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PubMed1984

Detection of immunologically sensitized isocyanate workers by RAST and intracutaneous skin tests.

Antibody estimations by RAST were performed on 621 partially selected isocyanate workers whose case histories were well-documented. Two hundred forty-seven of the workers were clinically suspected to be sensitized to isocyanates since they had suffered from occupationally related recurrent asthmatic attacks, chronic obstructive lung diseases, bronchitis, rhinitis, conjunctivitis, cutaneous hypersensitivity reactions, and/or fever. RAST studies with seven different isocyanates conjugated to human serum albumin (HSA) demonstrated that 14% of these symptomatic subjects had significant levels of specific-IgE antibodies. On the other hand, only one of the 374 asymptomatic workers had such antibodies. In contrast to toluene diisocyanate (80:20% mixture of 2, 4 and 2, 6-isomers, if not otherwise mentioned)-HSA, a toluene diisocyanate-ovalbumin conjugate exhibited no antigenicity in nearly all of the cases. Intracutaneous skin testing with five different isocyanate-HSA conjugates performed in 203 workers produced immediate-type wheel-and-flare reactions in 14 of the 53 symptomatic persons but in none of the 150 asymptomatic probands. There was a good overall correlation between RAST and skin test results. Our findings provide strong evidence for IgE-mediated sensitization to isocyanates in a subgroup of the subjects with isocyanate-induced diseases. By means of RAST and/or skin testing these immunologically sensitized persons can be identified.

Antibodies, Anti-Idiotypic↗
PubMed1987

Effects of carbamoylation with alkyl isocyanates on the assay of proteins by dye binding.

The effect of carbamoylation with alkyl isocyanate was used both to monitor the stability of the isocyanates and to study the influence of charge modification on protein assay. Carbamoylation of poly (L-lysine) with methyl isocyanate, ethyl isocyanate and 2-chloroethyl isocyanate was observed to decrease binding of methyl orange. The data emphasized the lability of alkyl isocyanates and indicated the importance of preparing aqueous solutions at low temperatures for studies on protein carbamoylation. After carbamoylation of several proteins, there was decreased metachromasia on binding to Coomassie Blue G. Poly (L-lysine) and H1 histone showed anomalous behavior in that with low concentrations of Coomassie Blue G the metachromasia was increased by carbamoylation, but at high concentrations of the dye the metachromasia was decreased by carbamoylation. In contrast to some reports in the literature, the data indicated that there is not always a simple relationship between the positive charge on a protein and the interaction with anionic dyes.

Azo Compounds↗
PubMed1987

Small airway hyperreactivity among lifelong non-atopic non-smokers exposed to isocyanates.

The development of isocyanate asthma is little understood. To gain more knowledge in this area, a group of 20 workers occupationally exposed to isocyanates, five subjects with clinical isocyanate asthma, and a control group of 10 people not exposed to isocyanate were examined with lung function tests and a methacholine provocation test. Forced expiratory volume in one second and tests aimed at detecting small airways obstruction such as volume of trapped gas, closing volume, and wash out volume were made. To detect abnormal airway reactivity, tests were made before and after inhalation of methacholine and of salbutamol. A significant increased reactivity to methacholine in the exposed and asthma groups was seen compared with the control group as measured by volume of trapped gas. The increase was reversed by inhaling salbutamol. In neither group could a statistically significant reaction be shown in the large airways. The study group had increased small airways reactivity of the same magnitude as the group with isocyanate asthma. The subjects in the study group had no clinical symptoms or spirometric abnormalities. The volume of trapped gas in combination with methacholine seems to disclose significantly altered reactivity of the small airways in workers exposed to isocyanate with no subjective symptoms of disease.

Adult↗
PubMed1992

Closed-circuit methodology for inhalation challenge tests with isocyanates.

The diagnosis of isocyanate-induced occupational asthma can be made by exposing subjects to isocyanates in small challenge rooms. There are, however, several pitfalls inherent in this procedure. Isocyanate concentrations may not remain stable throughout the exposure and may exceed the recommended TLV ceiling of 20 ppb. This can induce irritant or unduly severe bronchial reactions. To overcome these problems, a closed-circuit apparatus for generating isocyanates in a gaseous form was developed; it was assessed in 20 subjects suspected of having isocyanate-induced asthma. Subjects were tested using both the small challenge room method and the new closed-circuit method in a randomized sequential way. Isocyanate concentrations were more stable with the closed-circuit apparatus than with the challenge room method (mean of individual variance of 6.3 and 61.8, respectively; p less than 0.001). The percentage of the total exposure time during which concentrations were above 20 ppb was reduced from 11.3 to 4.5% (p less than 0.001). The two methods yielded the same number of positive and negative responses, except for one subject who did not have a positive reaction when tested with the challenge room method. The pattern and magnitude of asthmatic reactions were similar for both methods. However, the duration of exposure was shorter with the challenge room method than with the closed-circuit methods (p = 0.04).

Administration, Inhalation↗
PubMed1988

Occupational asthma due to isocyanates.

162 subjects who had been exposed to isocyanates, who had developed symptoms during the exposure period, or in the evening or night and, therefore, had a history compatible with isocyanate-induced asthma, were studied with inhalation challenge testing to isocyanates (toluene diisocyanate and methylene diphenyl diisocyanate) and methacholine, because they were suspected of having occupational asthma. None of these subjects had symptomatic asthma before employment. The diagnosis of occupational asthma was delayed (duration of symptoms before diagnosis: 3.9 +/- 0.4 yrs). Isocyanate-asthma documented by a positive inhalation challenge to isocyanates was present in 57.4% of the subjects. A higher degree of airway responsiveness to methacholine was present in subjects with a positive isocyanate inhalation challenge compared to subjects with a negative challenge (Gmean and GESM: 0.407 (1.14) vs 0.942 (1.14) mg). The majority of the subjects complained of shortness of breath and cough. The low proportion of atopic subjects (21.5%) and of smokers (7.5%), and the high proportion of subjects with the late component in the asthmatic reaction (71%) appear to be common features in this disease.

Adult↗
PubMed1990

S-(N-methylcarbamoyl)glutathione: a reactive S-linked metabolite of methyl isocyanate.

S-(N-methylcarbamoyl)glutathione, a chemically-reactive glutathione conjugate, has been isolated from the bile of rats administered methyl isocyanate and characterized, as its N-benzyloxycarbonyl dimethylester derivative, by tandem mass spectrometry. The ability of this glutathione adduct to donate an N-methylcarbamoyl moiety to the free -SH group of cysteine was evaluated in vitro with the aid of a highly specific thermospray LC/MS assay procedure. The glutathione adduct reacted readily with cysteine in buffered aqueous media (pH 7.4, 37 degrees C) and after 2 hr, 42.5% of the substrate existed in the form of S-(N-methylcarbamoyl)cysteine. The reverse reaction, i.e. between the cysteine adduct and free glutathione, also took place readily under these conditions. It is concluded that conjugation of methyl isocyanate with glutathione in vivo affords a reactive S-linked product which displays the potential to carbamoylate nucleophilic amino acids. The various systemic toxicities associated with exposure of animals or humans to methyl isocyanate could therefore be due to release of the isocyanate from its glutathione conjugate, which thus may serve as a vehicle for the transport of methyl isocyanate in vivo.

Animals↗
PubMed2005

Anomeric O-acylation of Kdo using alkyl and aryl isocyanates.

To develop a convenient method for the preparation of an alpha-Kdo derivative carrying a functional spacer at the reducing end, we examined anomeric O-acylation using Kdo and halogenated alkyl/aryl isocyanates as nucleophile and electrophiles, respectively. Reaction of a Kdo derivative with 2-chloroethyl isocyanate in the presence of DMAP gave an alpha-spiro product (82%) and an alpha-Kdo derivative of a dimeric isocyanate adduct (10%). Similar reaction with 4-(chloromethyl)phenyl isocyanate gave only the corresponding alpha-spiro product (81%). The NMR data show that the pyranose rings of both the alkyl and aryl spiro products adopt the 5C2 conformation. Thus, we accomplished alpha-selective anomeric O-acylation by coupling the Kdo derivative with alkyl and aryl isocyanates.

Acylation↗
PubMed1991

Indirect determination of isocyanates by gas chromatography.

A gas chromatographic method was developed to determine the purity of synthesized isocyanate monomers, specifically isocyanatoacrylates, and to determine the isocyanate content of synthesized polymers and prepolymers. The method is a modification of an ASTM procedure in which an isocyanate is allowed to react with excess di-n-butylamine. In the ASTM method, the amount of isocyanate present is calculated indirectly from the amount of unreacted di-n-butylamine, determined by back titration with standard hydrochloric acid. Determination of the excess di-n-butylamine by the gas chromatographic method developed has the advantages of providing better precision and requiring less sample than the titrimetric method. The two methods were compared using phenyl isocyanate as a model test compound. A synthesized monomer, methyl alpha-isocyanatoacrylate, was also analyzed, for comparison by both methods.

Chromatography, Gas↗
PubMed1999

Isocyanate-conjugated human lung epithelial cell proteins: A link between exposure and asthma?

BACKGROUND: Isocyanates are a group of highly reactive cross-linking chemicals that cause airway inflammation and asthma in exposed individuals. Isocyanates have been detected along the airway epithelia of exposed workers and animals, prompting the hypothesis that isocyanates can directly bind to epithelial cell proteins. OBJECTIVE: We tested the hypothesis that hexamethylene diisocyanate (HDI) binds directly to lung epithelial cell proteins and initiated studies to evaluate the immunostimulatory potential of HDI-conjugated lung epithelial cell proteins. METHODS: Human lung epithelial cell lines were exposed to vapor- and liquid-phase HDI, and the cellular proteins were analyzed for HDI conjugation by Western blotting and tested for the ability to induce lymphocyte proliferation in vitro. RESULTS: A number of epithelial cell polypeptides, ranging from 25 to 110 kd in apparent molecular weight, were conjugated with HDI after exposure of the human lung epithelial cell lines (A549 and NCI-H292) to HDI concentrations greater than 0.005% (vol/vol) in the liquid phase. Vapor-phase HDI exposure resulted in a more restricted HDI conjugation pattern, with major HDI-conjugated polypeptides migrating at 47, 71, and 91 kd. HDI-conjugated epithelial cell proteins specifically stimulated proliferation of PBMCs from subjects with isocyanate-induced asthma but not HDI-exposed nonasthmatic individuals or atopic subjects with nonisocyanate-related asthma. CONCLUSIONS: The data demonstrate that epithelial cell proteins readily react with HDI and that HDI-conjugated epithelial cell proteins can stimulate lymphocyte proliferation. Further characterization and evaluation of HDI-conjugated epithelial cell proteins will elucidate their potential role in the pathogenesis of isocyanate-induced asthma.

Air Pollutants↗
PubMed1996

Phenyl isocyanate is a potent chemical sensitizer.

Diisocyanates, as a chemical class, are recognized for their ability to cause respiratory and dermal sensitization. By contrast, monofunctional isocyanates have not been associated with cases of clinical sensitization. We investigated the immunologic activity of phenyl isocyanate (PI), an aromatic monoisocyanate, which is a trace constituent in commercial diphenyl methane diisocyanate (MDI) products, since it is has been reported to cause an "asthma-like' syndrome in rats. The potency of PI as a contact sensitizer was assessed using the mouse ear swelling test. PI was found to be the most potent isocyanate tested yielding an SD50 (dose predicted to sensitize 50% of the mice) of 0.04 mumol/kg, compared with SD50 values of 0.5, 2.1, and 30.4 mumol/kg, for the diisocyanate sensitizers hexamethylene diisocyanate, MDI, and toluene diisocyanate (TDI), respectively. When tested for ability to stimulate humoral immune responses, antibody titers to PI were more than ten-fold greater than those induced by TDI. The mean hapten-specific IgG antibody titer to PI was 1.4 x 10(4), compared with 1.3 x 10(3) for TDI. The anti-PI IgG1 anaphylactic antibody titer (1.2 x 10(4) was significantly greater than the anti-TDI IgG1 titer of 6.4 x 10(2). Hapten-specific IgE was not detected to either isocyanate. These results indicate that phenyl isocyanate is a potent inducer of both cellular and humoral immune responses. This activity may be a significant contribution to the sensitization potential of commercial products in which it is a trace contaminant.

Animals↗
PubMed2001

Mechanisms of isocyanate sensitisation. An in vitro approach.

Although there is an abundance of clinical evidence which suggests that the inhalation of isocyanates can induce occupational asthma, the immunological basis for the disease is not understood. We have investigated immune cell responses to isocyanate using the cell line mono-mac-6, by measuring the production of hydrogen peroxide, and the expression of ICAM-1 following challenge with isocyanates and their corresponding amines. We observed an increase in the levels of intracellular peroxide, in addition to an upregulation of ICAM-1 expression (P<0.05), following cell stimulation with isocyanates, which was not apparent following stimulation with amines. From the results of this study we hypothesise that the production of reactive oxygen species (ROS) by monocytic cells at the site of exposure to an isocyanate may have two potential outcomes. The first is that the ROS may contribute to tissue damage at the site of inflammation, and then secondly, it is possible this production of hydrogen peroxide may also induce the upregulation of adhesion markers on monocytic cells, specifically ICAM-1, which may potentiate the infiltration and adhesion of cells at the site of inflammation.

Cyanates↗
PubMed2006

Preparation, isolation, and characterization of Nalpha-Fmoc-peptide isocyanates: solution synthesis of oligo-alpha-peptidyl ureas.

The N(alpha)-Fmoc-peptide isocyanates 3a-q, 4a-c, and 5a-c were prepared by the Curtius rearrangement of N(alpha)-Fmoc-peptide acid azides in toluene under thermal, microwave, and ultrasonic conditions. All the N(alpha)-Fmoc-oligo-peptide isocyanates made were isolated as stable crystalline solids with 71 to 94% yield and were fully characterized by 1H NMR, 13C NMR, and mass spectroscopy. Their utility for the synthesis of oligo-alpha-peptidyl ureas 7a-f and 8a-c by the divergent coupling approach was demonstrated. The coupling of N(alpha)-Fmoc-dipeptide isocyanates with amino acid ester or with N,O-bis(trimethylsilyl)amino acids resulted in N(alpha)-Fmoc-tripeptidyl urea ester and acids containing one each of peptide bond and urea bond. The divergent approach is extended to the synthesis of tetrapeptidyl ureas by the 2 + 2 strategy using bis-TMS-peptide acid as an amino component. To incorporate urea bonds in adjacent positions, N(alpha)-Fmoc-peptidyl urea isocyanates 9a-d were prepared and employed in the synthesis of three tetrapeptidyl ureas 10a-b and 11 containing one peptide bond and two urea bonds in series from the N-terminal end. The protocol was then employed for the synthesis of five urea analogues 13-15, 18, and 21 of [Leu5]enkephalin containing urea bonds at the 2, 3, 4 positions as well as at the 2, 4 and 2, 3, 4 positions. The analogue 2l was made by the convergent synthesis by the N --> C terminal chain extension. Finally, two urea analogues 22 and 23 of repeat units of bioelasto polymers, namely Val-Pro-Gly-Val-Gly-OH and Pro-Gly-Val-Gly-Val-OH, were synthesized incorporating the urea bond by the concomitant isocyanate generation and urea bond formation under thermal conditions.

Amino Acid Sequence↗
PubMed2002

Occupational allergic contact dermatitis caused by isocyanates.

Between 1978 and 2001, 22 patients were diagnosed with occupation-related allergic contact dermatitis from isocyanates and/or polyurethanes in our clinic. 13 had a positive reaction to the isocyanates, of whom 10 also reacted to diaminodiphenylmethane (MDA), which is used in the production or processing of isocyanates and polyurethanes; 9 reacted only to MDA. The object of the present study was to identify the trades and industries responsible for the development of contact allergy to these resins. Such patients must be patch tested with the isocyanates contacted at work, and account must be taken of positive reactions to MDA as a marker for isocyanate sensitivity.

Adult↗
PubMed2002

Exposure to airborne isocyanates and other thermal degradation products at polyurethane-processing workplaces.

The thermal degradation products of polyurethanes (PURs) and exposure to isocyanates were studied by stationary and personal measurements in five different occupational environments. Isocyanates were collected on glass fibre filters impregnated with 1-(2-methoxyphenyl)piperazine (2MP) and in impingers containing n-dibutylamine (DBA) in toluene. connected to a glass fibre postfilter. The derivatives formed were analysed by liquid chromatography: 2MP derivatives with UV and electrochemical detection and DBA derivatives with mass spectrometric detection. The release of aldehydes and other volatile organic compounds into the air was also studied. In a comparison of the two sampling methods, the 2MP method yielded about 20% lower concentrations for 4,4'-methylenediphenyl diisocyanate (MDI) than did the DBA method. In car repair shops, the median concentration of diisocyanates (given as NCO groups) in the breathing zone was 1.1 microg NCO m(-3) during grinding and 0.3 microg NCO m(-3) during welding, with highest concentrations of 1.7 and 16 pg NCO m(-3), respectively. High concentrations of MDI, up to 25 and 19 microg NCO m(-3), respectively, were also measured in the breathing zone during welding of district heating pipes and turning of a PUR-coated metal cylinder. During installation of PUR-coated floor covering, small amounts of aliphatic diisocyanates were detected in the air. A small-molecular monoisocyanate, methyl isocyanate, and isocyanic acid were detected only during welding and turning operations. The diisocyanate concentrations were in general higher near the emission source than in the workers' breathing zone. A sampling strategy to evaluate the risk of exposure to isocyanates is presented.

Air Pollution, Indoor↗
PubMed2003

[Isocyanates: occupational exposures and disorders].

Isocyanates are extensively used for the production of different foams and elastomers. They also serve as glues, lacquer hardeners, inks, adhesives, fillers, finishes, sealants, coating and insulation materials. Usually, their application results in inhalative, partly also in cutaneous uptake. This review describes occupational exposures to isocyanates as well as hazardous effects. Isocyanates are used in the automotive/mechanical engineering/building and construction/mining/casting/electricity and electronic/plastics/printing/timber and furniture/white goods and textile industry, partly also in medicine. Hazardous exposures to thermal degradation products of isocyanate-based polyurethanes and other materials have also be taken into consideration. Obstructive airway diseases are the major disorder caused by isocyanates. Rare cases suffer from extrinsic allergic alveolitis or eczema. In addition to regulation-based primary prevention qualitative medical surveillance mostly prevents disorders. There is also a need for the establishment of a validated biomonitoring of endangered employees.

Humans↗
PubMed1998

Prevalence of respiratory symptoms and increased specific IgE levels in West-African workers exposed to isocyanates.

Respiratory symptoms and immunological effects from chronic exposure to isocyanates (toluene diisocyanate) were studied in a cross survey of workers from West African factories producing paints and polyurethane foam. A questionnaire, a pulmonary function test, immunoglobulin E (IgE) levels, radioallergosorbent test (RAST) and an atmospheric sample to quantify isocyanate exposures were carried out in the workplace for each worker. Ninety-six workers, of whom 44 had occupational isocyanate-induced asthma, were included in the study. Twenty-four viral-infected subjects were excluded from the immunological study. Specific antibodies to isocyanates were detected in two of the symptomatic individuals. This low proportion appeared to be a common feature of this disease. The prevalence of isocyanate-induced asthma in a West African working population appears to be significant in the context of chronic human exposure, as current data are based on excessive acute exposure due to an accident as seen in India.

Adult↗
PubMed2004

A survey of airborne isocyanate exposure in 13 Swedish polyurethane industries.

Exposure to isocyanates can be harmful to workers by causing different disorders of the airways. The main objectives of this study were to survey the personal 8 h time-weighted average exposure to isocyanates at 13 Swedish plants that handled either polyurethane, diisocyanates or both, including four types of manufacturing processes: moulding, continuous foaming, flame lamination and low or no heating processes. A total of 223 air samples were collected for 111 workers with personal air monitoring using a dry filter method with 1-(2-methoxyphenyl)piperazine (2MP) as derivatization reagent. A further 272 stationary samples were collected, using the 2MP method, a modified 2MP method and an impinger method using dibutylamine in toluene. With the applied strategy, a large number of workers were monitored and four industrial environments were compared regarding the isocyanate exposure. All workers were found to be exposed to isocyanates in the range 0.004-5.2 p.p.b. On average, the personal exposure levels in the different types of manufacturing processes were, in decreasing order: continuous foaming > flame lamination > moulding >> low or no heating processes. However, there were variations in exposure levels in plants with similar processes and also between different shifts performing the same tasks. Isocyanic acid, which could not be sampled by the 2MP method used for personal monitoring, was found by short-term stationary monitoring in levels up to 38 p.p.b. in the flame lamination plants.

Air Pollutants, Occupational↗
PubMed2004

Determination of isocyanates in air using 1-(2-methoxyphenyl)piperazine-impregnated filters: long-term sampling performance and field comparison with impingers with dibutylamine.

Isocyanates may be harmful to workers and methods for monitoring air exposure in the field are necessary. The main aim of this study was to study the field performance of a method using 1-(2-methoxyphenyl)piperazine (2MP)-impregnated filters, by side-by-side comparison of long-term sampling with consecutive short-term samplings and also by short-term comparisons with other methods. Apart from using 2MP-impregnated filters, air monitoring was also performed by a modified 2MP method (FINMP) and by an impinger method using dibutylamine (DBA), which was the reference method. For short-term sampling the compared methods performed equally well for 2,6-toluenediisocyanate (2,6-TDI) and for isocyanic acid. For 2,4-toluenediisocyanate (2,4-TDI), the DBA method gave approximately 10% higher results according to linear regression than the 2MP method and for phenyl isocyanate, the DBA method gave significantly higher results than both the 2MP and FINMP methods. During long-term sampling (2-4 h) of TDI with the 2MP method, significantly lower levels were found compared with parallel sampling with consecutive short-term samplings. A time-dependent correction factor for long-term sampling was calculated to be 1.7 for 2,4-TDI and 1.5 for 2,6-TDI for 4 h sampling. The long-term sampling performance for other isocyanates was not studied. In conclusion, short-term monitoring shows that the 2MP method slightly underestimates the true air concentration for some of the isocyanates studied, but the error is relatively small considering the variation in exposure. For long-term monitoring the 2MP method can be applied for TDI but, since the method underestimates the concentrations, a correction factor is needed which needs to be corroborated further.

Air Pollutants, Occupational↗