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Incubation of serum serpin (alpha-1-antitrypsin) with 5 mM 1,6-diaminohexane causes significant loss of heterozygotic inhibitor activity. While serpin genes have several alleles, the enzyme complex that acetylates the amine to render it suitable for excretion has primarily two phenotype populations, i.e. slow and fast N-acetylators. This study shows that diacetyl-1,6-diaminohexane does not cause in vitro loss of serpin activity, and that all regional cases (eleven in all) referred to us during one year with a diagnosis of occupational organic diisocyanate asthma were slow acetylators except one who presented a marginally fast reaction type.

We report the clinical findings and the results of inhalation challenge with toluene diisocyanate (TDI) and methacholine in 113 subjects with a history of exposure to TDI and work-related respiratory symptoms. Only some of the subjects (40.7%) had isocyanate asthma, diagnosed by a positive TDI inhalation challenge. Most reactors had a dual (30.4%) or a late (41.3%) response. The interval between the last occupational exposure and the specific challenge was significantly shorter in reactors, and among this group the number of immediate reactions to TDI decreased progressively with an increasing interval. The reactors had a significantly higher proportion of positive responses to methacholine and a significantly lower mean PD15 FEV-1 (provocative dose of methacholine which provoke a 15% decrease in forced expiratory volume in 1 second) (reactors: 557 micrograms, SEM 92.3; nonreactors: 1346 micrograms, SEM 128, P less than .01). Methacholine challenge could not identify subjects with isocyanate asthma.

Sensitized subjects may develop symptoms of asthma after exposure to isocyanates in their place of work. After challenge with isocyanates in the laboratory, sensitized subjects develop immediate, late and dual asthmatic reactions. We speculated that toluene diisocyanate (TDI) might cause late asthmatic reactions and increase bronchial responsiveness by causing an acute inflammatory reaction in the airways, and that airway inflammation may be responsible for persistence of occupational asthma induced by isocyanates. To test these hypotheses, we examined sensitized subjects during asthmatic reactions induced by exposure to toluene diisocyanate in the laboratory. We observed that late and dual, but not early, asthmatic reactions are associated with a transient increase of bronchial responsiveness which is associated with an acute inflammatory reaction of the airways characterized by an increase of neutrophils followed by eosinophils, by an increase of leukotriene B4 and albumin in bronchoalveolar lavage fluid, and that all these effects are inhibited by steroids. Longitudinal studies suggest that the majority of subjects with occupational asthma continue to have persistent asthma months and years after the cessation of exposure, and the results of our studies combined with the results of studies performed by others suggest that the persistence of asthma may be related to the persistence of airway inflammation.

To determine the importance of airway inflammation for the development of late asthmatic reactions, we examined sensitized subjects during late asthmatic reactions induced by exposure to toluene diisocyanate (TDI) in the laboratory. Late asthmatic reactions are associated with a transient increase of bronchial responsiveness and, at the same time, with an increase of neutrophils followed by eosinophils, and of LTB4 and albumin in bronchoalveolar lavage fluid. Late asthmatic reactions, increased bronchial responsiveness, and increase of neutrophils, eosinophils, LTB4, and albumin concentration in bronchoalveolar lavage induced by exposure to TDI are all prevented by pretreatment with prednisone but not with the nonsteroidal anti-inflammatory agent indomethacin. Aerosolized steroids (beclomethasone and dexamethasone isonicotinate) completely inhibit late asthmatic reactions induced by TDI, whereas theophylline has a partial, and verapamil, ketotifen, and cromolyn have no protective effect. These results suggest that late asthmatic reactions induced by TDI may be caused by airway inflammation, and that anti-inflammatory steroids should be recommended in the prophylaxis of TDI asthma.

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.

Five men were exposed to toluene diisocyanate (TDI) atmospheres for 7.5 h. The TDI atmospheres were generated by a gas-phase permeation method, and the exposures were performed in an 8-m3 stainless-steel test chamber. The mean air concentration of TDI was ca. 40 micrograms/m3, which corresponds to the threshold limit value (TLV) of Sweden. The inhaled doses of 2,4- and 2,6-TDI were ca. 120 micrograms. TDI in the test chamber air was determined by an HPLC method using the 9-(N-methylaminomethyl)-anthracene reagent and by a continuous-monitoring filter-tape instrument. After hydrolysis of plasma and urine, the related amines, 2,4- and 2,6-toluenediamine 2,4-, and 2,6-TDA), were determined as pentafluoropropionic anhydride (PFPA) derivatives by capillary gas-chromatography using selected ion monitoring (SIM) in the electron-impact mode. The urinary elimination of the TDAs showed a possible biphasic pattern, with rapid first phases for 2,4-TDA (mean t1/2 for the concentration in urine, 1.9 h) and for 2,6-TDA (mean t1/2 for the concentration in urine, 1.6 h). The cumulative amount of 2,4-TDA excreted in urine within 28 h ranged from 8% to 14% of the estimated dose of 2,4-TDI, and the cumulative amount of 2,6-TDA in urine ranged from 14% to 18% of the 2,6-TDI dose. The average urinary level of 2,4-TDA was 5 micrograms/l in the 6 to 8-h sample (range 2.8-9.6 micrograms/l), and the corresponding value for 2,6-TDA was 8.6 micrograms/l (range, 5.6-16.6 micrograms/l). Biological monitoring of exposure to 2,4- and 2,6-TDI by analysis of 2,4- and 2,6-TDA in urine is feasible.

To determine the importance of airway inflammation for exacerbation and prognosis of asthma induced by toluene diisocyanate (TDI), we first examined sensitized subjects during asthmatic reactions induced by exposure to TDI in the laboratory. We observed that late and dual, but not early, asthmatic reactions induced by TDI are accompanied by a transient increase of airway responsiveness, bronchoalveolar neutrophilia followed by eosinophilia and by an increase of LTB4 and albumin in bronchoalveolar lavage fluid. All these effects were prevented by pretreatment with prednisone. In addition, we examined the lung pathology of 1 sensitized subject who died after exposure at work. The pathologic features of fatal asthma induced by TDI and of chronic asthma induced by TDI suggest the importance of inflammation for the exacerbation and prognosis of the disease.

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.

Nine cases of occupational asthma due to isocyanates are described. The isocyanates involved included toluene diisocyanate (TDI), diphenyl-methane diisocyanate (MDI) and polyisocyanates. The importance of asking the occupational history in a patient with asthma is illustrated. The importance of early diagnosis and removal from further exposure is also discussed.

To evaluate the morphologic basis of the different outcomes of toluene diisocyanate (TDI) asthma after quitting occupational exposure, we examined ten patients with TDI asthma who showed, at diagnosis, a positive TDI challenge test and nonspecific bronchial hyperresponsiveness (NSBH) to methacholine. After diagnosis, all patients ceased work and a 4- to 40-month follow-up was obtained with three to eight determinations of the cumulative dose producing a 15 percent fall in FEV1 (PD15FEV1) methacholine in each patient. Bronchoalveolar lavage (BAL) and biopsy of bronchial muscosa were performed 3 to 39 months after cessation of work, in the absence of acute exacerbations of the disease. Total cell count in BAL fluid was moderately increased in four of ten patients, eosinophils were increased in five of ten patients, and neutrophils were increased in eight of ten patients. Mucosal biopsy specimens of main or lobar bronchi were available in eight of ten patients; epithelial damage and thickening of basement membrane was observed in almost all patients, as well as a mild-to-moderate inflammatory reaction in the submucosa, mainly represented by lymphocytes, eosinophils, and neutrophils. No relationship was observed between the cellularity of BAL and the degree of NSBH at the time of BAL; mean values of total cells and differential count were not different between patients with presence or absence of the different histologic findings. Mucosal biopsy and BAL were performed also in four subjects exposed to dusts without respiratory symptoms or NSBH; similar findings were obtained except for the absence of eosinophils in BAL and a lesser degree of basement membrane thickening and inflammatory reaction in the submucosa. The study of the changes in NSBH after quitting exposure showed that five of ten patients had a significant improvement in NSBH to methacholine, as evaluated by a positive significant linear regression between months of work cessation and PD15FEV1 methacholine; only one of these five patients had an increased number of eosinophils in BAL fluid. By contrast, four of the five patients with persistent NSBH after quitting exposure had an increased number of eosinophils in BAL. We suggest that persistent NSBH in TDI asthma after cessation of work may be related to an inflammatory reaction in which eosinophil infiltration seems to be a major determinant.

Serum IgG and IgE to isocyanate haptenized human serum albumin (HSA) were estimated by ELISA in 55 isocyanate workers who underwent isocyanate inhalation challenge studies in Montreal, Canada. The challenges were negative in 29 workers and positive in 26 workers. Isocyanate antibodies were estimated by ELISA index. The mean IgG indices were found to be significantly higher in the challenge-positive workers, and there was a similar trend for the IgE indices. Antibody specificities for toluene diisocyanate-HSA, diphenylmethane diisocyanate-HSA, and hexamethylene diisocyanate-HSA were determined by inhibition studies with a variety of isocyanate haptenized carriers. The other isocyanate substituted carriers were either noninhibitory or caused only partial inhibition as contrasted with the complete inhibition achieved by HSA conjugated to the isocyanate to which the worker was exposed. We interpret these specificity studies as indicating that the inhalation of isocyanates results in production of antibody that recognizes new antigenic determinants that develop from the coupling of isocyanates to homologous proteins.

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.

We investigated whether leukotriene B4 (LTB4) is released from the lungs of sensitized subjects during asthmatic reactions induced by toluene diisocyanate (TDI). We examined three groups of TDI-sensitized subjects, one after no exposure to TDI, the second 8 h after an exposure to TDI that caused an early asthmatic reaction, and the third 8 h after an exposure to TDI that caused a late asthmatic reaction. We analyzed bronchoalveolar lavage (BAL) fluid by reverse-phase high-performance liquid chromatography and by specific radioimmunoassay. The mean concentration of LTB4 was higher [0.31 +/- 0.09 (SE) ng/ml, range 0.15-0.51] in BAL fluid of sensitized subjects who developed a late asthmatic reaction than in BAL fluid of subjects who developed an early asthmatic reaction (0.05 +/- 0.04 ng/ml, range 0-0.224), and no LTB4 was detectable in the control subjects. We also performed BAL 8 h after TDI exposure on four TDI-sensitized late-dual reactors who were on steroid treatment. In this group of subjects no LTB4 was detectable. These results suggest that LTB4 may be involved in late asthmatic reactions induced by TDI.

Six polyurethane foam workers were shown to have TDI-induced asthma by specific inhalation challenge testing. All remained in the workplace in jobs with minimal TDI exposures. Mean and time-weighted average exposure concentration for the asthmatic group was 0.64 +/- 0.46 ppb, less than 5 percent of the permissible exposure limit and significantly less (p less than 0.01) than the mean TWA exposures occurring in the foam line and the finishing workers. Serial evaluation of the respiratory health of these six showed all persisted with respiratory symptoms, none had improvement in bronchial hyperresponsiveness to methacholine, and three had a greater than 15 percent decline in FEV1 on one of the days of spirometric testing over the five-year period from 1982 to 1986. Although we could not have predicted the outcome of asthma had these workers left the workplace and ceased isocyanate exposure entirely, occupational asthma persisted despite negligible ongoing TDI exposures.

The occurrence of hemoptysis, dyspnea, and bilateral pulmonary opacities progressed to respiratory failure in a 34-yr-old man. Recovery occurred with corticosteroid therapy. In the absence of evidence for an infectious etiology, the possibility of immunologic trimellitic anhydride (TMA) hemorrhagic pneumonitis was considered when the lung biopsy excluded Goodpasture's and other diseases and because the patient was a spray painter. Serologic evaluation for antibodies against TMA was requested. Because the immunologic studies for TMA were negative, and because the patient was a spray painter, immunoassays for three isocyanates conjugated to human serum albumin (HSA) were carried out although there was no specific history of isocyanate exposure at that time. High levels of IgG and IgE antibodies were detected against hexamethylene diisocyanate (HDI)-HSA and toluene diisocyanate (TDI)-HSA. Further investigation documented exposure to spray paint that contained HDI and another isocyanate. The paint was sprayed on warm metal, and subsequently the worker developed an acute illness. Further plant studies were not possible. We propose that the pathogenesis of this case of hemorrhagic pneumonitis is immunologic because of uncontrolled exposure to HDI and TDI, is analogous to the immunologic hemorrhagic pneumonia caused by TMA, and should be considered as a possible cause of a similar acute lung disease after isocyanate exposure.

The respiratory health of 277 workers in a new toluene diisocyanate (TDI) manufacturing plant was studied prospectively during 5 yr of exposure. Personal TDI monitors were used to continuously measure peak and 8-h time-weighted average (TWA) concentrations in over 2,000 samples. Longitudinal change in pulmonary function was assessed in 223 men in whom 3 or more data points allowed construction of individual slopes of annual change. Regression of annual change on smoking (pack-years), atopic status, and cumulative TDI exposure dichotomized at 68.2 parts per billion (ppb) months into low and high exposure groups showed significant effects of smoking on spirometric tests and lung volumes. After adjusting for pack-years of smoking, the 74 men in the high cumulative TDI exposure category had significantly larger declines in FEV1, %FEV, and FEF25--75% than did the 149 men in the low category. Annual change in FEV1 was then examined in 6 smoking-exposure categories: in never smokers, average annual decline was 38 ml/yr greater in those with higher cumulative TDI exposure. Current and previous cigarette smokers did not show this effect of cumulative TDI exposure. Analysis of FEV1 change by time above 20 ppb TDI yielded a similar result in never smokers, a 24 ml/yr excess average decline attributable to longer time above 20 ppb. In current cigarette smokers, those with longer time above 20 ppb had excess decline of 18 ml/yr (42 versus 24 ml/yr). our low and high cumulative exposure groups spent 2 and 15%, respectively, of their working time above 5 ppb TDI. The different health effects observed in these groups supports the NIOSH-recommended standard of 5 ppb TDI as an 8-h TWA.

Two strains of guinea pigs were parenterally immunized with well-characterized diisocyanate-protein conjugates. Hapten-specific IgE antibodies were detected in the sera of English short-hair strain guinea pigs immunized with either toluene diisocyanate-human serum albumin (TDI-HSA) or hexamethylene diisocyanate-HSA (HDI-HSA) when these sera were analyzed by the 168 hr passive cutaneous anaphylaxis (PCA) technique followed by intravenous challenges with conjugates of respective ligands coupled to an unrelated carrier protein, transferrin. IgG1 antibodies and precipitating antibodies were demonstrated in Hartley strain guinea pigs immunized with TDI/HDI-HSA conjugates. The hapten specificity of these antibodies was proved by PCA inhibition experiments and antibody absorption experiments. In the precipitating antibody system, this was further confirmed by immunoelectrophoretic analysis. Cross-reactivity between HDI and TDI was not observed in the PCA experiments. However, apparent cross-reactivity in the double gel diffusion experiments was due to new antigenic determinants formed by isocyanates after conjugation with proteins. It was therefore apparent that immune responses of guinea pigs immunized with protein conjugates of bifunctional isocyanates were heterogeneous and involved multiple specificities for hapten, carrier protein, and new antigenic determinants. It was postulated that the complex nature of the immune response generated by diisocyanate compounds in the guinea pig may also serve as a more appropriate model of isocyanate-induced human sensitivity reactions, which are known to involve diverse immunologic and nonimmunologic mechanisms.

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.

We report the case of a 43-yr-old car painter who died within 1 h of exposure to a polyurethane paint in the workplace. A diagnosis of asthma induced by toluene diisocyanate (TDI) had been established 6 yr before, when he underwent inhalation challenges with carbachol and with TDI. The subject had airway hyperresponsiveness to carbachol (PD20FEV1 carbachol = 0.32 mg; normal value greater than 1.0 mg) and developed an early and long-lasting asthmatic reaction after exposure to TDI in the laboratory. Although it was recommended that he change his job or stop using paints containing isocyanates, he continued to work as a car painter, taking antiasthmatic drugs both at work and at home to control asthma symptoms. On Monday, October 6, 1986, at 11:30 A. M., he developed a severe attack of asthma while he was mixing the 2 components of a polyurethane paint. Taken to hospital, he was dead on arrival. Autopsy showed no evidence of cardiac or brain disease; lungs were overinflated, the cut surface showed grey glistening mucous plugs in in the airways. Histologic examination showed denudation of airway epithelium and thickening of the basement membrane with infiltration of the lamina propria by polymorphonuclear leukocytes, mainly eosinophils, and diffuse mucous plugging of bronchioles. Bronchial smooth muscle appeared hyperplastic and disarrayed, and lung parenchyma showed focal areas of alveolar destruction adjacent to areas of perfectly intact alveolar walls.(ABSTRACT TRUNCATED AT 250 WORDS)

Two antigens, both containing tolyl groups, were compared for ability to detect IgE antibodies in workers hypersensitive to toluene diisocyanate. One antigen, formed by reaction of p-tolyl isocyanate with human serum albumin, detected antibodies in each of ten hypersensitive workers. A second tolyl antigen, formed by reaction of p-toluoyl chloride and human serum albumin, and therefore lacking isocyanate linkages, detected antibodies in seven of the ten workers. In RAST assays, sera from toluene diisocyanate-sensitive workers demonstrated higher binding to human serum albumin-coated control discs than did sera from non-sensitive workers. The significance of this binding in calculating tolyl-reactive antibody titres is discussed.

Two workers, who developed asthmatic symptoms, were studied with inhalation provocation tests using diphenylmethane diisocyanate (MDI) and toluene diisocyanate (TDI). The subjects showed specific asthmatic reactions to MDI challenge (more than 20% fall in FEV1), and one also had an alveolar response. Alveolitis was suggested by fever, basal crackles, increased neutrophil counts in venous blood and in bronchoalveolar lavage. The asthmatic reaction to MDI challenge was associated with an increase in airway responsiveness to methacholine in both subjects. We conclude that MDI is a cause of asthma and/or hypersensitivity pneumonitis in workers exposed to diphenylmethane diisocyanate.

The importance of airways inflammation for the development of bronchial hyperresponsiveness and for exacerbation of asthma was investigated in subjects with occupational asthma. We examined subjects sensitized to isocyanates, a small molecular weight compound that causes occupational asthma. Studies in asthmatic subjects sensitized to toluene diisocyanate (TDI) demonstrated that late, but not early, asthmatic reactions induced by TDI were associated with an acute increase in bronchial responsiveness, and with a marked infiltration of neutrophils and a slight infiltration of eosinophils into the airways, both prevented by steroids. As the late asthmatic reactions and the increase in responsiveness induced by TDI were prevented by steroids, but not by indomethacin, we speculated that cell membrane phospholipid metabolites, which are inhibited by steroids but not by indomethacin, may be involved in TDI induced hyperresponsiveness. The results of these studies suggest that bronchial hyperresponsiveness and exacerbation of asthma may be related to inflammation of the airways and that cell membrane phospholipid metabolites may be involved.

In sixty-three workers exposed to toluene di-isocyanate (TDI), no overall differences in bronchial reactivity to histamine inhalation and to exercise testing were found between the total groups of positive and negative TDI reactors to provocation tests. A subgroup of TDI highly sensitive subjects reacting to very low concentrations (less than or equal to 0.001 p.p.m.) were more sensitive to both histamine and exercise than the group who were less sensitive to TDI, and who reacted to higher concentrations (0.002--0.02 p.p.m.) than the group of non-reactors. There were, however, in the last group a number of subjects with high degrees of histamine reactivity who did not react to the TDI. These findings suggest that, on the one hand, the asthmatic reactions to TDI cannot be attributed solely to non-specific mechanisms and, on the other, that in subjects with high degrees of specific sensitivity non-specific mechanisms may also be playing a part.

In a car factory employing 203 women machinists making seat covers more women complained of respiratory symptoms after the introduction of a new seat cover fabric, cropped nylon backed with flame-bonded polyurethane foam (CNPF). 68 women working in the trim shop were studied on the first day back at work after a week's holiday and then at the end of a working week; the incidence of wheezing and/or shortness of breath was greater than expected but there was no difference between peak flow rates. A second study of 192 of the 203 women working in the trim shop confirmed this recent increase in incidence of asthmatic symptoms and showed that significantly more machinists who had worked with this new fabric had a reduced peak flow rate than machinists who had not. Asthma developed in one subject when she was working in the factory sewing CNPF, when she was handling this fabric in the challenge cabinet in the laboratory, and on challenge with toluene di-isocyanate in the laboratory. Airways resistance increased in 3 other workers after exposure to CNPF in the laboratory. Low concentrations (between 0.0003 to 0.003 ppm) of toluene di-isocyanate were found in the air around this fabric. 4 of 9 women with symptoms had IgE antibodies to toluene di-isocyanate.

To determine the importance of airway inflammation for late asthmatic reactions and increased airway responsiveness induced by TDI, we investigated whether late asthmatic reactions and increased responsiveness induced by TDI are associated with airway inflammation and whether steroids prevent them by modifying the inflammatory response within the airways. We measured FEV1 before and at regular intervals after exposure to TDI and performed dose-response curves to methacholine and bronchoalveolar lavage 8 hr after TDI in two subjects with previously documented late asthmatic reaction; then we repeated the same procedure a few weeks after treatment with steroids. Airway responsiveness and polymorphonuclear cells were increased in both subjects after the late asthmatic reaction; treatment with steroids prevented late asthmatic reaction and the increase in airway responsiveness and polymorphonuclear cells in bronchoalveolar lavage. These results suggest that late asthmatic reaction induced by TDI may be caused by airway inflammation.

Occupational lung diseases can be conveniently classified into disorders of the airways, the alveoli, and the lung interstitium. Diseases of each category have a distinct clinical and pathologic presentation despite diverse causes.

20 patients with toluene diisocyanate (TDI)-induced asthma were examined in order to assess their threshold of response to TDI during specific bronchial provocative tests (BPT). Specific bronchial hyperresponsiveness was evaluated by performing, on different days, specific BPT with increasing concentrations of TDI until a positive response was obtained; the threshold of response to TDI (low: 0.02-0.05 ppm; moderate: 0.1 ppm; high: 0.2-0.25 ppm) and the pattern of positive response were evaluated in comparison with some clinical features of the disease. The threshold of airway response to TDI was low in 9, moderate in 7 and high in 4 patients. No evident relationship was observed between the threshold of response to TDI and the pattern of positive response to the lower TDI concentration (immediate in 5, late in 8 and dual in 7 subjects) or other clinical features (duration of asthmatic symptoms, smoking habits, cessation of work, nonspecific bronchial hyperresponsiveness to methacholine); however, 6 out of 9 patients with low threshold had nonspecific bronchial hyperreactivity in comparison with 6 out of 11 patients with moderate or high threshold. In 10 out of 13 patients who performed two positive BPT with different TDI concentrations, the pattern of response was the same either at lower and at higher TDI concentrations; 3 subjects who had a late reaction at the lower concentration showed a dual reaction to the higher TDI concentration. A relationship between the degree of the specific bronchial reaction (% fall in FEV1 from baseline value) and TDI concentration during BPT was observed for the immediate reaction but not for the late reaction.

The AA. describe two cases of occupational asthma in the wood industry. Bronchial provocations tests (BPT) showed that the sensitizing agents were not only TDI, but also the "base" of the painting system used in the varnishing. The AA. discuss on the method of stimulation in performing BPT.

The specific IgE antibodies were studied with the Phadebas RAST technique in 35 patients with asthma due to diisocyanates. Two had been sensitized to toluene diisocyanate (TDI), 17 to methylene diisocyanate (MDI) and 16 to hexamethylene diisocyanate (HDI). In each case the diagnosis was confirmed with a bronchial provocation test (BPT). The asthmatic reaction was immediate in 17 cases, of which three had also a late reaction (dual). Eighteen patients reacted only with a late reaction. Seven (20%) had specific IgE to diisocyanates. All RAST-positive patients had an immediate asthmatic reaction. None of the late reactors and referents had positive RASTs. RAST inhibition tests with 94-100% inhibition confirmed the specificity of the method. There was cross-reactivity between different diisocyanates, however. The patients with positive RAST to diisocyanates had a higher level of total IgE than the RAST negative group and the referents.

A specific IgE-mediated response was evaluated in twenty-eight workers exposed to TDI or MDI, with diagnosis of occupational asthma and positive to bronchial provocative challenge. The presence of anti-diisocyanate IgE was observed in 27% of subjects exposed to TDI and 83% of those exposed to MDI, particularly in individuals who experienced an acute massive exposure. An immediate-type response to bronchial provocative test was found in 66% of individuals with specific antibodies. Specific IgE are prevalent (91%) in subjects who developed symptoms before 6 years of exposure to isocyanates. The results suggest an association between the presence of specific IgE, early asthmatic symptoms and heavy episodic exposure.

During September-November, 1985, four employees of a factory were seen at the occupational clinic complaining of cough, shortness of breath, and wheezing. All four worked in the same area of the factory where an adhesive containing toluene diisocyanate (TDI) was applied to velcro-like tape during manufacturing. To confirm the diagnosis of TDI-induced asthma and determine the prevalence among workers, 38 workers were interviewed and examined (84%) in the factory. Air samples were also taken from several areas in the factory to determine the TDI concentration. For analysis, the factory was divided into three areas based on the concentration of TDI: low (0.012 +/- 0.002 ppm), medium (0.021 +/- 0.006 ppm), and high (0.047 +/- 0.054 ppm). The distribution of workers with symptoms of asthmatic bronchitis was highly associated with TDI concentration (p less than 0.001). After stopping work for a period of 10 days, workers in areas with a high concentration of TDI showed marked improvement in pulmonary function tests (PFTs). After isolation of the exposure site, improvement of the ventilation system, and substitution of the TDI with less volatile diphenylmethane diisocyanate (MDI), air concentration of isocyanates was usually below 0.007 ppm. Three of the four clinically overt asthma cases went back to work without any difficulty. The PFTs of affected workers showed a significant improvement 5 months later. We conclude that TDI was responsible for the occupational asthma among velcro-like tape manufacturers and that the TDI-induced impairment of pulmonary functions was at least partially reversible.

A group of 182 workers exposed to diisocyanates (varnishers, carpenters, producers of polyurethane resins and expanded plastic) were examined to study the immunogenic capacity of these substances. The skin tests, particularly the intradermal tests, revealed reactions of the immediate, accelerated and/or delayed types due to the presence of IgE and IgG, in addition to responses of the cellular type. This was confirmed by passive transfer in guinea-pigs and man and immunohaematological tests such as passive haemagglutination and lymphocyte transformation. In 4 cases it was possible to demonstrate thermoresistant, homocytotropic immunoglobulins, that were not dependent on complement and behaved like reagins (i.e. short-term anaphylactic IgG). Exposure tests were performed on 45 cases; the results are analyzed and compared with those of the skin tests. It is concluded that both these groups of tests are of value in investigating the aetiopathogenesis of the pathology of the isocyanates: the skin tests for initial screening, and then the exposure tests for resolving doubtful diagnoses. Cross-reactions were also demonstrated between toluene-diisocyanate and methylene-diisocyanate. Two phases could be considered in the pathogenesis; in the first phase, signs of inflammation appeared at the primary sites of contact with the irritant, then the ability of the diisocyanates to form a conjugate with organic proteins results in the production of a complete antigen and consequent sensitization of the exposed person. The appearance of symptoms naturally depends on subsequent exposure and the immunogenic capacity of the patient: the response is mainly of the reagin type in atopic patients and of type 3 in non-atopic patients.

Clinical and serologic effects of TDI exposure were studied in 112 occupationally exposed plant workers. Sera were obtained before and after commencement of TDI production. All subjects were skin-tested with common inhalant allergens and a TDI-HSA conjugate. Total eosinophil counts, immunoglobulin quantitations, and specific antibody assays by PCA, P-K, and radioimmunoassay were performed. Clinically "sensitive" individuals were tested by provocative inhalation challenge with from 0.005 ppm to the threshold limit value of 0.02 ppm TDI. No TDI-induced immunologic changes were noted with the exception of 3 individuals who demonstrated small positive wheal-and-erythema reactions to TDI-HSA but not to HSA alone. Inhalation challenge with TDI vapor produced airways obstruction, as measured by FEF (25-75). These responses were of the immediate, delayed, and dual type, and were provoked in some cases with levels as low as 0.005 ppm TDI.