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PubMed1980

Mutagenic action of isocyanates used in the production of polyurethanes.

Isocyanates used in the production of polyurethanes were investigated for mutagenic action in Salmonella typhimurium. These investigations showed that the most commonly used isocyanates, toluene diisocyanate (TDI) and 4,4'-methylene-diphenylisocyanate (MDI), are mutagenic. This effect can be ascribed to the amine analogues formed during the hydrolysis of isocyanates: TDI is mutagenic in TA 1538 and TA 98 after metabolic activation. This finding agrees with the results obtained with the amine analogue 2,4-toluenediamine. MDI, like the amine analogue 4,4'-methylenedianiline, is mutagenic in TA 100 after metabolic activation by rat liver enzymes (S-9 mix). A prepolymerized polyisocyanate of the MDI type is also mutagenic in assays using TA 100 and S-9 mix. It is concluded that isocyanates are potentially mutagenic and carcinogenic to man. In view of their widespread use in the work environment and in light of the high production figures for polyurethanes in industrialized countries, isocyanates must be considered to represent a serious health hazard.

Cyanates↗
PubMed1990

[Isocyanate-induced respiratory tract diseases in Switzerland].

From 1980 to 1986 the Swiss National Accident Insurance Company (SUVA) recognized isocyanate-induced airway diseases as an occupational illness in 245 cases, which are presented retrospectively. Since isocyanates are widely used they are found at a large variety of workplaces. At present, isocyanates are the most frequent cause of occupational asthma in the Swiss industrial field. After complete avoidance of any further exposure respiratory symptoms persisted or airway obstruction could still be documented in one third of patients. An unfavourable prognosis is significantly associated with the following factors: (1) bronchial obstruction (FEVl/VC) at first pulmonary function test; (2) RAST positive for isocyanates; (3) long latency period between onset of symptoms and end of exposure. Therefore, individuals with isocyanate-induced airway diseases must be immediately removed from any further exposure to these substances.

Adolescent↗
PubMed1983

[Respiratory pathology of isocyanates].

Isocyanates are chemical compounds used in making polyurethane (for flexible or rigid foam, paint, varnish, glue and textiles). In strong concentrations isocyanates are powerful irritants producing chemical bronchopulmonary lesions. In weak doses they are responsible for occupational asthma and more rarely allergic alveolitis. Long term exposure to isocyanates may produce a deterioration in pulmonary function in asymptomatic patients. The pathophysiology of isocyanate asthma remains uncertain: immunological data remains contradictory while isocyanates have been shown to have a Betablocking effect. The maximum allowable concentration in the working environment, at present proposed in the U.S.A. is 0.005 ppm.

Alveolitis, Extrinsic Allergic↗
PubMed1996

Humoral and cellular immune responses in asthmatic isocyanate workers: report of two cases.

Two workers (23 and 28 years old) developed rhinitis and bronchial asthma after occupational contact with the isocyanate MDI. Positive skin prick test results for MDI-HSA and IgE antibodies to all isocyanate-HSA conjugates were obtained in both cases, and the inhalation challenge test with MDI produced immediate and late asthmatic reactions. In the patch test and the stimulation assay of peripheral mononuclear blood cells, a specific sensitization to the diamine MDA (in both cases) and to further amines (in one case), as well as to hydrolysates of the respective diisocyanates, was seen, which appears to be independent of the IgE response to isocyanate-HSA conjugates. Our results offer evidence of IgE-mediated, as well as lymphocyte, responses induced by exposures to isocyanate products over several months or years.

Adult↗
PubMed1997

No evidence for the influence of HLA class II in alleles in isocyanate-induced asthma.

Isocyanates are one of the main causes of occupational asthma. The aim of this investigation was to study the possible genetic background of isocyanate-induced asthma under consideration of the atopy status and different lung function parameters. We investigated the human leukocyte antigen (HLA) genes DRB1,3,4,5, DQB1, and DQA1 in 55 isocyanate-exposed patients with workplace-related dyspnea (32 asthmatics, 23 nonasthmatics) and 90 nonexposed controls. In contrast to other studies, we found no significant differences for any HLA class II allele tested in our study group. Furthermore, no significant differences concerning the aspartic amino acid residue 57 of DQB1 was observed. Therefore, we are unable to confirm an involvement of a specific HLA class II allele or DQB1-Asp57 in conferring susceptibility to isocyanate asthma in our study group.

Adult↗
PubMed1989

Specific serum antibodies against isocyanates: association with occupational asthma.

Although increased levels of specific IgE and/or IgG antibodies have been documented in individual cases of occupational asthma caused by common types of isocyanates (hexamethylene diisocyanate [HDI] and diphenylmethane diisocyanate [MDI]), the frequency among workers with occupational asthma is still unknown. The sera of 62/65 workers referred for specific inhalation challenges with isocyanates were analyzed for the presence of specific antibodies to the relevant isocyanate. Most workers (39, 63%) were exposed to HDI, some to MDI (17, 27%), and a few to toluene diisocyanate (six, 10%). Specific inhalation challenges were positive in 29 subjects, eliciting either immediate (seven), early late (two), late (13), or dual (seven) reactions. Specific inhalation challenges were more often positive in those subjects with increased nonspecific bronchial responsiveness. Twenty-nine subjects demonstrated increased levels of specific IgE and/or IgG antibodies to isocyanates in the absence of antibodies against human serum albumin (increased IgE only, no subject; IgG only, 20; both IgE and IgG, nine subjects). Although there was a loose association between the results of specific inhalation challenges and levels of specific IgE, the association was much better with the level of specific IgG. Indeed, 21 of the 29 subjects (72%) with positive challenges had increased levels of specific IgG, whereas 25 of the 33 subjects (76%) with negative challenges had normal levels of antibodies. The association was significant with both HDI and MDI. The levels of antibodies were not significantly associated with the type of temporal reaction.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies↗
PubMed2005

Differential inhibition of cellular glutathione reductase activity by isocyanates generated from the antitumor prodrugs Cloretazine and BCNU.

The antitumor, DNA-alkylating agent 1,3-bis[2-chloroethyl]-2-nitrosourea (BCNU; Carmustine), which generates 2-chloroethyl isocyanate upon decomposition in situ, inhibits cellular glutathione reductase (GR; EC 1.8.1.7) activity by up to 90% at pharmacological doses. GR is susceptible to attack from exogenous electrophiles, particularly carbamoylation from alkyl isocyanates, rendering the enzyme unable to catalyze the reduction of oxidized glutathione. Evidence implicates inhibition of GR as a cause of the pulmonary toxicity often seen in high-dose BCNU-treated animals and human cancer patients. Herein we demonstrate that the prodrug Cloretazine (1,2-bis[methylsulfonyl]-1-[2-chloroethyl]-2-[(methylamino)carbonyl]hydrazine; VNP40101M), which yields methyl isocyanate and chloroethylating species upon activation, did not produce similar inhibition of cellular GR activity, despite BCNU and Cloretazine being equally potent inhibitors of purified human GR (IC(50) values of 55.5 microM and 54.6 microM, respectively). Human erythrocytes, following exposure to 50 microM BCNU for 1h at 37 degrees C, had an 84% decrease in GR activity, whereas 50 microM Cloretazine caused less than 1% inhibition under the same conditions. Similar results were found using L1210 murine leukemia cells. The disparity between these compounds remained when cells were lysed prior to drug exposure and were partially recapitulated using purified enzyme when 1mM reduced glutathione was included during the drug exposure. The superior antineoplastic potential of Cloretazine compared to BCNU in animal models could be attributed in part to the contribution of the methyl isocyanate, which is synergistic with the co-generated cytotoxic alkylating species, while at the same time unable to significantly inhibit cellular GR.

Animals↗
PubMed2005

Cytokine mRNA profiles for isocyanates with known and unknown potential to induce respiratory sensitization.

Isocyanates are low-molecular-weight chemicals implicated in allergic asthmatic-type reactions. Identification of chemicals likely to cause asthma is difficult due to the lack of a validated test method. One hypothesis is that differential cytokine induction (Th1 versus Th2 profiles) in the draining lymph node following dermal application can be used to identify asthmagens and distinguish them from contact allergens. In this study, we compared the cytokine mRNA profiles of six chemicals: toluene diisocyanate (TDI), diphenylmethane-4,4'-diisocyanate (MDI), dicyclohexylmethane-4,4'-diisocyanate (HMDI), isophorone diisocyanate (IPDI), p-tolyl(mono)isocyanate (TMI), and meta-tetramethylene xylene diisocyanate (TMXDI). Whereas TDI and MDI are well-known respiratory sensitizers, documentation for HMDI, IPDI, TMI, and TMXDI is limited, but suggests that HMDI and IPDI may have respiratory sensitization potential in humans and TMI and TMXDI do not. Following dermal exposure of BALB/c mice, all six isocyanates induced cytokines characteristic of a Th2 response. Although LLNAs suggested that the doses chosen for the RPA were immunologically equivalent, the isocyanates tested differentiated into two groups, high responders and low responders. However, two of the low responders (TMI and TMXDI) were further tested and induced higher levels of Th2 cytokine message than dinitrochlorobenzene (not an asthmagen). Further study of these chemicals is needed to determine whether the Th2 cytokine responses observed for these low responders is predictive of asthmagenic potential or represents an insufficient signal.

Allergens↗
PubMed2003

Conformational analysis and comparison between theoretical and experimental vibrational spectra for chloroacetyl isocyanate.

The conformational stability and vibrational infrared and Raman spectra of chloroacetyl isocyanate (CH2ClCONCO) were investigated by ab initio MP2 and density functional B3LYP calculations using the 6-311 + + G** basis set. From the potential energy scans of the internal rotations of both the halomethyl and the isocyanate rotors, chloroacetyl isocyanate was predicted to exist predominantly in a mixture of the cis-cis (chlorine atom and NCO group eclipse C=O bond) and the gauche-cis (one hydrogen atom and NCO group eclipse C=O bond) conformations with a comparable relative stability. The vibrational wavenumbers of each of the two conformers of the molecule were computed at DFT-B3LYP/6-311 + + G** level. Normal coordinate calculations were carried out to obtain the potential energy distributions (PED) among the symmetry coordinates of the normal modes for each of the stable conformers of chloroacetyl isocyanate. The theoretical vibrational assignments are compared with experimental ones and a ratio of observed/calculated wavenumbers of about 0.97-1.04 was obtained.

Isocyanates↗
PubMed2002

Isocyanate emission from PUR adhesives: influence of temperature, monomer content, and curing mechanism.

The isocyanate emission potential of polyurethane (PUR) adhesives was evaluated by measuring the area-specific emission rate (SERa;microg m(-2) h(-1)) in a laboratory emission test chamber. The chamber was constructed for the analysis of reactive substances allowing quantitative trapping of all isocyanate monomers emitted from the substrate. Isocyanates were analyzed as their 1-(2-pyridyl)piperazine derivatives by HPLC with fluorescence and UV detection. The influence of temperature, the content of the diisocyanate in the resin, and the system pressure were investigated. These parameter studies gave evidence thatthe diisocyanate emission from the resins is a gas-phase-limited mass transfer. The overall mass-transfer coefficient (beta = Ddelta(-1)) was calculated for HDI and MDI. From the temperature dependence of emission rates, the enthalpies of evaporation for 2,4'-MDI, 4,4'-MDI, and HDI from their resins were determined. The influence of monomer content on SERa followed Henry's and Raoult's laws in the cases of HDI and MDI, respectively, allowing the prediction of emission rates proportional to diisocyanate content. Therefore, from simple parameters such as application temperature and monomer content, isocyanate emission rates can be predicted. Additionally, MDI emission from curing PUR adhesives was studied. These results elucidate the influence of monomer reactivity and curing mechanism on the decrease of MDI emission with time.

Adhesives↗
PubMed1994

Latent alkyl isocyanates as inhibitors of aldehyde dehydrogenase in vivo.

On the basis of our previous observation that N1-alkyl substituted chlorpropamide derivatives when administered to rats nonenzymatically eliminated n-propyl isocyanate, a known inhibitor of aldehyde dehydrogenase (AlDH), we have synthesized other latentiated n-propyl isocyanates as in vivo inhibitors of AlDH. N1-Allylchlorpropamide 3 was, as expected, a potent inhibitor of hepatic AlDH in rats, as indicated by the 4-fold increase in the levels of ethanol-derived blood acetaldehyde relative to that elicited by chlorpropamide itself. Closely following in activity in decreasing order were N3-(n-propylcarbamoyl)uracil (7),N-(n-propylcarbamoyl)saccharin (6), and the S-(n-propylcarbamoyl) derivative (9) of benzyl mercaptan. However, two hydantoin derivatives, 5 and 8, were totally inactive in inhibiting AlDH in vivo. A prodrug of N1-ethylchlorpropamide, viz., its N3-trifluoroacetyl derivative (4b), was a good in vivo inhibitor of AlDH, mimicking the activity of the parent N1-ethylchlorpropamide. These results suggest that latent alkyl isocyanates are inhibitors of AlDH, giving further support to the hypothesis that the inhibition of AlDH in vivo by the hypoglycemic agent chlorpropamide may be due to the release of n-propyl isocyanate following metabolic bioactivation.

Aldehyde Dehydrogenase↗
PubMed2000

What is the respiratory retention of inhaled hexamethylene di-isocyanate?

Isocyanates are a frequent cause of occupational asthma. Specific inhalation challenges are often required to confirm the diagnosis. The inhaled concentration has to be assessed during this procedure. However, the respiratory retention of di-isocyanate has not, to the authors knowledge, been evaluated in humans. The existence of a closed-circuit apparatus, designed to carry out these challenges, makes it possible to assess the dose. The respiratory retention of hexamethylene di-isocyanate (HDI) generated in vapour form, in both normal subjects (n=4) and subjects referred for the investigation of occupational asthma due to HDI in whom the diagnosis was excluded (n=5), was assessed. The latter group included four subjects with nonoccupational asthma. The HDI was generated at concentrations varying 5.1-15.2 ppb. The expired concentrations of HDI during such challenges varied 1.4-5.3 ppb. Therefore, the respiratory retention was 61-90%. To conclude, the majority of inhaled hexamethylene di-isocyanate vapour is retained within the airways and/on lung parenchyma.

Asthma↗
PubMed2005

Solvent-free sampling with di-n-butylamine for monitoring of isocyanates in air.

The solvent-free sampler for airborne isocyanates consisted of a polypropylene tube with an inner wall coated with a glass fibre filter, coupled in series with a 13 mm glass fibre filter. The filters were impregnated with reagent solution containing equimolar amounts of di-n-butylamine (DBA) and acetic acid. Air sampling was performed with an air flow of 0.2 l min(-1). The formed isocyanate-DBA derivatives were determined using liquid chromatography and tandem mass spectrometry. The sampler was investigated in regard to collection principle and extraction of the formed derivatives with good results. The possibility to store the sampler before sampling and to perform long-term sampling was demonstrated. Field extraction of the sampler was not necessary, as there was no difference between immediately extracted samples and stored ones (2 days). In comparative studies, the sampler was evaluated against a reference method, impinger-filter sampling with DBA as reagent. The ratios between the results obtained with the sampler and the reference in a test chamber at a relative humidity (RH) of 45% was in the range of 83-109% for isocyanates formed during thermal decomposition of PUR. At RH 95%, the range was 72-101% with the exception of isocyanic acid. In two field evaluations, the ratios for fast curing 2,4'- and 4,4'-methylene bisphenyl diisocyanate (MDI) was in the range 81-113% and for the 3-ring MDI the range was 54-70%. For the slower curing 1,6-hexamethylene diisocyanate (HDI) and HDI isocyanurate, the ratios were in the range 78-145%. In conclusion, the solvent-free sampler is a convenient alternative in most applications to the more cumbersome impinger-filter sampler.

Acetic Acid↗
PubMedDate not supplied

An approach to area sampling and analysis for total isocyanates in workplace air.

An approach to sampling and analysis for total isocyanates (monomer plus any associated oligomers of a given isocyanate) in workplace air has been developed and evaluated. Based on a method developed by the Occupational Health Laboratory, Ontario Ministry of Labour, Ontario, Canada, isocyanates present in air are derivatized with a fluorescent reagent, tryptamine, in an impinger and subsequently analyzed via high-performance liquid chromatography (HPLC) with fluorescence detection. Excitation and emission wavelengths are set at 275 and 320 nm, respectively. A modification to the Ontario method was made in the replacement of the recommended impinger solvents (acetonitrile and 2,2,4-trimethylpentane) with dimethyl sulfoxide (DMSO). DMSO has the advantages of being compatible with reversedphase HPLC and not evaporating during sampling, as do the more volatile solvents used in the Ontario method. DMSO also may dissolve aerosol particles more efficiently during sampling than relatively nonpolar solvents. Several formulations containing diisocyanate prepolymers have been tested with this method in the laboratory. This method has been issued as National Institute for Occupational Safety and Health (NIOSH) Method 5522 in the first supplement to the fourth edition of the NIOSH Manual of Analytical Methods. This method is recommended for area sampling only due to possible hazards from contact with DMSO solutions containing isocyanate derivatives. The limits of detection are 0.1 microgram/sample for 2,4-toluene diisocyanate, 0.2 microgram/sample for 2,6-toluene diisocyanate, 0.3 microgram/sample for methylene bisphenyl diisocyanate, and 0.2 microgram/sample for 1,6-hexamethylene diisocyanate.

Air Pollutants, Occupational↗
PubMed1984

Airborne isocyanates in polyurethane spray painting: determination and respirator efficiency.

The concentrations of airborne isocyanates were measured during spray painting with two-component polyurethane paint. The isocyanate component - hexamethylene-diisocyanate (HDI) and its prepolymer of the biuret type - were determined by high performance liquid chromatography after derivatization to stable urea derivatives with N-4-nitrobenzyl-N-n-propylamine. Samples were collected on reagent impregnated glassfiber filters, and the derivatives were eluted with the chromatographic eluent. An impregnation technique is reported; it facilitates the chromatographic separation and the subsequent quantitative determination. Recovery studies from filters were performed in the range of 0.05 to 30 micrograms for the HDI monomer, and 0.5 to 100 micrograms for the HDI oligomer on the same filter. Average recoveries of the monomer and the oligomer were 97 +/- 2% (standard deviation) and 92 +/- 4%, respectively. The concentrations of the isocyanate components, measured during spray painting, were very high. For example, the level of the monomer frequently exceeded the hygienic limit value of 0.07 mg/m, set by the National Board of Labour Protection in Finland. As the concentrations of the HDI oligomer were at least one order of magnitude higher, appreciable exposure to isocyanate occurred if the respiratory protection was inadequate. The filter sampling technique made it possible to measure concentrations inside respirators.

Air Pollutants, Occupational↗
PubMed1995

Analytical problems encountered with NIOSH method 5521 for total isocyanates.

A recent analysis for total isocyanates in air using National Institute for Occupational Safety and Health Method 5521 presented difficulties in the identification of an oligomeric isocyanate species. Two problems were encountered during the analysis. A false negative response in the high performance liquid chromatography chromatogram was encountered in a majority of the field samples. An anomalous peak served to give a false positive in some of the field blanks and in some of the field samples. Through supplementing the ratio criterion of Method 5521 using the complete UV absorption spectrum from a photodiode array (PDA) UV detector, the two peaks were successfully identified. However, this need for additional data to identify an oligomeric isocyanate species raises the question of whether the ratio criterion of Method 5521 allows the qualitative identification of isocyanate oligomers.

Air Pollutants, Occupational↗
PubMed1996

Exposure to isocyanates and organic solvents, and pulmonary-function changes in workers in a polyurethane molding process.

The extent of adverse health effects of isocyanates when combined with other chemicals is not well documented. This study was conducted as a 2.5-year follow-up as well as to determine daily and weekly effects of exposure to isocyanates and organic solvents on pulmonary function. The concentrations of chemicals sampled were below the recommended exposure criteria. No daily or weekly reduction in the subjects' pulmonary function was observed. The isocyanate/solvent-exposed subjects showed significant long-term reduction in their forced vital capacity (P < 0.05) and expiratory volume in 1 second (P < 0.001). No such changes were observed in non-exposed subjects or in those exposed only to organic solvents. The proportion of subjects who developed respiratory symptoms in the isocyanate-exposed group was not significantly greater than that of the non-exposed group. The results of this study indicate that long-term exposure to isocyanates, even in very low concentrations, may contribute to impaired pulmonary function.

Aerosols↗
PubMed2005

Surveillance for isocyanate asthma: a model based cost effectiveness analysis.

AIMS: Because logistical and financial obstacles impede using large prospective cohort studies, surveillance decisions in occupational settings must often be made without evidence of relative benefits and costs. Using the example of isocyanate induced asthma, the most commonly reported immune mediated occupational asthma, the authors developed a model based approach to evaluate the costs and benefits of surveillance from both an employer and a societal perspective. METHODS: The authors used a mathematical simulation model of isocyanate asthma to compare annual surveillance to passive case finding. Outcome measures included symptom free days (SFD), quality adjusted life years (QALY), direct costs, productivity losses, and incremental cost effectiveness ratio (CER), measured from the employer and the societal perspectives. Input data were obtained from a variety of published sources. RESULTS: For 100,000 exposed workers, surveillance resulted in 683 fewer cases of disability over 10 years. Surveillance conferred benefits at an incremental cost of 24,000 dollars/QALY (employer perspective; 13.33 dollars/SFD) and was cost saving from the societal perspective. Results were sensitive to assumptions about sensitisation rate, removal rates, and time to diagnosis, but not to assumptions about therapy costs and disability rates. CONCLUSIONS: Baseline results placed the CER for surveillance for isocyanate asthma within the acceptable range. Costs from the societal and employer perspective differed substantially with a more attractive CER from the societal perspective, suggesting opportunities for employer/societal cost sharing. The analysis demonstrates the value of a model based approach to evaluate the cost effectiveness of surveillance programmes for isocyanate asthma, and to inform shared decision making among clinicians, patients, employers, and society. Such a modeling approach may be applicable to surveillance programmes for other work related conditions.

Absenteeism↗