Cause Of Occupational Asthma Research Articles

IMMUNOHISTOCHEMICAL DETECTION OF TOLUENE DIISOCYANATE (TDI) ADDUCTS IN PULMONARY TISSUE OF GUINEA PIGS FOLLOWING INHALATION EXPOSURE

Toluene diisocyanate (TDI) is currently the most prevalent cause of occupational asthma. Inhalation of vapors of the reactive chemical may result in irritation and inflammation of the respiratory tract as well as in pulmonary sensitization. Although numerous studies have characterized the pulmonary inflammation, the mechanism underlying sensitization remains controversial. This investigation sought to address the problem by following the localization of TDI in the respiratory tract of guinea pigs using a well-characterized animal model that displays both immunologic and respiratory hypersensitivity to TDI. Nonanesthetized and minimally restrained guinea pigs were exposed to a sensitizing regimen of TDI that consisted of inhalation of 1.0 ppm TDI vapor for 3 h/day on 5 consecutive days. Pulmonary inflammation was present in animals sacrificed immediately following the exposure as evidenced histologically, and by increased protein and inflammatory cells in the bronchoalveolar lavage. Using a specific and sensitive rabbit antiserum prepared to TDI-keyhole limpet hemocyanin, the presence of TDI adducts in respiratory tissues was investigated. TDI adducts were detected primarily in the apical region of the epithelium of the nares, trachea, bronchi, and bronchioles. The amount of adduct was greatly reduced in animals sacrificed 18 days later. Sensitized guinea pigs that were challenged on day 23 with 80-250 ppb TDI demonstrated the same distribution of TDI adducts as did shamexposed animals similarly challenged. These results are the first to employ immunohistochemistry to detect TDI adducts in respiratory tract tissue. Findings indicate that one exposure to the chemical results in detectable adducts, and that the location of adducts is dependent upon both the concentration of TDI inhaled and the number of exposures. Isolation and characterization of the cellular adducts should assist in elucidation of the role of adducts in the sensitization process.

ABC of work related disorders. Occupational asthma and other respiratory diseases.

In the United Kingdom, over the past 40 years, there has been a shift away from manufacturing industries and a sharp reduction in the numbers of coal miners. These factors, together with stricter health and safety legislation, have resulted in a substantial decline in the prevalence of silicosis and pneumoconiosis. In contrast, occupational asthma has become increasingly recognised. In developing countries, however, the traditional occupational lung diseases of silicosis, pneumoconiosis, and asbestosis remain common in rapidly industrialising areas. View this table: Cases of work related respiratory disease in United Kingdom in 1994 (based on Ross et al1 Our understanding of the epidemiology of occupational lung disease in Britain has been greatly enhanced by the SWORD project (surveillance of work related and occupational respiratory disease), which was established in 1989 sponsored by the Health and Safety Executive. Occupational and respiratory physicians are invited to report new cases of occupational lung diseases together with the suspected agent. The data are regularly analysed and the results published. Further information is available from the Department of Occupational and Environmental Medicine, National Heart and Lung Institute, London. Occupational asthma is caused by specific sensitising agents inhaled in the workplace—it does not include bronchoconstriction induced by irritants such as exercise and cold air that are encountered at work. There are over 200 known respiratory sensitisers, and more are identified each year. Some sensitisers may not be immediately obvious: thus, it has recently been recognised that workers such as those in health services can develop occupational asthma as a result of wearing latex gloves. The allergen is latex protein, which becomes airborne as the gloves are used. View this table: Major causes of occupational asthma and groups at risk in 1993-4 (based on Sallie et al2) A comprehensive and detailed occupational history is essential in the initial assessment of a …

Overview of diisocyanate occupational asthma

Surveillance programs established around the world have determined that diisocyanate chemicals are the most common cause of occupational asthma. In the United States approximately 100000 workers are exposed to these chemical compounds in the workplace each year and 5–10% of these workers will develop occupational asthma. There are no known reliable risk factors or biomarkers which can be used to predict which exposed worker will develop diisocyanate-occupatonal asthma. Diisocyanate-occupational asthma workers manifest characteristic physiologic responses after specific bronochoprovocation which correlate with pathologic changes in their airways. However, the mechanism(s) for diiocyanate-occupational asthma remains unclear. Specific IgE antibody production to diisocyanates is found in only 10–30% of these workers. Bronchial biopsies and bronchoalveolar lavage have confirmed the presence of T-lymphocytes and eosinophils in the airways of these workers suggesting that T-cell mediated immune responses are more likely to play a central role in this disease. It is essential to diagnose diisocyanate-occupational asthma as early as possible in order to prevent or reduce the significant asthma morbidity associated with continuous long term exposure to these chemicals. Treatment of choice is removal of the worker from further exposure. Prospective studies evaluating larger populations of diisocyanate-exposed workers is essential for a better understanding of the pathogenesis and natural course of diisocyanate-occupational asthma.

A cross sectional study of chemical industry workers with occupational exposure to persulphates.

Hair bleaches containing persulphates have been identified as the cause of occupational asthma in hairdressers. Also employees in persulphate production with occupational asthma have been described. It was the aim of this study to give an estimate of the prevalence of asthma due to persulphates in chemical workers with exposure to ammonium and sodium persulphate. A cross sectional study was performed in 32 of 33 employees of a persulphate producing chemical plant. Eighteen of 23 workmen from the same plant with no exposure to persulphates were taken as controls. Also, information was collected from medical records of the seven subjects who had left the persulphate production for medical reasons since 1971. Data were recalled by a questionnaire, skin prick tests were performed with five environmental allergens, and ammonium and sodium persulphate (80 mg/ml). Specific immunoglobulin E (IgE) to the same environmental allergens as in the skin test, and total IgE were measured. Lung function and bronchial responsiveness to histamine were assessed by standard procedures. Workplace concentrations of ammonium and sodium persulphate were estimated by area and personal monitoring. The amount of persulphate was analysed as sulphur by inductively coupled plasma emission spectrometry. Work related rhinitis was reported by one subject with exposure to persulphates, conjunctivitis and bronchitis were reportedly related to work by two controls. There were no cutaneous reactions to persulphates in either group. Four non-atopic subjects exposed to persulphates, and two controls, one atopic and one non-atopic, were considered to be hyperresponsive to histamine. Three subjects exposed to persulphates with bronchial hyperresponsiveness (provocation dose of histamine causing a 15% fall in forced expiratory volume in one second (PD15 FEV1) < or = 1 mg) did not show variability in peak expiratory flow of > or = 20%, the rest refused peak flow measurements. None of the variables showed significant differences between the groups (P > 0.05). Six of the exworkers left because of work related contact dermatitis. Mean values for workplace concentrations of ammonium and sodium persulphate within the bagging plant were below 1 mg/m3, and the maximal concentrations were 1.4 mg/m3 and 3.6 mg/m3, respectively. Exposure to workplace concentrations of ammonium and sodium persulphate of about 1 mg/m3 in this chemical plant was not associated with a risk of occupational asthma.

Feasibility Study of Respiratory Questionnaire and Peak Flow Recordings in Autobody Shop Workers Exposed to Isocyanate-containing Spray Paint: Observations and Limitations

Diisocyanates, highly reactive monomers which cross-link polyurethane, are the most widely recognized causes of occupational asthma. Many exposed workers are end-users, including autobody spray painters who form a large population at risk. Neither the factors which determine incidence rate nor strategies for control have been adequately studied in this setting. We have conducted a cross-sectional survey of 23 (about one in five) autobody shops in the New Haven area to determine the feasibility of clinical epidemiological studies in this population. Among 102 workers, there was a high rate of airway symptoms consistent with occupational asthma (19.6%). Symptoms were most prevalent among those with the greatest opportunity for exposure (dedicated spray painters) and least among office workers; part-time painters had intermediate rates. Atopy was not associated with risk while smoking seemed to correlate with symptoms. Regular use of air-supplied respirators appeared to be associated with lower risk among workers who painted part- or full-time. We were unable to validate the questionnaire responses with peak expiratory flow record data attempted on a 1/3 sample of the workers. Despite intensive training and effort, subject compliance was limited. Among those who provided adequate data (24 of 38), only two demonstrated unequivocal evidence of labile airways; two others demonstrated lesser changes consistent with an occupational effect on flow rates. There was no clear association between these findings and either questionnaire responses or exposure classification. Overall, the survey suggests that there is a high prevalence of airway symptoms among workers in autobody shops, at least in part due to work-related asthma. However, there is need for both methodological and substantive research in this setting to document rates of occupational asthma and to develop a scientific basis for its effective control.

Immunologic Responses to Isocyanates in Sensitized Asthmatic Subjects

Isocyanates, highly reactive compounds used extensively in industry, are the most commonly reported cause of occupational asthma in industrial populations.1 Sensitized individuals may develop immediate and/or late asthmatic responses following isocyanate exposure.2 The mechanisms by which isocyanates cause asthma are not well defined. The limited information available suggests that isocyanate asthma is mediated via predominantly non-IgE mechanisms, and that isocyanates may act like a foreign low molecular weight hapten, inducing antigen-specific T-cell responses and airway inflammation.

Association between toluene diisocyanate-induced asthma and DQB1 markers: a possible role for aspartic acid at position 57.

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.

Work-related late asthmatic response induced by latex allergy

Background: The occupational uses of latex gloves may be associated with asthma. Hypersensitivity to latex has been shown to be IgE-mediated. The asthmatic reaction to latex is usually early; however, the natural history of latex asthma is still unknown. Objective: The purposes of this study were to investigate asthmatic responses induced by natural rubber latex and to assess the long-term respiratory consequences of latex-induced asthma after removal from exposure. Methods: This report describes the clinical and immunologic study of six nurses with work-related respiratory and skin disorders induced by the use of latex gloves. To determine whether the symptoms induced by latex gloves were IgE-mediated, we assessed latex IgE antibody levels by skin prick tests (SPTs) and RASTs with latex extracts. To confirm work-related latex reactions, we assessed respiratory symptoms, skin reactions, and FEV 1 after a glove exposure test and an inhalation provocation test with latex gloves. All subjects were followed up for 7 months to 7 years after the first observation. Results: All subjects had positive SPT and RAST responses to latex extracts, positive double prick test responses to latex gloves, and negative SPT responses to cornstarch and common allergens. Ten atopic and 10 nonatopic control subjects had negative SPT responses to latex and cornstarch extracts and negative double prick test responses to latex gloves. In three subjects latex allergy was associated with allergy to fruit (banana and chestnut). After the glove exposure test, four of six subjects had contact urticaria, all had rhinoconjunctivitis, and two had a late asthmatic response. The inhalation provocation test was performed on four subjects: all had rhinoconjunctivitis, two had urticaria and late asthmatic response, and one had laryngeal edema. A late asthmatic response was recorded in four subjects. Three subjects continued to have chronic asthma, and four subjects had increased nonspecific bronchial responsiveness 7 months to 7 years after being assigned to duties not involving latex gloves. Conclusions: This study of six nurses shows that latex is a potential cause of occupational asthma, rhinoconjunctivitis, and urticaria-angioedema. Latex seems to include antigens that elicit IgE-mediated hypersensitivity and may cause a late asthmatic reaction. Occupational asthma caused by latex may lead to permanent respiratory disability, even after removal from exposure. (J ALLERGY CLIN IMMUNOL 1995;96;457-64.)

Albumin adducts, hemoglobin adducts and urinary metabolites in workers exposed to 4,4'-methylenediphenyl diisocyanate.

4,4'-Methylenediphenyl diisocyanate (MDI) is the most widely used isocyanate in the manufacture of polyurethanes. MDI has been implicated as one of the major causes of occupational asthma. Hydrolysis of MDI can yield 4,4'-methylenedianiline (MDA), which is a suspected human carcinogen. Thus the need to monitor occupational exposure to MDI is of great significance. The use of air monitors alone has been found to be insufficient and there is a need for sensitive markers of recent and long-term exposure. We obtained biological samples from a group of 20 workers exposed to MDI vapor during the manufacture of polyurethane products. The air levels of MDI in the factory were measured using personal, work room and work station monitors. In most cases the levels were below detection limits. The blood and urine samples were analyzed for the presence of adducts and metabolites using GC-MS methods. Urinary base-extractable metabolites were found above control levels in 15 of the 20 workers and ranged from 0.035 to 0.83 pmol MDA/ml. The level of the acetylated metabolite N'-acetyl-4,4'-methylenedianiline (AcMDA) ranged from 0.13 to 7.61 pmol/ml. The amount of MDA released after acid hydrolysis was on average 6.5 times higher than the amount of free MDA and AcMDA present in urine. MDA was detected as a hemoglobin (Hb) adduct in all of the 20 subjects. The level ranged from 70 to 710 fmol/g Hb. In one individual the Hb adduct of AcMDA was detected. This is the first time a Hb adduct of AcMDA has been detected after occupational exposure to MDI. This is a further piece of evidence for the biological availability of the suspected human carcinogen MDA from in vivo hydrolysis of MDI. Plasma albumin conjugates of MDI can cause the onset of respiratory disorders in both man and animal models. Thus we investigated the presence of plasma protein adducts. The plasma MDA levels ranged from 0.25 to 5.4 pmol/ml. Up to 120 fmol/mg were found to be covalently bound to albumin.

Neurogenic goblet cell secretion and bronchoconstriction in guinea pigs sensitised to trimellitic anhydride

Trimellitic anhydride is a cause of occupational asthma in humans. We have previously found that tracheal instillation of trimellitic anhydride conjugated to guinea pig serum albumin induces acute bronchoconstriction and airway plasma exudation in sensitised animals, responses mediated primarily via histamine release. In the present study, neural mechanisms mediating bronchoconstriction and goblet cell secretion were determined in trimellitic anhydride-sensitised guinea pigs using the ganglionic blocker hexamethonium to eliminate efferent reflex mechanisms, pretreatment with capsaicin to eliminate afferent mechanisms, or cimetidine and mepyramine to eliminate histamine-mediated mechanisms. The magnitude of secretion of intracellular mucus from tracheal goblet cells was quantified morphometrically as a mucus score which is inversely related to the degree of discharge. Guinea pigs were injected intradermally either with 0.1 ml 0.3% trimellitic anhydride in corn oil or with corn oil alone as control. Fourteen to eighteen days later all sensitised animals had developed specific immunoglobulin (Ig) G1 antibodies whereas the controls had not. Tracheal instillation of conjugated trimellitic anhydride in anaesthitised animals significantly increased airway lung resistance ( R L) 24-fold in sensitised guinea pigs (34.3 ± 7.9 cm H 2O · ml −1 · s) compared with controls (1.4 ± 0.1 cm H 2O · ml −1 · s). Mucus score was significantly reduced by 51% (indicating goblet cell secretion) in sensitised guinea pigs (183 ± 22 mucus score units) compared with controls (372 ± 41 mucus score units). The antihistamines significantly inhibited conjugated trimellitic anhydride-induced bronchoconstriction by 89%, but did not significantly affect goblet cell discharge. Hexamethonium alone did not significantly affect conjugated trimellitic anhydride-induced bronchoconstriction or goblet cell secretion. Capsaicin pretreatment (in combination with hexamethonium) significantly inhibited golet cell discharge (by 80%) but had no significant effect on bronchoconstriction. We conclude that conjugated trimellitic anhydride challenge of trimellitic anhydride-sensitised guinea pigs induces goblet cell discharge and bronchoconstriction via different mechanisms with activation of capsaicin-sensitive sensory nerves responsible for secretion and histamine release responsible for airway constriction. The guinea pig model of trimellitic anhydride-induced occupational asthma may prove useful in examination of mechanisms of goblet cell secretion in allergic diseases.

Respiratory and other hazards of isocyanates.

Isocyanates are increasingly being used for manufacturing polyurethane foam, elastomers, adhesives, paints, coatings, insecticides, and many other products. At present, they are regarded as one of the main causes of occupational asthma. The large number of workers who are exposed to these chemicals have a concentration-dependent risk of developing chronic airway disorders, especially bronchial asthma. Different pathophysiologic mechanisms are involved. Immunoglobulin E (IgE)-mediated sensitization and irritative effects have been clearly demonstrated in both exposed subjects and animals. Presumably, neural inflammation due to neuropeptide release of capsaicin-sensitive afferent nerves is crucial. We collected data on 1780 isocyanate workers who had been examined by our groups. Of them 1095 (including subjects from outpatient departments) had work-related symptoms, predominantly of the respiratory tract. Specific IgE antibodies were found in 14% of the 1095 subjects. The methacholine challenge test was shown to be an inadequate predictor of the results of inhalative isocyanate provocation tests in workers and in asthmatic controls. Isocyanate (toluene diisocyanate TDI) air concentrations of 10 ppb (0.07 mg/m3) and 20 ppb (0.14 mg/m3), respectively, did not cause significant bronchial obstruction in the majority of previously unexposed asthmatics with bronchial hyperreactivity. IgG-mediated allergic alveolitis, a rare disease among isocyanate workers, was found in approximately 1% of the symptomatic subjects. Experimental studies exhibit dose-dependent toxic effects and give evidence for tachykinin-mediated bronchial hyperreactivity after exposure to isocyanates. The clinical role of genotoxic effects of isocyanates and their by-products demonstrated here in vitro and in vivo has yet to be clarified.

Colophony--uses, health effects, airborne measurement and analysis.

Colophony (rosin) is a widespread natural product obtained form species of the pine family Pinaceae. One of the most important uses of unmodified rosin is in electronic solder fluxes while the main areas of use of chemically modified rosin are paper sizing, adhesives, paints, varnishes, printing inks and plasticisers. Colophony is well recognized as a skin sensitizer and is also the third highest cause of occupational asthma. However, the specific allergens involved particularly in occupational asthma have not been comprehensively assessed or identified. This paper reviews method of colophony production, its uses and health effects and discusses the important issue of its chemical analysis and the choice of a suitable marker for monitoring colphony fume.

Statistical approaches to the identification of late asthmatic reactions

Late asthmatic reactions can be difficult to recognize because of their prolonged time course and the confounding effects of superimposed circadian rhythms of ventilatory function. Conventional methods of analysis are rather arbitrary. They depend for example on a 15 or 20% fall in forced expiratory volume in one second (FEV1) from baseline or from time-matched control measurements. We have, therefore, investigated whether statistical approaches applied to individual subjects can assist in the identification of late asthmatic reactions. In two separate series of aerosol inhalation tests, three symptomatic workers, three asthmatic controls and three nonasthmatic controls were challenged blindly with increasing doses of two chemical agents, and saline. One of the agents, sodium isononanoyl oxybenzene sulphonate (SINOS) was a suspected cause of occupational asthma. Prior to the challenges, FEV1 was measured hourly on three control days. Cumulative late changes on both control and active challenge days were quantified as the area between a line extrapolated from a 10.00 h baseline and the actual measurements from 12.00-22.00 h (the 2-12 h area decrement). The area decrement measurements on control and active challenge days were compared using Student's t-tests. The sensitivity of this method for detecting late asthmatic reactions among potentially positive tests (SINOS challenge tests in the workers) was examined, as was its specificity. The latter was determined from the false positive rate among the negative tests. A second statistical method based on the pooled standard deviation of serial (hourly) FEV1 measurements was investigated in the same way. In total, the data from 220 challenge and 30 control days were available for analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical reactions to Aspergillus niger in a biotechnology plant: an eight year follow up.

The manufacture of citric acid by fermentation of molasses with Aspergillus niger has previously been described as a cause of occupational asthma in a factory. A longitudinal survey of the workforce of this factory has been carried out from 1984 to 1991. Over this period 160 of the original 278 workers left the workforce, together with 39 of 76 new recruits. Partial enclosure of the process and exhaust ventilation, installed in 1984, was effective in preventing any new cases of occupational asthma over the eight year period, and no new skin sensitisation was detected. Spore counts of A niger averaged about 100 times those in the outside air. Health in the 1984 survey had a striking influence on subsequent retiral; only 11 of the 79 with respiratory symptoms remained in 1991, compared with 90 of the 182 with no symptoms. In conclusion A niger is a weak antigen and simple hygiene measures protect the workforce. Exclusion of recruits with positive skin tests is not necessary if such measures are taken. The survey provided evidence of the selection factors operating within a workforce over this period contributing to retiral of the less healthy.

Dust mite allergy: An important cause of respiratory disease in farmers

In 2,578 Swedish farmers, 6.2% were found to have an allergy to storage mites. The storage mite Lepidoglyphus destructor has been identified by both RAST and bronchial challenges as a significant cause of occupational asthma in rural environments. Immunohistochemical studies of L. destructor disclosed that at least one L. destructor allergen is associated with digestion.

Effect of a topical corticosteroid on airway hyperresponsiveness and eosinophilic inflammation induced by trimellitic anhydride exposure in sensitized guinea pigs

Background: Topical corticosteroids are effective in the treatment of asthma by improving bronchial hyperresponsiveness and reducing airway inflammation. Methods: We assessed the effect of a nebulized corticosteroid, budesonide, on airway hyperresponsiveness and inflammatory response provoked by inhalation of trimellitic anhydride (TMA) dust, a known cause of occupational asthma in human beings, in guinea pigs sensitized to the free hapten. Male Dunkin-Hartley guinea pigs ( n = 24) were injected intradermally with 0.1 ml of 0.3% TMA in corn oil, followed by exposure 21 to 28 days later to five consecutive doses of budesonide aerosol (0.5 mg/ml) or saline solution, administered for 10 minutes every 12 hours. They were then exposed (noses only) to TMA dust (8 mg/m 3) or air for 1 hour (four groups, n = 6 in each). Airway responsiveness to acetylcholine, defined as the concentration needed to cause a 200% increase in lung resistance (PC 200), was measured 8 hours later. Results: In saline-treated guinea pigs exposed to TMA, mean PC 200 was 0.094 mmol/L (geometric SEM, 1.4 mmol/L) compared with 0.31 mmol/L (geometric SEM, 1.3 mmol/L, p < 0.05) in those guinea pigs pretreated with budesonide. In sham-exposed sensitized guinea pigs, PC 200 was 0.35 mmol/L (geometric SEM, 1.2 mmol/L), which was not significantly different from the budesonide-treated group (0.36 mmol/L; geometric SEM, 1.3 mmol/L). There was a significant increase in the number of eosinophils in the subepithelium of guinea pigs further exposed to TMA dust (71.5 ± 6.8 cells/unit area [mean ± SEM]) compared with those exposed to air (22.7 ± 6.7, p < 0.01). Budesonide did not inhibit the number of subepithelial eosinophils of guinea pigs exposed to TMA dust (54.0 ± 3.7cells/unit area) or in those exposed to air (24.3 ± 6.7 cells/unit area) and did not affect the increase in eosinophlis found in bronchoalveolar fluid. Conclusions: Budesonide significantly inhibited the increase in airway responsiveness but not the eosinophilic inflammation induced by exposure to TMA dust in sensitized guinea pigs.

The low prevalence of occupational asthma and antibody-dependent sensitization to diphenylmethane diisocyanate in a plant engineered for minimal exposure to diisocyanates

Background: Diisocyanate chemicals are leading causes of occupational asthma (OA). Methods: We conducted a cross-sectional study of 243 workers exposed to diphenylmethane diisocyanate (MDI) in a methane mold plant that had been designed to minimize MDI exposure (levels were maintained below 0.005 ppm and were continuously monitored). All participants were screened by questionnaire and tests for serum antibodies to MDI-human serum albumin (HSA). On the basis of questionnaire responses, diagnoses were derived that included OA; non-OA; work-related and non-work-related rhinitis; and lower respiratory irritant responses. Serial peak expiratory flow rate studies were performed for 2 weeks in 43 workers with and in 23 workers without lower respiratory symptoms. Results: Results of serial peak expiratory flow rate studies were abnormal in 3 (33%) of 9 workers with OA, in 2 (50%) of 4 with non-OA, and in 2 (9%) of 23 case control subjects. A significant association was found between peak flow rate variability and a questionnaire asthma diagnosis (χ 2 p < 0.002). Physicians confirmed three cases of OA, one of which occurred in a control worker who was free of symptoms. In all three cases asthma symptoms remitted after the worker left the workplace. Serum specific IgE and IgG levels were elevated in 2 of 243 workers, one of whom was prick test positive to MDI-HSA and had had cutaneous anaphylaxis after MDI exposure. Conclusions: On the basis of these cases, specific work activities associated with exposure to MDI were identified and corrective measures were instituted. Strict control and monitoring of ambient MDI exposure was associated with a low prevalence of specific sensitization to MDI and a lower than expected prevalence of OA.

Prepolymers of hexamethylene diisocyanate as a cause of occupational asthma

Background: Occupational asthma (OA) caused by products that contain hexamethylene diisocyanate (HDI) has been ascribed to the highly volatile monomer of HDI. Most two-component paints are now made up primarily of nonvolatile prepolymers of HDI (30% to 60%) with only trace amounts (<0.1%) of the monomer. The respective role of the two chemical forms of HDI in causing OA has never been investigated. Methods: Twenty workers who were consecutively referred for possible OA that resulted from exposure to spray paints underwent inhalation challenges on separate days with pure HDI monomer and the commercial formulation of HDI prepolymers to which they had been exposed at work. Results: Specific inhalation challenges elicited a positive asthmatic reaction in 10 of the 20 subjects. Among these subjects, four had positive bronchial reactions (two early, one late, and one dual) to both the monomer and the prepolymers. Four other subjects had asthmatic reactions (two early, one late, and one dual) after exposure to the prepolymers but not after exposure to the monomer. The discordance in bronchial response elicited by the monomer and the prepolymers could not be due to differences in the level of baseline nonspecific bronchial reactivity or in HDI concentrations during the tests. One subject showed an atypical progressive reaction after exposure to the monomer but not after exposure to the prepolymer. In this case, the discordant response could be explained by differences in HDI concentration. Conclusion: These observations show that, although they are nonvolatile, the prepolymers of HDI can induce OA and that asthmatic reactions as a result of exposure to prepolymers but not the monomer is not a rare occurrence.

Hypersensitivity Pneumonitis-like Reaction among Workers Exposed to Piphenylmethane Diisocyanate (MDI)

Isocyanates are well documented as a cause of occupational asthma. A hypersensitivity pneumonitis type of reaction has also been reported but only in a few isolated cases. We investigated nine subjects who complained of respiratory and general symptoms related to workplace exposure. All the subjects had worked in a plant where a resin based on diphenylmethane diisocyanate (MDI) is used in the manufacture of woodchip boards. They underwent inhalation challenges using the MDI resin for progressively increasing periods of time on separate days. In eight subjects, exposure to subirritant amounts of MDI induced a pattern of reaction consistent with hypersensitivity pneumonitis, i.e., significant falls in both FEV1 and FVC associated with a rise in body temperature (> 38 degrees C) and an increase in blood neutrophils (> +2,500/mm3). Bronchoalveolar lavage, performed in two subjects 24 h after the end of challenge exposure, revealed an increase in lymphocytes and neutrophils. Specific immunoglobulin G (IgG) and IgE antibodies to MDI human serum albumin (HSA) conjugates were present in all subjects. We conclude that the MDI resin caused an hypersensitivity pneumonitis type of reaction in at least eight (4.7%) of the 167 potentially exposed workers employed in the plant. These findings indicate that in some workplaces, a hypersensitivity pneumonitis type of reaction may be a more frequent consequence of isocyanate exposure than is usually thought.

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.