Search

Diisocyanates are highly reactive substances and known causes of occupational asthma. Exposure occurs mainly in the occupational setting and can be assessed through biomonitoring which accounts for inhalation and dermal exposure and potential effects of protective equipment. However the interpretation of biomonitoring data can be challenging for chemicals with complex kinetic behavior and multiple exposure routes, as is the case for diisocyanates. To better understand the relation between external exposure and urinary concentrations of metabolites of diisocyanates, we developed a physiologically based kinetic (PBK) model for methylene bisphenyl isocyanate (MDI) and toluene di-isocyanate (TDI). The PBK model covers both inhalation and dermal exposure, and can be used to estimate biomarker levels after either single or chronic exposures. Key parameters such as absorption and elimination rates of diisocyanates were based on results from human controlled exposure studies. A global sensitivity analysis was performed on model predictions after assigning distributions reflecting a mixture of parameter uncertainty and population variability. Although model-based predictions of urinary concentrations of the degradation products of MDI and TDI for longer-term exposure scenarios compared relatively well to empirical results for a limited set of biomonitoring studies in the peer-reviewed literature, validation of model predictions was difficult because of the many uncertainties regarding the precise exposure scenarios that were used. Sensitivity analyses indicated that parameters with a relatively large impact on model estimates included the fraction of diisocyanates absorbed and the binding rate of diisocyanates to albumin relative to other macro molecules.We additionally investigated the effects of timing of exposure and intermittent urination, and found that both had a considerable impact on estimated urinary biomarker levels. This suggests that these factors should be taken into account when interpreting biomonitoring data and included in the standard reporting of isocyanate biomonitoring studies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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.

Toluene diisocyanate (TDI), a major intermediate agent used in the manufacturing industry, causes respiratory symptoms when exposed to the human body. In this study, we aimed to determine the molecular mechanism of TDI toxicity. To investigate the impact of TDI exposure on global gene expression, we performed transcriptomic analysis of human bronchial epithelial cells (BEAS-2B) after TDI treatment. Differentially expressed genes (DEGs) were sorted and used for clustering and network analysis. Among DEGs, dual-specificity phosphatase 6 (DUSP6) was one of the genes significantly changed by TDI exposure. To verify the expression level of DUSP6 and its effect on lung cells, the mRNA and protein levels of DUSP6 were analyzed. Our results showed that DUSP6 was dose-dependently upregulated by TDI treatment. Thereby, the phosphorylation of ERK1/2, one of the direct inhibitory targets of DUSP6, was decreased. TDI exposure also increased the mRNA level of p53 along with its protein and activity which trans-activates DUSP6. Since TRPA1 is known as a signal integrator activated by TDI, we analyzed the relevance of TRPA1 receptor in DUSP6 regulation. Our data revealed that up-regulation of DUSP6 mediated by TDI was blocked by a specific antagonist against TRPA1. TDI exposure attenuated the apoptotic response, which suggests that it promotes the survival of cancerous cells. In conclusion, our results suggest that TDI induces DUSP6 and p53, but attenuates ERK1/2 activity through TRPA1 receptor activation, leading to cytotoxicity.

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., Competing Interests: The authors have no financial conflicts of interest., (© Copyright: Yonsei University College of Medicine 2018.)

Toluene diisocyanate (TDI) exposure can directly activate and damage airway epithelium. Folliculin (FLCN) is a protein expressed by human airway epithelial cells (HAECs) to maintain airway epithelial integrity and survival. This study investigated the involvement of FLCN in the pathogenesis of TDI-induced occupational asthma (OA). Enzyme-linked immunosorbent assay was used to measure serum levels of FLCN in TDI-exposed subjects (93 TDI-OA patients and 119 asymptomatic exposed controls (AEC)), 200 non-occupational asthma (NOA) patients and 71 unexposed healthy normal controls (NCs). Significantly more subjects in the TDI-OA and AEC groups had high serum levels of FLCN compared to those in the NOA group (P=0.002 and P=0.001, respectively), all of which were higher than the NC group (all P<0.001). The serum level of FLCN was positively correlated with TDI exposure duration (r=0.251, P=0.027), but was negatively correlated with asthma duration of TDI-OA patients (r=-0.329, P=0.029). TDI-exposed subjects with high FLCN levels had higher serum levels of total IgE than those with lower levels. The effects of TDI exposure on FLCN production was investigated by treating HAECs (A549 cells) with TDI-human serum albumin conjugate, which showed increased expression and release of FLCN and interleukin-8 from HAECs. Co-culture with peripheral blood neutrophils also induced FLCN expression and release from HAECs. In conclusion, TDI exposure and TDI-induced neutrophil recruitment into the airways can activate and stimulate HAECs to produce FLCN, which could be involved in airway inflammation in workers exposed to TDI.

Background: While the importance of the Th2 cytokine IL-13 as a central mediator of airway hyperreactivity (AHR) has been described in allergic protein-induced asthma, this has never been investigated in chemical-induced asthma., Objective: We examined the importance of IL-13 in a mouse model of chemical-induced AHR, using toluene-2,4-diisocyanate (TDI)., Methods: In a first set-up, wild type (WT) and IL-13 knockout (KO) C57Bl/6 mice were dermally treated on days 1 and 8 with 1% TDI or vehicle (acetone/olive oil) on both ears. On day 15, mice received an intranasal instillation with 0.1% TDI or vehicle. In a second set-up, WT mice sensitized with 1% TDI or vehicle, received i.v. either anti-IL-13 or control antibody prior to the intranasal challenge., Results: TDI-sensitized and TDI-challenged WT mice showed AHR to methacholine, in contrast to TDI-sensitized and TDI-challenged IL-13 KO mice, which also showed lower levels of total serum IgE. TDI-sensitized and TDI-challenged IL-13 KO mice had lower numbers of T-cells in the auricular lymph nodes. TDI-treated WT mice, receiving anti-IL-13, showed no AHR, in contrast to those receiving control antibody, despite increased levels of IgE. Anti-IL-13 treatment in TDI-treated WT mice resulted in lower levels of serum IL-13, but did not induce changes in T- and B-cell numbers, and in the cytokine production profile., Conclusion and Clinical Relevance: We conclude that IL-13 plays a critical role in the effector phase of chemical-induced, immune-mediated AHR. This implicates that anti-IL-13 treatment could have a beneficial effect in patients with this asthma phenotype.

Flexible polyurethane foam (FPF) is produced from the reaction of toluene diisocyanate (TDI) and polyols. Limited and conflicting results exist in the literature concerning the presence of unreacted TDI remaining in FPF as determined by various solvent extraction and analysis techniques. This study reports investigations into the effect of several solvent/derivatization agent combinations on extractable TDI results and suggests a preferred method. The suggested preferred method employs a syringe-based multiple extraction of foam samples with a toluene solution of 1-(2-methoxyphenyl)-piperazine. Extracts are analyzed by liquid chromatography using an ion trap mass spectrometry detection technique. Detection limits of the method are ~10ng TDI g(-1) foam (10 ppb, w/w) for each TDI isomer (i.e. 2,4-TDI and 2,6-TDI). The method was evaluated by a three-laboratory interlaboratory comparison using two representative foam samples. The total extractable TDI results found by the three labs for the two foams were in good agreement (relative standard deviation of the mean of 30-40%). The method has utility as a basis for comparing FPFs, but the interpretation of extractable TDI results using any solvent as the true value for 'free' or 'unreacted' TDI in the foam is problematic, as demonstrated by the difference in the extracted TDI results from the different extraction systems studied. Further, a consideration of polyurethane foam chemistry raises the possibility that extractable TDI may result from decomposition of parts of the foam structure (e.g. dimers, biurets, and allophanates) by the extraction system.

Flexible polyurethane foam (FPF) is produced from the reaction of toluene diisocyanate (TDI) and polyols. Because of the potential for respiratory sensitization following exposure to TDI, concerns have been raised about potential consumer exposure to TDI from residual 'free TDI' in FPF products. Limited and conflicting results exist in the literature concerning the presence of unreacted TDI remaining in FPF as determined by various solvent extraction and analysis techniques. Because residual TDI results are most often intended for application in assessment of potential human exposure to TDI from FPF products, testing techniques that more accurately simulated human contact with foam were designed. To represent inhalation exposure to TDI from polyurethane foam, a test that measured the emission of TDI to air was conducted. For simulation of human dermal exposure to TDI from polyurethane foam, a migration test technique was designed. Emission of TDI to air was determined for a representative FPF using three different emission test cells. Two were commercially available cells that employ air flow over the surface of the foam [the Field and Laboratory Emission Cell (FLEC®) and the Micro-Chamber/Thermal Extraction™ cell]. The third emission test cell was of a custom design and features air flow through the foam sample rather than over the foam surface. Emitted TDI in the air of the test cells was trapped using glass fiber filters coated with 1-(2-methoxyphenyl)-piperazine (MP), a commonly used derivatizing agent for diisocyanates. The filters were subsequently desorbed and analyzed by liquid chromatography/mass spectrometry. Measurement of TDI migration from representative foam was accomplished by placing glass fiber filters coated with MP on the outer surfaces of a foam disk and then compressing the filters against the disk using a clamping apparatus for periods of 8 and 24 h. The sample filters were subsequently desorbed and analyzed in the same manner as for the emission tests. Although the foam tested had detectable levels of solvent-extractable TDI (56ng TDI g(-1) foam for the foam used in emissions tests; 240-2800ng TDI g(-1) foam for the foam used in migration tests), no TDI was detected in any of the emission or migration tests. Method detection limits (MDLs) for the emissions tests ranged from 0.03 to 0.5ng TDI g(-1) foam (0.002-0.04ng TDI cm(-2) of foam surface), whereas those for the migration tests were 0.73ng TDI g(-1) foam (0.16ng TDI cm(-2) of foam surface). Of the three emission test methods used, the FLEC® had the lowest relative MDLs (by a factor of 3-10) by virtue of its high chamber loading factor. In addition, the FLEC® cell offers well-established conformity with emission testing standard methods.

An attempt was made to clarify the additive suppressive effects of pranlukast, a cysteinyl leukotriene-receptor (LTR) antagonist, in combination with chlorpheniramine, an antihistamine, on the up-regulation of histamine H1-receptor (H1R) mRNA in toluene 2,4-diisocyanate (TDI)-sensitized rats. Although pre-treatment with pranlukast partially, but significantly, suppressed TDI-induced up-regulation of H1R mRNA and nasal symptoms, pre-treatment with the combination of pranlukast and chlorpheniramine significantly suppressed them in a manner greater than either drug alone. These findings suggest that the additive therapeutic effect of the combination of LTR antagonist and antihistamine is due to their additive suppression of H1R up-regulation.

Objectives: Diisocyanates (DIC) are highly reactive, low-molecular-weight chemicals which are the leading cause of occupational asthma (OA). The aim of the study was to analyze certain aspects of the pathogenesis of allergic inflammation in the airways induced by toluene diisocyanate (TDI) in an experimental model in mice., Materials and Methods: The experiment was carried out on 50 female BALB/cJ/Han/IMP mice, which were exposed by inhalation (intranasal and in the inhalation chamber) to toluene diisocyanate (2,4-TDI). After the experiment, the bronchoalveolar lavage fluid (BALF) was collected from the animals, and the composition of the induced inflammatory cells, and the concentrations of certain cytokines (IL-4, IL-5, TNF-α) were evaluated., Results: The total number of cells in BALF of the examined group of mice was significantly higher compared to the control mice. There was also a significant increase in neutrophils and eosinophils in the study group compared to the controls. The number of lymphocytes and macrophages did not differ significantly between the two groups. A statistically significant increase in the level of TNF-α was shown to occur in the group exposed to toluene diisocyanate in comparison to the control group. The concentration of IL-4 increased in the study group, compared to the control one, but the differences did not reach the level of significance, p > 0.05. Such difference was not observed for IL-5., Conclusions: We developed a murine model of TDI-induced asthma which caused the influx of inflammatory cells like eosinophils and neutrophils in the bronchoalveolar lavage fluid (BALF) in the TDI-treated mice. The increase of the concentration of some proinflammatory cytokines (TNF-α, IL-4) in BALF from the exposed mice was also observed.

Objectives: Toluene diisocyanate (TDI) is used in the manufacturing process of polyurethane (PU) foams and is a potent inducer of occupational asthma. The objective of this study was to evaluate the correlation between the exposure to total TDI (2,4- and 2,6-TDI) in air and the corresponding biomarker concentration of total TDA (2,4- and 2,6-TDA) in hydrolysed urine. The aim was also to propose an appropriate biological exposure limit for total TDA in urine., Methods: 9 workers from two production lines in a PU foam producing plant were studied. Personal exposure to TDI during four representative production shifts was monitored by an active air sampling method (filter impregnated with 1-(2-methoxyphenyl)piperazine) and quantified by high-performance liquid chromatography and diode array detection (NIOSH n° 2535, 5521). In parallel, pre-shift and post-shift urinary samples were collected from the exposed workers, and TDA concentrations were determined by gas chromatography-mass spectrometry after alkaline hydrolysis. All samples were collected on four measuring days: two Fridays (end of workweek) and two Mondays (start of workweek) separated by a weekend without exposure., Results: Strong correlations between the personal air concentrations of total TDI and the corresponding biomarker levels of total TDA in urine (r=0.816) were observed. An increase of 18.12 μg TDA/l (post-shift minus pre-shift concentration) corresponds to an exposure of 5 ppb (37 μg/m(3), the current American Conference of Governmental Industrial Hygienists threshold limit value) during the shift., Conclusions: The increase in TDA during the shift is a suitable biomarker for exposure to TDI during the same shift. Further research is needed to evaluate the use of start of week or end of week post-shift TDA in urine as biomarker since TDA was found to accumulate during the working week and thus the moment of sampling will clearly influence the result.

Aim: To identify those agents reported as being associated with reactive airways dysfunction syndrome (RADS)., Methods: A systematic review was undertaken. Abstracts were screened and those selected reviewed against pre-determined diagnostic criteria for RADS., Results: Significant information gaps were identified for all measures of interest. In some articles, even the causative agent was not reported. The most commonly reported agents were chlorine (nine subjects), toluene di-isocyanate (TDI) (n = 6) and oxides of nitrogen (n = 5). Most exposures occurred in the workplace (n = 51) and affected men (60%). Dyspnoea (71%) and cough (65%) were the commonest symptoms. Median symptom duration was 13 months (interquartile range = 6.5-43.5) for RADS., Conclusions: Although the most commonly reported agent associated with RADS was chlorine, the main finding of a general lack of adequate information on exposure, investigation and outcome suggests that to better explore RADS a more structured approach to gathering information is required. A minimum data set for reporting RADS cases is proposed.

Objectives: 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., Methods: 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., Results: 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., Conclusions: 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.

Background: Offspring of asthmatic mothers have increased risk of developing asthma, based on human epidemiologic data and experimental animal models. The objective of this study was to determine whether maternal allergy at non-pulmonary sites can increase asthma risk in offspring., Methods: BALB/c female mice received 2 topical applications of vehicle, dinitrochlorobenzene, or toluene diisocyanate before mating with untreated males. Dinitrochlorobenzene is a skin-sensitizer only and known to induce a Th1 response, while toluene diisocyanate is both a skin and respiratory sensitizer that causes a Th2 response. Both cause allergic contact dermatitis. Offspring underwent an intentionally suboptimal protocol of allergen sensitization and aerosol challenge, followed by evaluation of airway hyperresponsiveness, allergic airway inflammation, and cytokine production. Mothers were tested for allergic airway disease, evidence of dermatitis, cellularity of the draining lymph nodes, and systemic cytokine levels. The role of interleukin-4 was also explored using interleukin-4 deficient mice., Results: Offspring of toluene diisocyanate but not dinitrochlorobenzene-treated mothers developed an asthmatic phenotype following allergen sensitization and challenge, seen as increased Penh values, airway inflammation, bronchoalveolar lavage total cell counts and eosinophilia, and Th2 cytokine imbalance in the lung. Toluene diisocyanate treated interleukin-4 deficient mothers were able to transfer asthma risk to offspring. Mothers in both experimental groups developed allergic contact dermatitis, but not allergic airway disease., Conclusion: Maternal non-respiratory allergy (Th2-skewed dermatitis caused by toluene diisocyanate) can result in the maternal transmission of asthma risk in mice.

Eighty-seven cases of occupational asthma induced by toluene diisocyanate (TDI) were diagnosed by an inhalation challenge with TDI and methacholine. After an average follow-up interval of 11 yrs, all subjects were re-examined. Of the 87 subjects examined, 13 (15%) had remained in the same job, 44 (50.5%) had been removed from exposure for <10 yrs and 30 (34.5%) had been removed for >10 yrs. The proportion of subjects who experienced symptoms of asthma and those who were hyperresponsive to methacholine was significantly lower. Of the patients, 59% used short-acting bronchodilators, 8% long-acting bronchodilators and 18% were on regular inhaled glucocorticoids. Thus, multiple regression analysis showed a positive correlation between forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) at follow-up and FVC and FEV1 at diagnosis, and a negative correlation with smoking and with therapy with bronchodilators. Stepwise logistic regression showed that the follow-up provocative dose causing a 20% fall in the FEV1 (PD20) could be predicted from baseline PD20. These results indicate that respiratory symptoms and airway hyperresponsiveness to methacholine persist in subjects removed from exposure to TDI for >10 yrs. A more favourable prognosis was associated with a better lung function and a lower degree of airway hyperresponsiveness to methacholine at diagnosis.

Objectives: The composition of thermal degradation products from two types of polyurethane foams, one based on toluene diisocyanate (TDI) and the other on diphenylmethane diisocyanate (MDI), was analyzed and their toxic lung effects were compared., Methods: Isolated perfused lungs of guinea pig were subjected to thermal decomposition products of polyurethane foams from an aerosol generator with compartments for diluting, mixing, and sampling., Results: Thermal degradation of MDI-based polyurethane foams released MDI, phenyl isocyanate, and methyl isocyanate. The emitted particulate fraction was 75% for MDI, whereas that for TDI from TDI-based polyurethane foam was 3%. Thermal degradation products from MDI-based foam caused a pronounced dose-dependent decrease in the measured lung function parameters (conductance and compliance). In contrast, the thermal degradation products from TDI-based foam did not cause any decrease in lung function., Conclusions: Thermal degradation products generated from MDI-based polyurethane foam were more toxic to the lung than those generated from TDI-based polyurethane foam. This difference was probable due to MDI in the particle phase.

Background: An appreciable number of patients with toluene diisocyanate (TDI)-induced asthma have high serum levels of specific IgE (sIgE) antibody to TDI-human serum albumin conjugate (HSA). A recent investigation suggested a role of specific IgG (sIgG) in the development of TDI asthma., Methods: We observed the changes in the levels of specific IgE and IgG antibodies to TDIHSA conjugate in TDI-induced asthmatic patients during seven years avoidance., Results: Six subjects with high sIgE and five with high sIgG were enrolled. All of them had taken anti-asthmatic medications with complete avoidance. Serum levels of sIgE and sIgG to TDI-HSA conjugate were detected by ELISA. The level of sIgE continued to decline up to 7 years and the mean half-life was 3.9 years. The mean half-life of sIgG was 4.5 yrs., Conclusion: These findings suggest that both sIgE and sIgG to TDI-HSA conjugate may persist for several years after the last exposure to TDI.

Aims: To describe cause specific mortality and site specific cancer morbidity among workers employed in factories that produce polyurethane foams, and to determine if any part of the experience may be caused by occupation, in particular to investigate any association between respiratory disease (malignant and non-malignant) and exposure to diisocyanates., Methods: The mortality (1958-98) and cancer morbidity (1971-94) experienced by a cohort of 8288 male and female employees from 11 factories in England and Wales engaged in the manufacture of flexible polyurethane foams were investigated. All employees were employed for at least six months with some period of employment in the period 1958-79. Two analytical approaches were used, indirect standardisation and Poisson regression., Results: Compared with the general population of England and Wales, mortality from lung cancer in female employees was significantly increased (observed (Obs) 35, expected (Exp) 19.4, standardised mortality ratio (SMR) 181). A similar excess was not found for male employees (Obs 134, Exp 125.0, SMR 107). There were no significantly increased cause specific SMRs among the subcohort (n = 1782) with some period of isocyanate exposed employment. No significant positive trends were found between risks of lung cancer or risks of non-malignant diseases of the respiratory system and durations of "lower" or "higher" exposures to diisocyanates., Conclusions: The study has been unable to link isocyanate exposed employment either with risks of lung cancer or with risks of non-malignant diseases of the respiratory system. The increased SMR for female lung cancer is most likely caused by factors unrelated to the industry under study.

Nearly 9 million workers are exposed to chemical agents associated with occupational asthma, with isocyanates representing the chemical class most responsible. Isocyanate-induced asthma has been difficult to diagnose and control, in part because the biologic mechanisms responsible for the disease and the determinants of exposure have not been well defined. Isocyanate-induced asthma is characterized by airway inflammation, and we hypothesized that inflammation is a prerequisite of isocyanate-induced asthma, with tumor necrosis factor (TNF)-alpha being critical to this process. To explore this hypothesis, wild-type mice, athymic mice, TNF-alpha receptor knockout (TNFR), and anti-TNF-alpha antibody-treated mice were sensitized by subcutaneous injection (20 micro l on Day 1; 5 micro l, Days 4 and 11), and challenged 7 d later by inhalation (100 ppb; Days 20, 22, and 24) with toluene diisocyanate (TDI). Airway inflammation, goblet cell metaplasia, epithelial cell damage, and nonspecific airway reactivity to methacholine challenge, measured 24 h following the last challenge, were reduced to baseline levels in TNF-alpha null mice and athymic mice. TNF-alpha deficiency also markedly abrogated TDI-induced Th2 cytokines in airway tissues, indicating a role in the development of Th2 responses. Despite abrogation of all indicators of asthma pathology, TNF-alpha neutralization had no effect on serum IgE levels or IgG-specific TDI antibodies, suggesting the lack of importance of a humoral response in the manifestation of TDI-induced asthma. Instillation studies with fluorescein-conjugated isothiocyanate and TDI suggested that TNF-alpha deficiency also resulted in a significant reduction in the migration of airway dendritic cells to the draining lymph nodes. Taken together, these results suggest that, unlike protein antigens, TNF-alpha has multiple and central roles in TDI-induced asthma, influencing both nonspecific inflammatory processes and specific immune events.

In order to investigate the cytokine profile in toluene diisocyanate (TDI)-induced occupational asthma, we conducted a quantification of cytokine production in a murine model of respiratory hyperreactivity to TDI. Wistar rats were sensitized with intranasal application of 10% TDI and provoked with 5% TDI to induce airway hypersensitivity. The blood leucocytes were counted, and bronchoalveolar lavage (BAL) was performed and the cellular responses in BAL fluid were analysed. Lung histological examination was performed to investigate the inflammatory status in the airway. The production of IL-2, IL-4, IL-6 and IFN-gamma in serum, BAL fluid and spleen cell were determined with ELISA kits. The cellular results demonstrated that neutrophils and eosinophils in blood were significantly increased and the total cells and each different cell, in particular eosinophils in BAL fluid were markedly increased in TDI sensitized rats. Histological analysis showed that a respiratory inflammation represented by prominent infiltration of eosinophils in central and peripheral airways was present in TDI-sensitized rats. The cytokine assays revealed that in TDI-sensitized rats, IL-4 was predominately secreted in serum, and IL-4 and IL-6 rather than IL-2 and IFN-gamma were predominately secreted in BAL fluid and in spleen cell. These findings suggested that IL-4 and IL-6 are preferentially produced and may have an important role in occupational asthma induced by TDI.

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.

Objective: To assess the quality of health information on material safety data sheets (MSDS) for a workplace chemical that is well known to cause or exacerbate asthma (toluene diisocyanate, TDI)., Design: We reviewed a random sample of 61 MSDSs for TDI products produced by 30 manufacturers., Measurements and Main Results: Two physicians independently abstracted data from each MSDS onto a standardized audit form. One manufacturer provided no language about any respiratory effects of TDI exposure. Asthma was listed as a potential health effect by only 15 of the 30 manufacturers (50%). Listing asthma in the MSDS was associated with higher toluene diisocyanate concentrations in the product (P <.042). Allergic or sensitizing respiratory reactions were listed by 21 manufacturers (70%)., Conclusions: Many MSDSs for toluene diisocyanate do not communicate clearly that exposure can cause or exacerbate asthma. This suggests that physicians should not rely on the MSDS for information about health effects of this chemical.

Objective: To examine the quantitative relation between exposure to isocyanates and occupational asthma, and to explore the role of atopy and smoking in occurrence of the disease., Method: A case-referent study was undertaken of cases from two manufacturing companies (A and B) from which referents without disease could be selected and reliable exposure measurements were available. In company A, 27 cases mainly attributed to toluene diisocyanate (TDI) were matched to 51 referents on work area, start and duration of employment, sex, and age. Exposures were estimated from existing measurements by job category. In company B there were seven cases attributed to 4,4'-diphenylmethane diisocyanate (MDI) in two areas of the plant; 12 non-cases from the same areas were used as referents. Personal exposure measurements were available for all cases and 11 referents., Results: No difference in peak exposures between cases and referents was found in either plant; but in both, time weighted average (TWA) exposures at the time of onset of asthma were higher for cases. In A, the mean TWA exposure for cases was 1.5 (95% confidence interval (95% CI) 1.2 to 1.8) ppb compared with 1.2 (1.0 to 1.4) ppb for referents. From a matched analysis, the odds ratio (OR) associated with 8 hour TWA exposure to isocyanates greater than 1.125 ppb (the median concentration for the referent group) was 3.2 (95% CI 0.96 to 10.6; p=0.06). Occupational asthma was associated with a pre-employment history of atopic illness (OR 3. 5, p=0.04) and, less strongly, with smoking (OR 2.1, p=0.14). In B, small numbers limited analysis, but three of seven cases had at least one TWA exposure measurement greater than 5 ppb compared with one of 11 referents (OR 7.5, p=0.09)., Conclusion: Asthma can occur at low concentrations of isocyanates, but even at low concentrations, the higher the exposure the greater the risk. By contrast with other studies, smoking and atopy seemed to increase the odds of occupational asthma due to isocyanates, but did not affect the estimate of risk associated with exposure.

Two cases of paraoccupational asthma caused by toluene diisocyanate (TDI) are reported. The first patient was a metal worker in a machine shop situated near a factory producing polyurethane foam. Symptoms at work were not explainable by any specific exposure to irritants or allergens in the work site. As the patient recalled previous occasional work in the adjacent polyurethane factory with accompanying worsening of respiratory symptoms, a specific inhalation (SIC) test was performed with TDI, which confirmed the diagnosis of TDI asthma. The second case was a woman working part time as a secretary in the offices of her son's factory for varnishing wooden chairs. TDI was present in the products used in the varnishing shed. The SIC test confirmed the diagnosis of TDI asthma, despite the fact that the patient's job did not present risk of exposure to the substance. In both patients, symptoms disappeared when further exposure was avoided. These two cases confirm that paraoccupational exposure to TDI must be considered when evaluating patients with asthma not mediated by immunoglobulin E. They also suggest the need for more prospective studies evaluating the health risk for the general population living near polyurethane factories or other firms that use TDI.

In 1976-1992 245 new cases of asthma induced by diisocyanates were diagnosed, caused by hexamethylene diisocyanate (HDI) in 39%, diphenylmethane diisocyanate (MDI) in 39%, and toluene diisocyanate (TDI) in 17% of the cases. Our aim was to study the clinical outcome of diisocyanate-induced asthma. A questionnaire was sent to the 235 patients alive in 1995, and validated by reexamining clinically 91 of them. The study was carried out on average 10 () yr after the diagnosis. Of the patients 82% experienced symptoms of asthma, 34% used no medication, and 35% were on regular medication. The patients having displayed immunoglobulin E (IgE) antibodies to isocyanates used less medication (OR 0.273; CI 0.098, 0.758) and had fewer symptoms of asthma (OR 0.329; CI 0.124, 0.875) than the IgE-negative ones. They also had a significantly shorter duration of symptoms (p = 0.0025), latency period (p = 0.0249), and duration of exposure (p = 0.0008) than the IgE-negative patients. This did not, however, entirely explain the more favourable outcome of the IgE-positive patients. Patients with HDI-induced asthma used less medication (OR 0.412; CI 0.229, 0.739) than patients with MDI- and TDI-induced asthma. The results confirm the generally rather poor medical outcome of diisocyanate-induced asthma; the persistence of symptoms and unspecific bronchial reactivity were pronounced in TDI-induced asthma. A more favourable outcome was associated with IgE mediation and HDI inducement.

Objectives: To characterise irritant and allergic airway responses and assess changes in forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) relative to exposure to toluene di-isocyanate (TDI)., Methods: Employees (n = 313) ever assigned to a TDI production unit for > or = 3 months (1967-92) were identified from personnel records along with 158 frequency matched referents without known exposure to TDI. Reports made during visits to the occupational clinic of incidents related to exposure to TDI and annual periodic examination results (questionnaire, physical findings, and spirometry) were abstracted and assessed relative to industrial hygiene estimates of exposure to TDI., Results: Mean 8 hour time weighted average estimates of TDI concentrations ranged from 9.9 ppb in jobs with potentially high exposure during the early years of plant operations to 0.5 ppb in jobs with potentially low exposure in more recent years. The corresponding rates of visits to the clinic due to incidents of exposure to TDI (including both irritant and allergic airway responses) declined from 20.5 to 1.0 visits per 100 years of employment at the unit. The annual incidence of asthma induced by TDI declined from 1.8% before 1980 to 0.7% afterwards. Neither cross sectional nor longitudinal analyses of FVC and FEV1 showed significant dose-response findings relative to exposure to TDI across the total exposed population. Among cases of occupational asthma there was an apparent initial decline in FEV1 within 2 years of first reporting symptoms, but not an accelerated rate of decline in follow up tests from 4-30 years after induction of asthma., Conclusions: Occurrences of both asthma induced by TDI and irritant airway responses due to exposure to TDI were found in this cohort, but there was no relation between cumulative exposure to TDI and irreversible airflow obstruction as assessed by spirometry.

Increased non-specific bronchial hyperresponsiveness (BHR) has been reported after positive reaction to isocyanates in patients with isocyanate-sensitive asthma. The increased responsiveness may, however, also precede the asthma attack. We therefore compared non-specific BHR to a cholinergic agent before and after exposure to toluene-diisocyanate (TDI) that induced no asthma symptoms in 11 workers with isocyanate-related asthma. Patients were exposed for 3 consecutive days to progressively increasing doses of TDI (5, 10, and 20 ppb min-1 for 20 min) in an exposure chamber with continuous TDI monitoring. No immediate nor late asthmatic bronchial reaction was observed in any patient after any dose of TDI during or after challenge. A significant increase in non-specific BHR was noted 24 h after the last dose of TDI challenge, however. This increase was at least one doubling dose for seven of 11 patients. In conclusion, our study shows that, in patients with isocyanate-induced asthma, exposure to TDI induces a slight but significant increase in non-specific BHR in the absence of any immediate or late bronchial response to isocyanate. This result, which requires further confirmation, may justify a proposal to measure non-specific BHR, even after a negative specific inhalation test to TDI, as an additional diagnostic element for TDI-induced occupational asthma, to help lower the percentage of the undetected occupational asthma cases.

In August 1996, residents of a community in Randolph County, North Carolina, contacted the Agency for Toxic Substances and Disease Registry (ATSDR) because of health concerns about possible exposure to chemical emissions from a polyurethane manufacturing plant. ATSDR and the North Carolina Department of Environment, Health, and Natural Resources (NCDEHNR) conducted ambient air monitoring to characterize air contamination near the plant. ATSDR and Randolph County health officials also conducted biologic monitoring to determine whether residents were being exposed to toluene diisocyanate (TDI) emitted from the plant. This report summarizes the results of these investigations, which indicate that residents were being exposed to TDI in ambient air surrounding the plant.

Toluene diisocyanate (TDI) is the most prevalent agent in occupational asthma (OA) in Korea. The immuno-pathologic mechanism for TDI-induced bronchoconstriction remains to be clarified. We studied the immunohistochemical finding of inflammatory cells in bronchial mucosa in subjects with TDI-induced asthma. Fiberoptic bronchial biopsy specimens were obtained from nine subjects with TDI-induced asthma. Six allergic asthma sensitive to house dust mite were enrolled as controls. Bronchial biopsy specimens were examined by immunohistology with a panel of monoclonal antibodies to mast cell tryptase (AA1), secretary form of eosinophil cationic protein (EG2), pan T-lymphocyte (CD3) and neutrophil elastase (NE). There was a significant increase in the number of AA1+, EG2+ and NE+ cells in TDI-induced asthma compared to those of allergic asthma (p=0.02, p=0.04, p=0.03, respectively). No significant differences were observed in the number of CD3+ cells (p=0.27). These findings support the view that neutrophil recruitment together with eosinophil and mast cell, may contribute to the bronchoconstriction induced by TDI.

Objective: To evaluate cancer mortality among United States workers exposed to toluene diisocyanate (TDI) in the manufacture of polyurethane foam., Methods: This cohort mortality study included 4611 men and women employed in four polyurethane foam plants for at least three months between the late 1950s and 1987. The mortality experience of the cohort was then compared with that of the general United States population., Results: Current and past industrial hygiene data indicated that air concentrations in 1984-5 were below the current United States standard of 0.04 mg/m3 but exceeded the standard before 1980. Mortality ratio (SMR) 2.78, 95% confidence interval (95% CI) 0.57-8.13) and non-Hodgkin's lymphoma (SMR 1.54, 95% CI 0.42-3.95) were increased, but not significantly. There was one male breast cancer. However, breast cancer was not increased in women (SMR 0.74). No other cancer category had an increased number of deaths compared with the general population. Only non-Hodgkin's lymphoma and Hodgkin's disease showed a possible relation with time since first employment and no cancer death category showed a strong relation with duration of employment. Mortality from non-malignant respiratory disease was not increased (SMR 0.86)., Conclusions: This young cohort has few deaths and short follow up. The findings are therefore not conclusive. Further years of follow up will enable better evaluation of mortality.

Isocyanate is the most prevalent agent in occupational asthma(OA) in Korea. We analyzed 43 toluene diisocyanate(TDI) induced OA patients of whom 81% were found to be spray painters. The bronchial sensitivity of all subjects was confirmed by TDI-bronchial challenge test. Serum-specific IgE antibodies to isocyanate-human serum albumin(HSA) conjugate were detected by RAST technique(Pharmacia, Sweden). Bronchial challenge test results revealed 21(57%) early, 5 late only, 4 dual, and 12 atypical responders(5 prolonged immediate, 6 square-shaped, 1 progressive). Four(9%) subjects had negative results on the methacholine bronchial challenge test. High levels of serum specific IgE antibody to isocyanate-HSA were found in 17(40%) patients. The prevalence of a specific IgE antibody was not associated with a type of TDI-bronchial challenge test response, smoking and atopic status, presence of rhino-sinusitis and systemic symptoms, or a degree of airway hyperresponsiveness to methacholine(p > 0.05). The period of latency, ranging from 3 to 132 months, was significantly longer in high specific IgE responders (p < 0.05). These data suggest that 40% of isocyanate-induced occupational asthma patients had high specific IgE antibody to isocyanate-HSA conjugate. The presence of specific IgE antibody does not seem to correlate with clinical parameters.

Toluene diisocyanate (TDI) is the most common cause of occupational asthma in western countries. The aim of this study was to investigate whether genetic factors are involved in toluene diisocyanate-induced asthma. We studied the frequency of human leucocyte antigen (HLA) class II genetic markers in three groups of subjects: 1) subjects with TDI-induced asthma (n = 30); 2) exposed subjects with no history of TDI-induced asthma (n = 12); and 3) normal subjects not exposed to TDI (n = 126). Venous blood samples were collected from the three groups and the polymorphic second exon of DQA and DQB genes was amplified by the polymerase chain reaction (PCR) method. Evaluation of HLA class II gene products in TDI-induced asthma cases showed a positive association with HLA-DQB1 * 0503 and a negative association with HLA-DQB1 * 0501 alleles, which differed at residue 57 for a single amino acid, i.e. aspartic acid in DQB1 * 0503 and valine in DQB1 * 0501. No significant difference was found in the distribution of DQA1 alleles between asthmatics and controls. Our results confirm the hypothesis that HLA-DQB1 * 0503 has a role in conferring susceptibility to TDI-induced asthma and that residue 57 of HLA-DQB1 is a potentially critical location.

Objectives: The aims of the present study were to determine whether specific in vivo stimulation of asthmatics sensitized with toluene diisocyanate (TDI) induces the activation of T lymphocytes in bronchial mucosa and to characterize their phenotype and cytokine secretion profile., Methods: Bronchial biopsies from two subjects with occupational asthma due to TDI were obtained 48 h after an asthmatic reaction induced by an inhalation challenge with TDI and after three months of no exposure to TDI, at the time when the subjects had recovered from their asthma. The fragments of bronchial mucosa were cultured in the presence of interleukin-2 so that the in vivo activated T cells present in the tissue would expand, and T blasts were then cloned under limiting dilution conditions., Results: From the two 48-h specimens, 65 and 63 T-cell clones were obtained. Most of the clones exhibited the CD8 phenotype (82 and 83%). All of the CD8 clones produced interferon-gamma and 44% produced interleukin-5, but only 6% secreted interleukin-4 as well. Three months after the cessation of exposure, growing T cells could not be recovered from bronchial biopsies cultured in interleukin-2., Conclusions: The results suggest that, in sensitized subjects, exposure to TDI induces the activation of a subset of CD8 lymphocytes producing interferon-gamma and interleukin-5.

Objective: To assess the association between occupational exposure to toluene diisocyanate or methylene diphenyldiisocyanate and risk of cancer., Design: A cohort based case-referent study. STUDY BASE: 7023 subjects employed during the period 1958 to 1987 in nine Swedish polyurethane foam manufacturing plants., Main Outcome Measures: Odds ratios adjusted with respect to the matching factors (age at risk, calendar year at risk, sex, and plant), calculated from the conditional logistic regression model., Results: A non-significant association was found between high exposure to isocyanates and prostate cancer (OR 2.66, 90% confidence interval (90% CI) 0.39-18.1), which was not enhanced when an induction latency period of 10 years was applied. An association between isocyanate exposure and colon cancer was even weaker. No associations were seen for non-Hodgkin's lymphoma and rectal cancer., Conclusions: The tentative associations, derived from a previous cohort study, between isocyanate exposure and excess risk for non-Hodgkin's lymphoma and rectal cancer were not supported. Instead, non-significant associations with prostate cancer, and possibly colon cancer, were seen.

Toluene diisocyanate (TDI) and methylene diphenyldiisocyanate (MDI) are used in large quantities in the polyurethane foam manufacturing industry. Both substances are mutagenic and at least TDI is carcinogenic to animals, but the occupational hazard with respect to cancer is not known. Cancer incidence and mortality patterns were therefore investigated in a cohort of 4154 workers from nine Swedish plants manufacturing polyurethane foam, employed for at least one year. Each workplace and job task in the nine plants was categorically assessed for each calendar year by an experienced occupational hygienist, for "no exposure", "low or intermittent exposure", or "apparent exposure" to TDI and MDI. The observed deficit for all cause mortality (standardised mortality ratio (SMR) 0.78, (95% confidence interval (95% CI) 0.66-0.93) became smaller (SMR 0.92) excluding the first 10 years since the start of exposure and was ascribed to a healthy worker effect. No increased risk for death from bronchial obstructive diseases was found. An almost statistically significant deficit occurred for all malignant neoplasms (standardised incidence ratio (SIR) 0.81, 95% CI 0.63-1.02); slight (not significant) increased risks were found for rectal cancer (SIR 1.66) and non-Hodgkin's lymphoma (SIR 1.53). The SIR for non-Hodgkin's lymphoma increased to 2.80 (95% CI 0.76-7.16) when the first 10 years since first exposure were excluded from the observation period. The corresponding figure for rectal cancer was 1.92 (95% CI 0.52-4.92). Further restricting the analysis to those who had experienced an apparent exposure to TDI or MDI increased the SIR for both rectal cancer (3.19, 95% CI 0.66-9.33), and non-Hodgkin's lymphoma (3.03, 95% CI 0.37-10.9). These estimates were based, however, on few incident cases. As the cohort is still young and little time has elapsed since the start of exposure, future follow ups will enable a more conclusive evaluation.

All 20 workers exposed to toluene di-isocyanate (TDI) in a chemical processing and packing factory were tested for TDI-induced asthma. The assessment included a respiratory symptom questionnaire, spirometry, skin prick tests for common allergens and assessment of total and TDI-specific immunoglobulin E (IgE) levels by radio-allergosorbent tests. Six workers had symptoms suggestive of TDI-related asthma. Three of these 6 workers had a significant cross-shift decline in forced expiratory volume in 1 second (FEV1) (10% or greater). Two of the 6 had high levels of TDI-specific IgE. Of the 14 workers without work-related symptoms, 1 had a significant cross-shift decline in FEV1. There was no significant association between the levels of exposure to TDI and symptoms, lung function parameters or immunological findings. This study demonstrates the difficulties in correlating immunological status with clinical and lung function findings in workers exposed to TDI. Recommendations include a stepwise approach to diagnosing TDI-induced asthma in exposed workers.

Sixty patients with occupational asthma due to exposure to toluene diisocyanate (TDI) were re-evaluated, five years after the initial diagnosis had been confirmed by a specific bronchial provocation challenge. During both examinations the severity of asthmatic symptoms and the need for antiasthma treatment were graded and lung function tests, measurement of airway responsiveness to methacholine (PD15), and skin tests with common inhalant allergens were carried out. The evolution of the disease was established on the basis of the increase or decrease in asthmatic symptoms, requirements for medication, and FEV1 and PD15 methacholine between the two examinations. At follow up 17 patients (group A, 28.3%) had carried on working in the same environment after relocation to jobs with only occasional exposure to TDI; 15 of them used protective respiratory devices. The remaining 43 (group B, 71.7%) avoided further inhalation of TDI by moving to another sector. Group A showed a significant decrease in FEV1 and PD15 methacholine and significant increases in the severity of symptom score and requirement for medication; 13 subjects (76.5%) were worse, four (23.5%) were stable, and no one had recovered or improved. Group B showed significantly less severe symptoms and a threefold increase in PD15 methacholine; 12 subjects (28.2%) totally recovered, 10 (23.2%) improved, 16 (37.2%) were stable, and five (11.6%) were worse. In group B the duration of exposure to TDI and of symptoms before the initial diagnosis delineated the patients who recovered from those who did not improve; intermediate values in these features characterised the subjects who improved but did not recover. It is inferred that complete removal from exposure is the only effective way of preventing deterioration in patients with occupational asthma due to TDI. Early diagnosis and early removal from exposure after the onset of asthma are important factors for a favourable outcome of the disease.

Isocyanates are the most significant cause of occupational asthma in our country. To evaluate the prevalence of work-related respiratory symptoms and immunologic sensitization to it, we performed a questionnaire survey, allergy skin test, radioallergosorbent test (RAST) to toluene diisocyanate (TDI)-human serum albumin (HSA) conjugate and methacholine bronchial challenge test on 23 isocyanate-exposed employees and 9 unexposed controls working in a zipper factory. Six employees (26.1%) complained of work-related respiratory symptoms and three symptomatic workers showed significant bronchoconstrictions on TDI-bronchoprovocation test. Three (13%) asymptomatic workers had high specific IgE antibodies to TDI-HSA and none of the TDI-sensitive asthmatic workers had specific IgE antibody. One of the TDI-sensitive asthmatic workers showed a negative result on the initial methacholine bronchial challenge test, but bronchial hyperresponsiveness developed after the TDI challenge. It was suggested that TDI-sensitive asthma was noted in three (13%) of 23 exposed workers and that asymptomatic workers could have high specific IgE antibody. Measurement of the changes in bronchial hyperresponsiveness after the TDI challenge could be helpful to diagnose TDI-sensitive asthma.

The diurnal variation in peak expiratory flow rate (PEFR) was studied in 26 mixers from eight factories making polyurethane foam, who were exposed to toluene diisocyanate (TDI), and 26 unexposed controls matched for age, race, and smoking. They were all men. The mean diurnal variation in PEFR of the mixers was 6.2%, which was significantly higher than the 4.3% for controls. Six mixers had a diurnal variation of greater than 15% on at least one day compared with none among the controls. There was, however, no overt cause of occupational asthma. All but one of the 24 environmental samples taken exceeded the short term exposure limit of 0.02 ppm for TDI. This accounted for the high prevalence (50%) of irritative symptoms such as cough and eye irritation. Forced expiratory volume in one second (FEV1) and FEV1/forced vital capacity (FVC) (%) was negatively correlated with duration of exposure to TDI. Foam workers may still have high exposure to TDI, high prevalence of irritative symptoms, increased diurnal variation in PEFR and evidence of chronic airway obstruction, particularly in those with greater than or equal to 10 years of exposure.

Occupational asthma induced by toluene diisocyanate (TDI) shares several features with allergic asthma, but the mechanism of action of TDI is poorly understood. Ten sensitised subjects, previously shown to develop a dual or late asthmatic reaction after inhaling TDI were examined. In each subject, forced expiratory volume in one second (FEV1) was measured and venous blood was taken before, and 30 minutes and eight, 24, 48, and 72 hours after exposure to TDI (0.005-0.015 ppm for 10-30 minutes). Filtered air was used as a control. Differential leucocyte counts were determined and phenotypic analysis was performed by immunofluorescence on mononuclear cells using monoclonal antibodies (anti-CD3, anti-CD4, anti-CD8, and anti-HLA-DR). Five subjects developed a dual asthmatic reaction and five had a late reaction. Percentage of CD8 positive lymphocytes increased significantly eight hours after exposure to TDI (from 27 +/- 3 (SEM) % to 42.1 +/- 5%) in the subjects with an isolated late reaction. A delayed significant further increase in suppressor/cytotoxic T lymphocytes was seen in seven of the 10 subjects 48 hours after active exposure (from 27 +/- 2% to 42 +/- 4.8%), irrespective of the type of asthmatic reaction developed after exposure to TDI. Eosinophil percentage increased from 2.5% +/- 1.0 to 6.4% +/- 1.2 24 hours after exposure to TDI and the increase was sustained for up to 48 hours (4.7 +/- 1.1%). No significant variations of FEV1 or cell percentages were seen in the controls. In conclusion, the events triggered by exposure to TDI in sensitised subjects included changes in lung function and systemic effects which lasted longer than bonchoconstriction and concerned suppressor/cytotoxic lymphocytes and eosinophils. These results suggest that TDI induced late asthmatic reactions may be associated with an immunological response to TDI or to its products.

Current asthma is often diagnostically excluded by the presence of normal bronchial responsiveness. We report on a TDI-induced occupational asthma patient with normal bronchial responsiveness. He had suffered from shortness of breath during and after TDI exposure for several months. His initial methacholine bronchial challenge test showed a negative response. The bronchoprovacation test with TDI showed an isolated immediate bronchoconstriction. The following methacholine bronchial challenge tests revealed that the bronchial hyperresponsiveness developed seven hours after the TDI challenge (methacholine PC20:5.1 mg/ml), progressed up until 24 hours, and returned to normal on the seventh day. This case provides evidence that the response of the airway to TDI may not always be accompanied by bronchial hyperresponsiveness to methacholine. Screening programs utilizing methacholine challenges may not always identify TDI-sensitized asthmatic workers.

A cross-sectional study on suberosis was conducted to determine the prevalence of respiratory symptoms and the level of pulmonary function, and their relationships within job categories of exposure to cork dust, toluene diisocyanate (TDI) resin bonding and conidia, among cork workers. Exposure-response relationships, with confounders taken into account, showed specific associations between cork dust and chronic bronchitis, TDI and asthma, and conidia and symptoms of hypersensitivity pneumonitis. Workers exposed to these risk factors had reduced mean spirometric values. A significant correlation between a decrease in pulmonary function and length of exposure was found for the workers exposed to cork dust. These results strongly suggest that suberosis, as hitherto described, might in fact be comprised of three different diseases with different etiologic risk factors, ie, respiratory hypersensitivity from exposure to conidia, asthma from exposure to TDI, and chronic obstructive pulmonary disease from exposure cork dust.

Two police officers developed asthma like illness after a single but prolonged exposure to toluene diisocyanate (TDI) by being in the immediate vicinity of a tank car that had overturned on a highway. One officer experienced upper and lower respiratory tract symptoms with chest tightness about 4.5 hours after initial exposure. Shortness of breath, cough, and wheezing were noted the following day. The other experienced symptoms immediately on exposure, developed shortness of breath 20 minutes later, and presented with wheezing four hours after that. Follow up examinations over seven years showed persistence of respiratory symptoms and continuation of airway hyperreactivity requiring treatment.

An outbreak of occupational asthma, of unknown cause and extent, was detected in a steel coating plant. In 1979 a cross-sectional study which defined occupational asthma in terms of respiratory symptoms detected 21 people with suggestive symptoms among the 221 studied. They all worked in the coating shop, but the plastic coatings used at the plant contained many potential sensitising agents that might have caused the asthma. All 21 developed their symptoms after 1971, and it was found that in this year a supplier had modified a coating allowing, at the temperatures used in the process, toluene di-isocyanate to be liberated. Two of the symptomatic subjects were tested by inhalation of the isocyanate and showed asthmatic reactions and other subjects were found to have asthma related to periods spent at work by records of peak expiratory flow rate. Over half the 21 had a symptom free latent period after first exposure of three years or less, a pattern not seen in other subjects with respiratory symptoms. After the isocyanate had been removed from the process 17 of these subjects became asymptomatic or improved, a greater proportion than in other subjects with respiratory symptoms.

A prospective study of workers engaged in the manufacture of tolylene di-isocyanate (TDI) was carried out over nine years. The study was in two parts: (1) assessment of the symptoms and ventilatory function of men working on the plants who did not complain of respiratory symptoms; (2) assessment of the long-term effects in men who were removed from the plants because of respiratory symptoms. Use of the MRC Questionnaire on Respiratory Symptoms in a group of 76 TDI workers showed no significant differences in symptoms compared with 76 control subjects. Annual lung function tests were carried out on 180 asymptomatic men with possible exposure to TDI. The relationship of the forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) to the height, age, and duration of exposure was examined by linear regression analysis. The equations formulated did not differ significantly from those calculated for non-TDI exposed subjects. Thus exposure to very small concentrations of TDI does not necessarily cause symptoms or a drop in ventilatory capacity. Forty-six TDI workers who had developed symptoms reported more long-term symptoms than a comparable number of controls. The difference was significant at the 1% level. Ventilation test records of 61 TDI workers who had developed symptoms were available since it was possible to use the records of men who had left the company. The lung function of this group was matched against predicted figures obtained from a control group of 608 subjects living in the same area as the exposed group but not exposed to TDI. It was found that the FEV1 of the affected men was on average 267 ml lower than predicted, and the FVC 269 ml lower. These findings are confirmed by examination of the indivdual records of a futher 20 men.