of employment at the plant were comparable among participants working in production and nonproduction areas. Of the 100 participants who provided blood samples for antibody testing, specific IgG antibody to TDI was detected in two individuals, and none of the samples demonstrated specific IgE antibody to TDI. Of the 26 workers who underwent skin patch testing, none developed reactions to the diisocyanate allergens. These results suggest that the skin symptoms among study participants represent an irritant rather than an immunologic reaction to TDI, or to an unidentified allergen present in the foam.