TDI Exposure Research Articles

Distinct roles of PI3Kδ and PI3Kγ in a toluene diisocyanate-induced murine asthma model

TDI-induced asthma is characterized by neutrophil-dominated airway inflammation and often associated with poor responsiveness to steroid treatment. Both PI3Kδ and PI3Kγ have been demonstrated to play important proinflammatory roles in ovalbumin-induced asthma. We’ve already reported that blocking pan PI3K effectively attenuated TDI-induced allergic airway inflammation. Yet the specific functions of PI3Kδ and PI3Kγ in TDI-induced asthma are still unclear. Male BALB/c mice were first dermally sensitized and then challenged with TDI to generate an asthma model. Sellective inhibitors of PI3Kδ (IC-87114, AMG319) and PI3Kγ (AS252424, AS605240) were respectively given to the mice after each airway challenge. Treatment with IC-87114 or AMG319 after TDI exposure led to significantly decreased airway hyperresponsiveness (AHR), less neutrophil and eosinophil accumulation, attenuated airway smooth muscle (ASM) thickening, less M1 and M2 macrophages in lung, as well as lower levels of IL-4, IL-5, IL-6 and IL-18 in bronchoalveolar lavage fluid (BALF) and recovered IL-10 production. While mice treated with AS252424 or AS605240 had increased AHR, more severe ASM thickening, larger numbers of neutrophils and eosinophils, more M1 but less M2 macrophages, and higher BALF levels of IL-4, IL-5, IL-6, IL-10, IL-12, IL-18 when compared with those treated with vehicle. These data revealed that pharmacological inhibition of PI3Kδ attenuates TDI-induced airway inflammation while PI3Kγ inhibition exacerbates TDI-induced asthma, indicating distinct biological functions of PI3Kδ and PI3Kγ in TDI-induced asthma.

IL-4 and IL-5 Secretions Predominate in the Airways of Wistar Rats Exposed to toluene Diisocyanate Vapor

Objectives We established a Wistar rat model of asthma caused by TDI exposure, and investigated the relationship between TDI exposure concentrations and respiratory hypersensitivity, airway inflamm...

Inception cohort study of workers exposed to toluene diisocyanate at a polyurethane foam factory: initial one-year follow-up.

Isocyanates are one of the most commonly reported causes of occupational asthma; however, the risks of developing isocyanate asthma in modern production facilities remain poorly defined. We evaluated TDI exposure and respiratory health among an inception cohort of workers during their first year of employment at a new polyurethane foam production factory. Forty-nine newly hired workers were evaluated pre-employment, 6-months, and 12-months post-employment through questionnaire, spirometry, and TDI-specific serology. Airborne TDI levels were monitored by fixed-point air sampling and limited personal sampling. Qualitative surface SWYPE™ tests were performed to evaluate potential sources of skin exposure. Airborne TDI levels overall were low; over 90% of fixed-point air measurements were below the limit of detection (0.1 ppb). Over the first year of employment, 12 of the 49 original workers (24.5%) were lost to follow-up, no additional workers were enrolled, and seven of the 49 original workers (14.2%) developed either new asthma symptoms (N = 3), TDI-specific IgG (N = 1), new airflow obstruction (N = 1) and/or a decline in FEV1 ≥ 15% (N = 3), findings that could indicate TDI-related health effects. The prevalence of current asthma symptoms was significantly higher in the workers lost to follow-up compared to those who completed the 12-month follow-up (25% vs. 2.7%; P = 0.04). The findings suggest possible early TDI-related health effects in a modern polyurethane production plant. These findings also highlight the need for further longitudinal evaluation of these workers and the challenges of studying workers at risk for isocyanate asthma.

Vitamin E Attenuates the Degree of Histopathological Lung Damage Following Toluene Diisocyanate Administration in Rats

In the current study we used a rat model of bronchial hyperreactivity induced by intranasal administration of toluene diisocyanate TDI in Wistar rats. Four experimental groups of were formed: TDI administration (TDI), control - administration of ethyl acetate (C), administration of vitamin E and TDI (TDI+E) administration of ethyl acetate and vitamin E (M+E). Our aim was to evaluate the efficiency of Vitamin E in attenuating the histopathological lesions induced by TDI in the lungs. The presence of anti-TDI IgE antibodies was demonstrated through the passive cutaneous anaphylaxis assay. Histopathological analysis of lung changes was performed by comparing the degree of peribronchiolar inflammation and goblet cell percentage between the different groups studied. Our results showed that rats sensitized to TDI presented severe inflammation of the airways, eosinophilic infiltration was present in the mid bronchi, and not limited to the central airways. Bronchial associated lymphoid tissue (BALT) hyperplasia and perivascular lymphoplasmacytic infiltrate were also identified, which is evidence of chronic inflammation of the airways. These changes were consistent with the inflammatory symptoms of bronchial hyper-reactivity observed which are similar to those in asthma patients. Vitamin E administration resulted in a statistical significant reduction in the percentage of goblet cells in the bronchial mucosa associated with a decrease inflammatory semiquantitative score, compared to the TDI group, but without statistical significance. Our data suggest that administration of vitamin E could be beneficial in attenuating the effects of TDI in individuals that develop bronchial asthma following TDI exposure.

Determination of isocyanate specific albumin-adducts in workers exposed to toluene diisocyanates

Toluene diisocyanates (2,4-TDI and 2,6-TDI) are important intermediates in the chemical industry. Among the main damages after low levels of TDI exposure are lung sensitization and asthma. It is therefore necessary to have sensitive and specific methods to monitor isocyanate exposure of workers. Urinary metabolites or protein adducts have been used as biomarkers in workers exposed to TDI. However, with these methods it was not possible to determine if the biomarkers result from exposure to TDI or to the corresponding toluene diamines (TDA). This work presents a new procedure for the determination of isocyanate-specific albumin adducts. Isotope dilution mass spectrometry was used to measure the adducts in albumin present in workers exposed to TDI. 2,4-TDI and 2,6-TDI formed adducts with lysine: Nϵ-[({3-amino-4-methylphenyl}amino)carbonyl]-lysine, Nϵ-[({5-amino-2-methylphenyl}amino)carbonyl]-lysine, and Nϵ- [({3-amino-2-methylphenyl}amino)carbonyl]-lysine. In future studies, this new method can be applied to measure TDI-exposures in workers.

Protein adducts as biomarkers of exposure to aromatic diisocyanates in workers manufacturing polyurethane (PUR) foam

This work was undertaken to investigate the usefulness of diisocyanate-related protein adducts in blood samples as biomarkers of occupational exposure to toluene diisocyanate (TDI; 2,4- and 2,6-isomers) and 4,4'-methylenediphenyl diisocyanate (MDI). Quantification of adducts as toluene diamines (TDAs) and methylenedianiline (MDA) was performed on perfluoroacylated derivatives by gas chromatography-mass spectrometry (GC-MS/MS) in negative chemical ionisation mode. TDI-derived adducts were found in 77% of plasma and in 59% of globin samples from exposed workers manufacturing flexible polyurethane foam. The plasma levels ranged from 0.003 to 0.58 nmol mL(-1) and those in globin from 0.012 to 0.33 nmol g(-1). The 2,6-isomer amounted to about two-thirds of the sum concentration of TDA isomers. MDI-derived adducts were detected in 3.5% of plasma and in 7% of globin samples from exposed workers manufacturing rigid polyurethane foam. A good correlation was found between the sum of TDA isomers in urine and that in plasma. The relationship between globin adducts and urinary metabolites was ambiguous. Monitoring TDI-derived TDA in plasma thus appears to be an appropriate method for assessing occupational exposure. Contrary to TDI exposure, adducts in plasma or globin were not useful in assessing workers' exposure to MDI. An important outcome of the study was that no amine-related adducts were detected in globin samples from TDI- or MDI-exposed workers, alleviating concerns that TDI or MDI might pose a carcinogenic hazard. Further studies are nevertheless required to judge whether diisocyanates per se could be such a hazard.

Tissue Transglutaminase Can Be Involved in Airway Inflammation of Toluene Diisocyanate-Induced Occupational Asthma

This study was conducted to evaluate whether tissue transglutaminase (tTG) may be involved in airway inflammation of toluene diisocyanate-induced occupational asthma (TDI-OA). We enrolled 93 patients with TDI-OA, 177 asymptomatic exposed subjects, 43 patients with allergic asthma, and 70 unexposed normal controls. The prevalence of serum immunoglobulin G (IgG) to tTG in the TDI-OA group (20.2%) was significantly higher than that in the three other groups (P < 0.001). TDI-OA patients with serum IgG to tTG had significantly lower methacholine PC(20) values (P < 0.02) and significantly higher prevalence of specific immunoglobulin E to vapor type TDI-human serum albumin conjugate (P < 0.01; r(2) = 0.411, P < 0.05). TDI exposure could increase tTG activity via reactive oxygen species (ROS) production, which was found to cross-link with cytokeratin 19 on immunoblot analysis. Therefore, TDI exposure may activate tTG via ROS-mediated mechanism in the airway epithelium leading to persistent airway inflammation in TDI-OA patients.

Health Information in Material Safety Data Sheets for a Chemical Which Causes Asthma

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.

Health information in material safety data sheets for a chemical which causes asthma.

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). We reviewed a random sample of 61 MSDSs for TDI products produced by 30 manufacturers. 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%). 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.

Meeting report

Meeting report

Inhalation of Toluene Diisocyanate Is Associated with Increased Production of Nitric Oxide by Rat Bronchoalveolar Lavage Cells

Isocyanates are used commercially, particularly in the manufacture of polyurethane coatings and foam. These compounds can pose an occupational health hazard since there is a risk of respiratory disease following isocyanate exposure. The purpose of the present study was to investigate whether a single, sublethal isocyanate inhalation is associated with increased production of the free radical nitric oxide (NO). Mature male Sprague–Dawley rats were exposed to air or toluene diisocyanate (TDI; 2 ppm) for 4 hr. Indices of pulmonary function were assessed before and after exposure to TDI fumes. At 20 hr postexposure, bronchoalveolar lavage cells (BALC) and fluid were harvested. NO synthase (NOS)-dependent reactive species production by alveolar macrophages was assessed by determiningNω-nitro-l-arginine methyl ester-inhibitable chemiluminescence following stimulation with unopsonized zymosan. Northern blot analysis was used to index inducible NOS mRNA levels in BALC, while nitrite and nitrate (NOx) levels were measured to determine NOxlevels in the lavage fluid and the production of NO by cultured adherent BALC was indexed by measuring nitrite levels. Exposure to aerosolized TDI was associated with an increase in the number of alveolar macrophages, lymphocytes, and polymorphonuclear leukocytes harvested by bronchoalveolar lavage, relative to that from air-exposed rats. NOxlevels in the lavage fluid and NOS-dependent production of reactive species by alveolar macrophages were increased following TDI exposure. In addition, inducible NO production by BALC (i.e., mRNA levels and nitrite levels in BALC conditioned media) was elevated following TDI treatment. These findings indicate that pulmonary inflammatory responses induced by TDI exposure are associated with increases in inducible NO production. Therefore, the potential role of NO in the initial pulmonary response to TDI exposure warrants further investigation.

Setting acceptable exposure limits for toluene diisocyanate on the basis of different airway effects observed in animals

Little epidemiological data are available to enable the development of a dose-response relationship for the effects of isocyanates, powerful sensitizing agents in humans. Remarkably, most classes of effects have been reproduced in some animal models and parallels between animals and man are impressive. In this paper animal data concerning different effects of TDI on the respiratory system were used to calculate acceptable exposure levels for humans. Animal data on respiratory irritation, sensitization, airway hyperresponsiveness, and gradual loss of pulmonary function are discussed. Two different approaches for extrapolation to man were applied to these data. The two models used to extrapolate animal data to man gave similar results. The extrapolations lead to acceptable exposure varying from 6 to 46 ppb. Most international acceptable levels for occupational airborne TDI exposure are within this range. Interestingly, the lowest standard is obtained using the data on respiratory irritation. It is, however, concluded that there is no critical (adverse) effect to define acceptable toluene diisocyanate exposure since the data were obtained from different studies and the accuracy of the applied extrapolation approach might depend on the biological effect considered. We recommend prior testing of "alternative" diisocyanates in one of the animal models described and calibrated for TDI.

Australian TDI workers' sera assayed for IgE against a p-tolyl-isocyanate-human serum albumin conjugate

Sera of 91 people were assayed for IgE which bound to a p-tolyl-isocyanate-human serum albumin conjugate. The sera came from 20 blood donors, 70 factory workers, and 1 casualty patient. Three factory workers had abnormally high assay values in association with active TDI disease, as indicated by asthma or measurement showing chronic airway obstruction. One factory worker had an exceptionally high assay value without clinical evidence of TDI disease. Hapten inhibition studies are reported; they indicate possible heterogeneity of the IgE detected by the assay. Brief clinical histories of some cases of TDI disease are given, suggesting that TDI disease can include susceptibility to asthma triggered by events other than TDI exposure.

Diverse profiles of immunoreactivity in toluene diisocyanate (TDI) asthma.

Possible immunoreactivity to chemically well-characterized mono- and diisocyanate protein conjugates was reevaluated in 15 workers with TDI asthma and 17 normal (nonexposed) volunteers. Lymphocytes of nine sensitive workers were incubated with TDI human serum albumin (HSA) conjugates. Leucocyte inhibitory factor (LIF) was produced. Leucocyte inhibitory factor was also induced by hexamethylene diisocyanate (HDI) protein conjugates in four of these workers who had no prior history of exposure to HDI. Disappearance of TDI- and HDI-induced LIF was noted in several sensitive workers who were removed from further TDI exposure. Three LIF-positive workers also demonstrated positive intracutaneous reactivity to TDI-HSA. One workers had a markedly positive RAST (25.5% binding) to a monofunctional (p-tolyl isocyanate) protein reagent. These studies suggest that isocyanates have the potential for eliciting heterogeneous immune responses in certain subpopulations of exposed workers. Continued contact with isocyanates may be necessary for maintenance of specific immunity. Possible cross reactivity between TDI and HDI may be determined by new antigenic sites created by isocyanate protein interactions.

A Retrospective Study of Clinical, Physiologic and Immunologic Changes in Workers Exposed to Toluene Diisocyanate

A retrospective study was made of workers in a toluene disocyanate plant using an immunologic test procedure developed at the NIOSH laboratories. Case histories of 32 workers in seven response groupings are presented. Sensitization was found to correlate with the frequency and severity of significant exposures to TDI. Immunologic changes producing tolerance to TDI exposure also resulted in negative response to the antigen challenge tests. Some individuals exposed to TDI may have protective antibodies but still experience bronchoconstriction.