Isocyanate-induced Occupational Asthma Research Articles

Is Isocyanate Exposure and Occupational Asthma Still a Major Occupational Health Concern? Systematic Literature Review.

Isocyanate, whose disease-inducing mechanism is poorly understood, with poor prognosis, is widely used. Asthma is the most frequent manifestation of prolonged exposure. We assessed the evolution of the incidence of isocyanate-induced occupational asthma over time. PubMed and Cochrane databases were systematically searched for studies published since 1990 that assessed the relationship between occupational exposure to isocyanates and asthma. We identified 39 studies: five retrospective cohort studies, seven prospective cohort studies, three of which were inception cohorts), seven observational cross-sectional studies, five literature reviews, two case series, and 13 registry studies. The incidence of occupational asthma secondary to isocyanate exposure has decreased from more than 5% in the early 1990s to 0.9% in 2017 in the United States. Despite the wide use of optimal collective and individual protection measures, the risk of occupational asthma has stabilized. Occupational asthma risk can be assessed with good sensitivity using self-questionnaires and pulmonary function tests. Occupational avoidance should be implemented as soon as possible after the first symptoms appear because the prognosis becomes increasingly poor with the persistence of exposure. It is now necessary to study specifically cutaneous sensitization to isocyanates and to define what protective equipment is effective against this mode of exposure.

Fractional Exhaled Nitric Oxide (FeNO) in the Screening and Diagnosis Work-Up of Occupational Asthma

FeNO is a simple non-invasive tool used as a surrogate marker of airway inflammation in the management of asthma. FeNO has been assessed in several populations of workers exposed to high- and low-molecular weight agents. However, there are many confounding factors to consider in the interpretation of FeNO. As such, its use in the investigation of occupational asthma (OA) has yielded inconsistent results. In screening studies of OA to high molecular weight (HMW) agents, an increase of FeNO over time has been associated with the development of bronchial hyperresponsiveness (BHR). When used in the investigation of OA, increases in FeNO show high positive predictive values for a positive specific inhalation challenge (SIC) to HMW agents. Subjects with high specific IgE to their workplace allergens seem to present higher increases in FeNO than subjects without specific IgE to causal agent. Changes in FeNO have less frequently been observed in studies of OA to low molecular weight (LMW) agents than OA to HMW agents, except for isocyanate-induced OA. Cluster analyses of patients exposed to various HMW and LMW agents have documented significant increases of FeNO in clusters of patients with OA to HMW agents, but not LMW. Recent studies have provided useful information for improving our understanding of the pathophysiology of exhaled NO in OA despite the previously reported conflicting results. Future studies are still required to clarify its role in the screening, investigation, and management of OA.

Role of vitamin D-binding protein in isocyanate-induced occupational asthma

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

Occupational exposure to toluene diisocyanate and neutrophilic bronchitis without asthma

Context. Isocyanates represent a leading cause of occupational asthma, and sputum neutrophilia or eosinophilia has been described in subjects with isocyanate-induced occupational asthma after exposure to these chemicals. One case of non-asthmatic eosinophilic bronchitis due to methylene diphenil isocyanates has been reported, but a similar condition in the instance of neutrophilic bronchial inflammation has never been described. Case details. We report a 34-year-old woman, who, 18 months after beginning work in a plastic industry, reported the onset of dry cough at work. Spirometry was normal, reversibility and methacholine challenge tests were negative. A specific inhalation challenge with toluene diisocyanate elicited dry cough without significant changes in respiratory function. Sputum induction showed a post-challenge neutrophil increase. Discussion. The results of our case suggest that the occurrence of a neutrophilic bronchial inflammation without the functional characteristics of occupational asthma as a consequence of exposure to toluene diisocyanate may also be considered, suggesting a diagnosis of occupational non-asthmatic neutrophilic bronchitis.

Vit. D Binding Protein As A Diagnostic Marker For Isocyanate-induced Occupational Asthma

RATIONALE: Considering poor prognosis of isocyanate-induced occupational asthma (OA), it is essential to develop a relevant serologic marker for identifying susceptible subjects among exposed workers. We aimed to identify a new biomarker using a proteomic approach which was validated in sera of isocyanate exposed workers.

A case of isocyanate-induced asthma possibly complicated by food allergy after peanut consumption: a case report

BackgroundIsocyanates are extensively used in the manufacture of polyurethane foams, plastics, coatings or adhesives. They are a major cause of occupational asthma in a proportion of exposed workers. Recent findings in animal models have demonstrated that isocyanate-induced asthma does not always represent an IgE-mediated sensitization, but still a mixed profile of CD4+ Th1 and TH2, as well as a CD8+ immune response. Despite immunologic similarities between this pathology and IgE-mediated food allergies, this co-morbidity is rarely reported.Case presentationA 50-year old man employed as vehicle body painter, for 8 years complained about breathlessness, wheezing, sneezing, nasal obstruction and excessive production of mucus during the use of DuPont Refinish Centari Tintings – an acrylic enamel tint. Symptoms occurred 15–20 minutes after workplace exposure and usually persisted until evening, or at times, up to two consecutive days. The above mentioned symptoms were associated with a decrease of lung functions parameters. The use of inhaled adrenergic bronchio-dilatators and steroids relived the symptoms.In addition, three years ago he developed an anaphylactic reaction due to peanut consumption, experiencing urticaria, angioedema and airway obstruction. He was successfully treated in the hospital. Later, the subject exhibited labial itching, as well as orbital and perioral angioedema, 20 minutes after stationary performance of challenge test with peanuts.Evaluating the reported data, this process might be developed rather due to induction of a TH2 profile, because in both cases have occurred IgE-mediated symptoms. A less plausible mechanism could be the presence of isocyanates in peanuts due to a probable contamination by pesticides resulting in an allergic reaction after "consumption" of di-isocyanate as long as the isocyanate contamination of peanuts has not been proven.ConclusionDespite the lack of relevant laboratory findings, this might be the first case of isocyanate-induced occupational asthma described in a patient who developed peanut allergy symptoms later in his life. However, in order to take further suitable precautions, further studies are necessary to elucidate the questions posed in this report.

Impairment in Workers With Isocyanate-Induced Occupational Asthma and Removed From Exposure in the Province of Qu??bec Between 1985 and 2002

The objective of this project was to assess both the outcome for patients diagnosed with proven isocyanate-induced occupational asthma (IIOA) by specific inhalation challenge (SIC) and the functional impairment, 2 years after cessation of exposure to isocyanates, using the compensation insurance scale proposed in the province of Quebec. We used a retrospective cohort of 233 patients diagnosed in the province of Quebec between 1985 and 2002 and randomly chose 105 of those patients. We kept 89 subjects with complete data at T0 (the time of diagnosis) and 79 were reevaluated at T2, approximately 2 years after their removal from exposure, for final impairment-disability assessment. At each evaluation (T0 and T2), a clinical examination and lung function tests, including spirometry and methacholine challenge, were performed. At T2, 79 of 89 patients were reassessed (89%). The remaining patients were lost to follow up (8) or too unstable to be reassessed for final impairment-disability settlement (2). No statistical difference was observed for spirometry data and antiasthmatic medication use between T0 and T2 (P = 0.11). At T2, 73% of patients were still using short-acting beta2 agonists and 39% inhaled glucocorticoids. A forced expiratory volume in 1 second variation of +/-10% from T0 to T2 occurred in 31 subjects (40%). Forced expiratory volume in 1 second worsened in 14 (18%), remained significantly unchanged in 51 (64%), and improved in 14 (18%). Nonspecific bronchial hyperresponsiveness (BHR) improved in significantly in 19 (24%); the others remained unchanged. Both were not associated with smoking status (P > 0.05). Nonspecific BHR was normalized in nine of 79 (11%) patients. Clinical remission occurred in only four (5%) subjects. The mean impairment-disability score was 21% +/- 13% at 2 years according to the scale used by the Workers' Compensation Board. These results show the generally poor medical outcome of IIOA and suggest the importance of early detection and withdrawal of the workers from exposure to isocyanates. They also emphasize the need for medical surveillance program and adequate treatment of patients with IIOA.

Isocyanates, polyurethane and childhood asthma

Isocyanates are the most prominent and well-studied cause of occupational asthma. Over the decades, airborne isocyanates have been regulated to extremely low levels in the workplace, some of the lowest for any organic compound. Yet the incidence of isocyanate-induced occupational asthma remains high and the role of dermal exposure in disease etiology is only slowly being recognized. Almost completely overlooked is the potential relationship between isocyanates in consumer products and increasing prevalence of asthma in the general population, especially children. The steady rise in asthma over the past decades points strongly to a potential role of environmental exposures in its development. Imbalances in the immune system favoring respiratory diseases have been linked to biological and chemical stressor exposures early in life. Evidence for the presence of isocyanates in many polyurethane-containing materials, especially polyurethane foams, is presented as a possible contributor to the increase in asthma. Polyurethane foam is ubiquitous in western societies and used in bedding, furniture, automobile seats, footwear, etc., and numerous medical materials. Theoretical, epidemiologic, experimental and clinical evidence of a role for isocyanates and polyurethanes in the genesis of non-occupational allergy and respiratory disease are reviewed. These data all point to the urgent need for additional research on the links between isocyanates, polyurethanes and the role of the skin in non-occupational asthma.

Isocyanate-induced occupational asthma in far-east Asia: pathogenesis to prognosis.

Clinical & Experimental AllergyVolume 32, Issue 2 p. 198-204 Isocyanate-induced occupational asthma in far-east Asia: pathogenesis to prognosis H.-S. Park, Corresponding Author H.-S. Park Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon,Hae-Sim Park, Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Paldalgu, Wonchodong, San-5, Suwon, Korea. E-mail: [email protected]Search for more papers by this authorS.-H. Cho, S.-H. Cho Department of Medicine, Seoul National University, andSearch for more papers by this authorC.-S. Hong, C.-S. Hong Yonsei University Medical College, Seoul, KoreaSearch for more papers by this authorY.-Y. Kim, Y.-Y. Kim Department of Medicine, Seoul National University, andSearch for more papers by this author H.-S. Park, Corresponding Author H.-S. Park Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon,Hae-Sim Park, Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Paldalgu, Wonchodong, San-5, Suwon, Korea. E-mail: [email protected]Search for more papers by this authorS.-H. Cho, S.-H. Cho Department of Medicine, Seoul National University, andSearch for more papers by this authorC.-S. Hong, C.-S. Hong Yonsei University Medical College, Seoul, KoreaSearch for more papers by this authorY.-Y. Kim, Y.-Y. Kim Department of Medicine, Seoul National University, andSearch for more papers by this author First published: 08 April 2002 https://doi.org/10.1046/j.1365-2222.2002.01290.xCitations: 24Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume32, Issue2February 2002Pages 198-204 RelatedInformation

Meeting report

Meeting report

Specific IgE to isocyanates: A useful diagnostic role in occupational asthma

Background: Isocyanates are the most frequent cause of occupational asthma in industrialized countries. Objective: We sought to investigate the utility of specific IgE measurement in the diagnosis of isocyanate-induced asthma. Methods: Fifty-eight of 101 patients referred for investigation were diagnosed as having isocyanate-induced occupational asthma by means of history, serial peak flow records, and bronchial provocation tests. Specific IgE antibodies to toluene diisocyanate:human serum albumin (HSA), diphenylmethane diisocyanate:HSA, and hexamethylene diisocyanate:HSA were measured in all patients by Phadebas RAST. Results: Twenty patients had a RAST ratio of 2 or greater to at least one isocyanate. Thirteen (28%) of the 46 patients with a positive provocation test response had a RAST ratio of 2 or greater, and nine (20%) had a RAST ratio of 3 or greater. Raising the RAST cut-off from 2 or greater to 3 or greater reduced its sensitivity but increased the specificity of the test to 100%. RAST measurement was most likely to be positive within 30 days of exposure. Serial measurements suggested that the half-life of the IgE antibodies was approximately 6 months. Evidence of cross-reactivity between isocyanate RAST responses was found in eight subjects. Conclusion: Specific IgE to isocyanates is a more specific than sensitive index of occupational asthma. With a RAST score of 3 or greater, it is wholly specific and therefore diagnostic of isocyanate-induced asthma. The sensitivity of specific IgE measurement is highest when blood is taken less than 30 days from last exposure, which is consistent with the observed half-life.(J Allergy Clin Immunol 1998;101:709-15.)

Mechanisms of occupational asthma induced by isocyanates

Isocyanates are some of the most important low molecular weight chemicals associated with occupational asthma. These compounds are often volatile and they are highly reactive on mucous membranes, especially the conjunctivae and respiratory tract. Despite numerous data derived from experimental and clinical investigations, there is no agreement concerning the real mechanisms involved in isocyanate-induced occupational asthma. In fact, the cause of occupational asthma is multifactorial. The aim of this paper is to review the involved physiological causes of isocyanate-induced asthma; the main mechanisms are immunological, pharmacological and/or irritative.

Assessment of the relationship between isocyanate exposure levels and occupational asthma.

As part of a previous study, we identified Ontario cases of isocyanate-induced occupational asthma (OA) and the companies at which they worked. The Ontario Ministry of Labour maintained a computerized database including isocyanate air sampling determinations conducted by the Ministry. Within this database, we compared levels of isocyanate concentrations measured at 20 case companies [with compensated isocyanate asthma (OA) claims] with 203 noncase companies, based on air samples collected during the same 4-year period during which the OA claims arose. The proportion of case companies that were ever recorded as having a measured ambient isocyanate concentration of > or = 0.005 ppm was greater than that for noncase companies, for TDI users (43% vs 22%), and for MDI users (40% vs 27%). This reached conventional significance when combined across companies and isocyanate types (50% vs 25%; P < 0.05). This provides some evidence that facilities having OA claims have higher isocyanate exposures than do those without claims.

Prognostic factors for toluene diisocyanate‐induced occupational asthma after removal from exposure

The outcome of isocyanate-induced occupational asthma remains to be further defined. There have been few studies on the role of specific antibodies in prognosis of toluene diisocyanate (TDI) induced occupational asthma. Moreover, to the best of our knowledge, there have been no studies on the improvement pattern of airway hyperresponsiveness (AH). We analysed the prognostic factors that affected the outcome of 35 toluene diisocyanate-induced occupational asthma. To define clinical and laboratory parameters predicting favourable prognosis for TDI-induced occupational asthma. After confirmation of bronchial sensitivity by TDI bronchoprovocation test (BPT), 35 patients were recommended to avoid exposure to TDI; they were also given anti-asthmatic medications including inhaled steroids and monitored for 2 years. Seventeen (49%) recovered completely with disappearance of airway hyperresponsiveness (AH) to methacholine during the follow-up period (mean duration: 12 months, range of 3-30 months). Eleven (31%) showed a significant improvement in AH for first year, which improvement stabilized in the next year with mild symptoms. Seven (20%) patients did not show any evidence of improvement in AH and had persistent symptoms. Favourable prognosis was associated with a short duration of asthmatic symptoms before diagnosis (P < 0.05), immediate cessation of exposure after diagnosis (P < 0.05), milder degree of AH at diagnosis (P < 0.05), and the presence of specific IgE antibodies to TDI-human serum albumin conjugate (0.05 < P < 0.1). No association was found with atopic and smoking status, age, exposure duration, or length of latent period (P > 0.05). These data suggest that early detection of TDI-induced asthma and immediate cessation of exposure are important factors for a favourable prognosis.

Isocyanate-induced occupational asthma: challenge and immunologic studies.

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.

262 Prognostic factors for the isocyanate-induced occupational asthma(OA)

262 Prognostic factors for the isocyanate-induced occupational asthma(OA)

Isocyanate-induced occupational asthma: immunologic and challenge studies.

Background: Isocyanate is the most significant cause of occupational asthma in this country. The mechanism of isocyanate induced bronchoconstriction is unclear. Subjects and Method: To observe its immunologic and clinical findings, we performed methacholine bronchial challenge test (MBCT), toluene diisocyanate (TDI)-bronchoprovocation test (BPT) and RAST to TDI-, diphenylmethane diisocyanate (MDI)-, and hexamethylene diisocyanate (HDI)-human serum albumin (HSA) conjugate in 22 isocyanate-sensitive asthmatic workers. Results: BPT revealed early (11), dual (5), and late only (6) asthmatic responses. Their latent period ranged from 3 to 120 months (mean:45.9 months). Three cases (13.6%)showed a negative response on initial MBCT, but following MBeT performed 24 hours after TDI-BPT revealed the development of airway hyperresponsivenss. Twelve (54.5%) workers had increased specific IgE to TDI-HSA, seven (31.8%) had to MDI-HSA, and nine (40.9%) had to HDI-HSA conjugate. The prevalence of specific IgE was not associated with latent period, type of asthmatic responses, smoking, and atopic status. After 3 months' avoidance from workplace, airway hyperresponsiveness was improved in 10 (38.3%), among 12 followed cases. Conclusion: It is suggested that isocyanate can induce IgE-mediated bronchoconstriction in 59.1% of isocyanate-sensitive asthmatic workers. Isocyanate-induced asthma can occur even though MBeT showed a negative result, and measurement of the changes of airway hyperresponsivenss after isocyanate-BPT could be helpful to diagnose isocyanate-sensitive asthma.

Activated T-lymphocytes and eosinophils in the bronchial mucosa in isocyanate-induced asthma

We have studied the phenotype and activation status of leukocytes in the bronchial mucosa in patients with isocyanate-induced asthma. Fiberoptic bronchial biopsy specimens were obtained from nine subjects with occupational (five toluene- and four methylene diisocyanate-sensitive) asthma, 10 subjects with extrinsic asthma, and 12 nonatopic healthy control subjects. Bronchial biopsy specimens were examined by immunohistology with a panel of monoclonal antibodies and the alkaline phosphatase—antialkaline phosphatase method. There was a significant increase in the number of CD25 + cells (interleukin-2 receptor-bearing cells, presumed “activated” T-lymphocytes; p < 0.01) in isocyanate-induced asthma compared with that of control subjects. There were also significant increases in major basic protein (BMK-13)-positive ( p < 0.02) and EG2-positive ( p < 0.01) cells that represent total and “activated” eosinophil cationic protein—secreting eosinophils, respectively. In agreement with our previous findings, CD25 + ( p < 0.01), BMK-13 ( p < 0.03), and EG2 + ( p < 0.01) cells were also elevated in extrinsic asthma. No significant differences were observed in the numbers of T-lymphocyte phenotypic markers (CD3, CD4, and CD8) between subjects with asthma (isocyanate-induced and extrinsic) and control subjects. Similarly, no significant differences in immunostaining for neutrophil elastase (neutrophils) or CD68 (macrophages) were observed. The results suggest that isocyanate-induced occupational asthma and atopic (extrinsic) asthma have a similar pattern of inflammatory cell infiltrate. The results support the view that T-lymphocyte activation and eosinophil recruitment may be important in asthma of diverse etiology.