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Asthma due to non-occupational exposure to toluene (tolylene) di-isocyanate.

The production of asthma by toluene di-isocyanate, aspirated into the ventilating system and emanating from the exhausts of a neighbouring factory, was established in three otherwise non-exposed clerical workers. Occupational-type exposure tests with a polyurethane varnish/toluene di-isocyanate mixture elicited vigorous and prolonged non-immediate asthmatic reactions, thus enabling identification of the otherwise, obscure etiological cause of their asthma.

Adult↗

Allergic contact dermatitis from an organic di-isocyanate.

Organic di-isocyanates are used widely in industry. The concomitant respiratory complications are well-known. Cutaneous problems precipitated by skin contact with these chemicals are less well recognised. Allergic contact dermatitis caused by exposure to di-cyclohexylmethane 4,4'-di-isocyanate has been demonstrated in a factory where it was used to form a surface-coating polyurethane. Attention to hygiene methods may have reduced the incidence of cases.

Adolescent↗

Hypersensitivity pneumonitis after exposure to isocyanates.

Four patients exposed to isocyanate vapour developed dyspnoea associated with restriction and reduced gas transfer as well as moderate airways obstruction on lung function testing. In one patient bilateral radiographic shadowing was present and an open lung biopsy was performed. The microscopic appearances ranged from acute inflammation to end-stage fibrosis but the centribular accentuation of disease and the presence of areas resembling bronchopulmonary aspergillosis suggested that the process was a hypersensitivity response to inhaled allergen. Challenge tests with albumin and toluene diisocyanate-albumin were carried out in sensitized and control rabbits. The sensitized animals developed extensive lung damage of the type associated with an Arthus reaction. It is suggested that patients exposed to isocyanates may occasionally develop a hypersensitivity pneumonitis rather than the more usual asthmatic syndrome.

Animals↗

[On the pathogenesis of isocyanate-induced asthma].

3 asthmatic patients, occupationally exposed to vapors of toluylene diisocyanate (TDI), responded with a moderate to strong elevation of airway resistance up to the 26th h after inhalation challenge by 0.006--0.02 ppm TDI. No changes in chest radiographs and in DLCO were found. In none of the patients' sera, isocyanate-specific antibodies could be detected by RAST and Ouchterlony test. Change of job resulted in one case in an immediate interruption of the asthmatic symptoms, whereas in 2 patients recovery was slow over a period of 3 to 8 months and not complete. Our investigations suggest a toxic effect of isocyanates, which depends on their concentrations, and an important pharmacological reaction; but, up to now, there were no signs of allergic mechanisms.

Adult↗

Oligomers with pendant isocyanate groups as adhesives for dentin and other tissues.

Oligomers containing pendant isocyanate groups were synthesized from various vinyl monomers, m-isopropenyldimethylbenzyl isocyanate (TMI), and 2-isocyanatoethyl methacrylate (IEM). The liquids were characterized by their refractive indices, infrared spectra, and percentage of isocynate groups in the molecule. Adhesive properties of these compounds were compared with those of oligomers prepared from methacrylate esters, IEM, and/or TMI which had been synthesized previously. Bond strengths of the sodium salt of ethylenediamine-tetraacetic acid (Na2EDTA adjusted to pH 7.4) and glutaraldehyde-treated dentin cemented to composite resin with dilute solutions of the oligomers and then stored in water were determined by the procedure of Kemper and Kilian (1975). These adhesive compositions, especially formulations synthesized from vinyl monomers, adhered at least as well to dentin as did other dentin bonding agents. Oligomers synthesized with methacrylate esters bonded more strongly to bone than did other hard-tissue adhesives. These oligomeric compositions are also excellent soft-tissue adhesives. For example, they provide a strong bond between a collagenous substrate (such as calfskin) and cured denture-base resin. Provided that their biological properties prove satisfactory, these compositions could find many applications as hard- and soft-tissue adhesives in clinical dentistry.

Adhesiveness↗

Clinical and immunological evaluation of isocyanate-exposed workers.

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

Adult↗

Increased uptake of serotonin in platelets from car painters occupationally exposed to mixtures of solvents and organic isocyanates.

Twelve car painters occupationally exposed to mixtures of solvents and organic isocyanates were investigated concerning serotonin uptake in platelets. The data from the exposed workers were compared to data from a reference group consisting of 50 nonexposed volunteers. The mean platelet count in whole blood of the exposed workers was markedly lower than the corresponding value of the reference group. Three workers had values below the lower limit of the 95% tolerance interval of the referents. In both groups the serotonin transport strictly obeyed Michaelis-Menten's simple saturation kinetics. Nine of the twelve exposed workers had uptake rates which were significantly higher (p = 0.05) than those of the referents. The obtained data suggest that the present method may be used to reveal early organ damage, prior to the appearance of clinical symptoms, due to intermittent exposure to organic solvents and isocyanates.

Adult↗

Isocyanates and lung disease: experimental approaches to molecular mechanisms.

Isocyanates are reactive compounds that have commercial applications in the synthesis of a variety of products, including paints, coatings, elastomers, and foams. The correlation between isocyanates and a spectrum of respiratory disease has been established, primarily at the clinical level. The focus of this article is to bridge the gap of understanding from clinical symptoms to molecular reactivity, with emphasis on experimental approaches that serve to complement clinical and epidemiologic data.

Animals↗

Occupational asthma due to isocyanates in Singapore.

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.

Adolescent↗

Alkyl isocyanates as active site-directed inactivators of guinea pig liver transglutaminase.

Alkyl isocyanates are effective inactivators of guinea pig liver transglutaminase. Based on the specificity of the reaction the protection against inactivation by glutamine substrate, and the essential nature of calcium for the inactivation reaction, it is concluded that these reagents act as amide substrate analogs and, thus function in an active site-specific manner. Support for the contention that inactivation results from alkyl thiocarbamate ester formation through the single active site sulfhydryl group of the enzyme is (a) the loss of one free--SH group and the incorporation of 1 mol of reagent/mol of enzyme in the reaction, (b) similarity in chemical properties of the inactive enzyme derivative formed to those previously reported for another alkyl thiocarbamoylenzyme and an alkyl thiocarbamoylcysteine derivative, and (c) the finding that labeled peptides from digests of [methyl-14C]thiocarbamoyltransglutaminase and those from digests of iodoacetamide-inactivated enzyme occupy similar positions on peptide maps. Transglutaminase was found to be inactivated neither by urethan anlogs of its active ester substrates nor by urea analogs of its amide substrates. It is concluded on the basis of these findings that inactive carbamoylenzyme derivatives are formed only by direct addition of the transglutaminase active--SH group to the isocyanate C--N double bond, and not, like several serine active site enzymes, by nucleophilic displacement with urethan analogs of substrate, or by nucleophilic displacement with urea analogs of substrate.

Alcohols↗

Prevalence of occupational asthma in spray painters exposed to several types of isocyanates, including polymethylene polyphenylisocyanate.

The prevalence of occupational asthma was assessed in four paint shops of a large assembly plant where 51 employees were exposed to several types of isocyanates, including polymethylene polyphenylisocyanate (PPI). Three employees were first referred by their physician for asthma symptoms. A questionnaire was administered to the other 48 employees. Seven of these were suspected of having work-related asthma. Airway hyperexcitability to inhaled histamine was demonstrated in these ten subjects (three referred and seven screened). The diagnosis of occupational asthma was confirmed in six subjects (three referred and three screened) through specific inhalation challenges in the laboratory to a paint system component containing PPI. Thus, the prevalence of occupational asthma was 11.8% in these paint shops using several types of isocyanates, including PPI.

Adult↗

Isocyanates and health--a review.

Isocyanates are chemical compounds used increasingly frequently in industry for the production of a wide range of goods. They can produce severe asthmatic responses in the sensitive. Health hazards, diagnosis, first-aid measures, prevention and legislation are discussed. Patients presenting with apparently work-related asthma should be questioned about exposure to these substances, and workers should be informed of the dangers of such exposure. Legislation should be passed setting limits for exposure to isocyanates and ensuring compensation for those workers whose health is affected by exposure to these compounds.

Asthma↗

[Pneumopathy caused by hypersensitivity to isocyanates. Value and dangers of a realistic provocation test].

Organic isocyanates are responsible for bronchial pathology and in rare cases of hypersensitivity pneumonia. We present a new observation supported by a complete lung function assessment, histology of a transbronchial biopsy and a positive bronchial challenge test. The progress of the disorder was followed by repeated lung function measurements and bronchoalveolar lavage. The alveolar response at first showed an alveolar leukocytosis, then a mixed picture, finally becoming a pure lymphocytosis. The activity of the alveolar cells was assessed for T lymphocytes by cytofluorimetry, the presence of DRa like and LMR antigens and lastly for macrophages with Gallium scans. The inflammatory response was followed by analysing the proteins in the lavage liquid. The value of studying alveolar cell-activity and equally alveolar protein content is underlined in this study and reminds one of the character, sometimes unpredicted and dangerous, of challenge tests using isocyanates.

Bronchi↗

Protective effect of nifedipine upon specific bronchial responses to isocyanates.

In order to evaluate the effect of nifedipine, a calcium channel blocker, upon specific bronchial responses to isocyanates, 5 subjects with occupational asthma due to TDI were examined. Each subject was exposed to an atmosphere containing 0.01 ppm of TDI in an inhalation chamber for 15 minutes; the test was repeated on a different day 45 minutes after administration of placebo or nifedipine (20 mg sublingually) in a random fashion. Our data show an effectiveness of nifedipine at the above mentioned dose in preventing the responses arising immediately or within one hour after the exposure (cases n. 1, 2, 3, 4, 5). For preventing late responses it was necessary to repeat the administration of nifedipine (10 mg sublingually) 2 hours after the exposure (cases n. 4 and n. 5). The mechanism by which nifedipine prevents bronchial responses to isocyanates has not been elucidated.

Adult↗

Epiglottic dysfunction after isocyanate inhalation exposure.

Epiglottic dysfunction due to environmental exposure is a well-known entity. The most common causes of epiglottic dysfunction include trauma (thermal, chemical, and blunt), infection, allergy, neoplasm, and neurologic disorders. We report an unusual case of epiglottic dysfunction due to isocyanate inhalation exposure and review the literature concerning this subject. Following inhalation exposure to diphenylmethane diisocyanate, our patient developed persistent repeated airway obstruction during inspiration. Fiberoptic rhinolaryngoscopy showed that the epiglottis obstructed the glottic airway during each inspiratory cycle. The epiglottic dysfunction was also well demonstrated by barium contrast cineradiography. Total epiglottectomy resulted in resolution of the patient's upper airway obstructive symptoms. Histologically, marked inflammatory changes of the epiglottis were noted, including a focal infiltrative pattern, focal fibrosis, edema, and reactive changes.

Adult↗

Isocyanate medical surveillance: respiratory referrals from a foam manufacturing plant over a five-year period.

This study assesses the causes of medical surveillance changes leading to specialist referral from one isocyanate-using company where 39 workers (about 20% of all employees) were referred to a hospital occupational clinic during a 5-year period for concerns regarding their surveillance respiratory questionnaire or spirometry results. The respiratory assessment determined that the questionnaire had detected 5 workers with non-occupational asthma, 2 with possible occupational asthma (OA), and 1 with subsequently confirmed OA, while no additional asthmatics were detected by spirometry without questionnaire findings. The surveillance questionnaire in this study was sensitive but not specific (no additional compensation claims for OA were made during this time period): workplace spirometry, however, did not add to the detection rate of asthma.

Adult↗

Changes in brain and plasma amino acids of mice intoxicated with methyl isocyanate.

Precolumn derivatization with OPA was used for the analysis of brain and plasma free amino acids of mice after the administration of different doses (0.25 LD50, 0.5 LD50 and LD50) of methyl isocyanate (MIC) for different durations (45 min, 4 h, 4 days and 7 days). In general, there were a dose-dependent decrease in brain free amino acid content with the exception of glycine and arginine (increased above the control level with 0.25 LD50 and 0.5 LD50 doses), and taurine which increased with 0.5 LD50 and LD50 doses in 45 min. All the amino acids from plasma were increased with all the three doses, with the exception of arginine which decreased at the 0.25 LD50 dose in 45 min. With increase in duration of observation to 4 h, 4 days and 7 days, the brain amino acid content was still below the control levels and plasma levels were higher as compared to the respective controls. The only exceptions were serine, histidine, alanine and arginine, which decreased on the 7th day. This study suggests that MIC produced an imbalance of both the brain and plasma amino acids, suggesting neurotoxic and systemic effects.

Amino Acids↗

Immunological evaluation of four arc welders exposed to fumes from ignited polyurethane (isocyanate) foam: antibodies and immune profiles.

Four arc welders having a flu-like illness with multiple health complaints following an exposure to high concentrations of isocyanate fumes from ignited polyurethane foam underwent immunological tests as follows: ELISA antibody assays, activated lymphocyte profiles, and lymphocyte blastogenesis. ELISA procedures revealed the presence of antibodies to hexamethylene diisocyanate (HDI) and formaldehyde (F) conjugated to human serum albumin (HDI-SA and F-SA). The results from the activated lymphocyte profiles showed deviations from the norm as follows: three welders had elevated helper/suppressor (H/S) ratios; all four had elevated percentages of Tal positive cells; two had decreases in B cells; and one had low total white cell and lymphocyte counts. In contrast, the percentage and absolute numbers of ILS receptor cells were normal in the four subjects. T cell blastogenesis to PHA, Con A and PWM resulted in the following: T-cells from one subject responded normally; in another, a high response (212% of controls) to PHA occurred with normal mitogenesis to Con A and PWM. In the remaining two welders, the T cells responded abnormally low (50 to 75% of controls) to the three mitogens. In conclusion, the existence of IgG antibodies to HDI-SA and F-SA, the altered activated immune profiles, the elevated Tal cells, and the abnormal blastogenesis are interpreted as being linked with the episode of HDI and F exposure and the subsequent flu-like illness of the four welders.

Adult↗