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PubMed1987

Biochemistry of protein-isocyanate interactions: a comparison of the effects of aryl vs. alkyl isocyanates.

In addition to their use in the polyurethane and pesticide industries, isocyanates have proven to be useful probes for the exploration of protein structure. This paper focuses on three aspects of isocyanates: their broad reactivity, their reversible interaction with cholinesterases, and the relative hydrolysis rates of alkyl and aryl isocyanates. The broad reactivity of isocyanates as well as the demonstrated affinity labeling of serine and sulfhydryl esterases are discussed. Extension of the affinity labeling studies to include the analysis of the inhibition of cholinesterases by methyl isocyanate shows that methyl isocyanate is not an effective inhibitor of any of the cholinesterases. The inhibition of cholinesterases by alkyl isocyanates shows a pattern of decreased specificity with decreased alkyl chain length. The inhibition of cholinesterases by isocyanates is shown to be reversible, with a maximum rate of reversal seen at physiological pH. This reversal is characteristic of the reaction of an isocyanate with a sulfhydryl group. Finally, the affinity labeling of proteins must compete successfully with the hydrolysis of isocyanates in aqueous solution. The hydrolysis of alkyl isocyanates is shown to be significantly slower than that of the aryl isocyanates.

Affinity Labels↗

PubMed1990

[Diagnosis of irritative-toxic isocyanate asthma with the isocyanate exposure test].

We investigated 10 healthy control subjects, 15 asthmatics without occupational exposure to isocyanate, and 45 "isocyanate workers" with workplace-related respiratory symptoms. In none of the cases did the skin test or the IgE-RAST reveal a type I sensitisation to isocyanate. The investigation programme included a lung function test, provocation with metacholine or acetylcholine, and an isocyanate challenge test under controlled clinical conditions. A total of 17 "isocyanate workers", and 1 asthma patient with no occupational exposure to isocyanate revealed a positive bronchial obstructive reaction to the isocyanate challenge test. In 10 of the patients, the MCH (ACH) test was positive; 2 were chronically obstructive, but 6 patients showed no signs of bronchial hyperreactivity. No significant differences in the severity of the bronchial obstructive reaction induced by isocyanate exposure were observed between patients with and those without bronchial hyperreactivity. In the group of "isocyanate workers", the isocyanate challenge test was observed to be superior to the MCH (ACH) provocation test in terms of sensitivity (0.68 versus 0.62) and specificity (1.0 versus 0.61), this difference being more obvious in the overall group (sensitivity 0.71 versus 0.62; specificity 0.98 versus 0.49).

Airway Resistance↗

PubMed1990

The use of an immunoassay index for antibodies against isocyanate human protein conjugates and application to human isocyanate disease.

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.

Antibodies↗

PubMed1990

Application of tryptamine as a derivatising agent for airborne isocyanate determination. Part 3. Evaluation of total isocyanates analysis by high-performance liquid chromatography with fluorescence and amperometric detection.

Determination of total airborne isocyanates using tryptamine as the derivatising agent was investigated. Tryptamine derivatised isocyanates were analysed by reversed-phase high-performance liquid chromatography (HPLC). The column was equipped with dual detectors of fluorescence emission and amperometric oxidation. The characteristics of fluorescence emission and amperometric oxidation of tryptamine were retained even after its reaction with isocyanates. With this unique behaviour, all tryptamine derivatised isocyanates can be quantified using HPLC by employing a single, pure derivative, such as tryptamine derivatised hexamethylene diisocyanate as the calibration standard. This is especially important for analysing polymeric isocyanates when identical calibration standards are not always available. The applicability of this method for air sampling was evaluated by comparison with the established method of Bagon et al. involving 1-(2-methoxyphenyl)piperazine. Simulation of air sampling was performed in a Test Atmosphere Generation System by the vaporisation of toluene diisocyanate. Satisfactory results were obtained, indicating the applicability of this technique for the determination of total airborne isocyanates.

Air Pollutants, Occupational↗

PubMed1998

Determination of complex mixtures of airborne isocyanates and amines. Part 5. Determination of low molecular weight aliphatic isocyanates as dibutylamine derivatives.

A method is presented for the determination of low molecular weight aliphatic isocyanates, methyl isocyanate (MIC), ethyl isocyanate (EIC), propyl isocyanate (PIC) and butyl isocyanate (BIC), as their dibutylamine (DBA) derivatives. The method is based on sampling in midget impinger flasks containing 10 ml of 0.01 mol l-1 DBA in toluene (as in Parts 1-4 in this series). The samples are analysed using liquid chromatography-electrospray mass spectrometry (LC-ESP-MS) or gas chromatography-mass spectrometry using chemical ionisation with ammonia, monitoring positive ions (GC-PCI). Quantification was effected by monitoring the molecular ions MH+. Aliquots of 10 ml of toluene solutions containing 0.01 mol l-1 DBA were spiked with 0.03-0.85 microgram of MIC-, EIC-, PIC- and BIC-DBA. The correlation coefficients for LC-ESP-MS were in the range 0.9952-0.9999 (n = 14). The repeatability (RSD) was in the range 0.37-1.2% (0.12-0.34 microgram ml-1, n = 10). The instrumental detection limit for MIC was about 15 micrograms l-1, which corresponds to about 0.5 microgram m-3 in a 15 l air sample. The correlation coefficients for GC-PCI were in the range 0.9913-0.9990. The repeatability (RSD) was in the range 1.1-4.9% (0.12-0.34 microgram ml-1, n = 10). The instrumental detection limit for MIC was about 0.2 microgram l-1, which corresponds to about 0.05 microgram m-3 in a 15 l air sample. Using electron ionisation, the instrumental detection limit for MIC was about 10 micrograms l-1. No derivatisation reaction losses were seen when the derivatization reaction between PIC and DBA took place in the presence of morpholine, propylamine, ethanol, phenol and water. When mineral wool with a phenol-formaldehyde-urea resin was thermally degraded, 0.1% m/m of MIC was released. In air samples taken on top of a new electric oven insulated with mineral wool, MIC was found in the range 0.1-3 mg m-3. No MIC in air was found from a pre-heated oven.

Air Pollutants, Occupational↗

PubMed1998

Increase in non-specific bronchial hyperresponsiveness without specific response to isocyanate in isocyanate-induced asthma: a pilot study.

Increased non-specific bronchial hyperresponsiveness (BHR) has been reported after positive reaction to isocyanates in patients with isocyanate-sensitive asthma. The increased responsiveness may, however, also precede the asthma attack. We therefore compared non-specific BHR to a cholinergic agent before and after exposure to toluene-diisocyanate (TDI) that induced no asthma symptoms in 11 workers with isocyanate-related asthma. Patients were exposed for 3 consecutive days to progressively increasing doses of TDI (5, 10, and 20 ppb min-1 for 20 min) in an exposure chamber with continuous TDI monitoring. No immediate nor late asthmatic bronchial reaction was observed in any patient after any dose of TDI during or after challenge. A significant increase in non-specific BHR was noted 24 h after the last dose of TDI challenge, however. This increase was at least one doubling dose for seven of 11 patients. In conclusion, our study shows that, in patients with isocyanate-induced asthma, exposure to TDI induces a slight but significant increase in non-specific BHR in the absence of any immediate or late bronchial response to isocyanate. This result, which requires further confirmation, may justify a proposal to measure non-specific BHR, even after a negative specific inhalation test to TDI, as an additional diagnostic element for TDI-induced occupational asthma, to help lower the percentage of the undetected occupational asthma cases.

Adult↗

PubMed2001

Two routes to [11C-carbonyl]organo-isocyanates utilizing [11C]phosgene ([11C]organo-isocyanates from [11C]phosgene).

Two generic radiosynthetic routes for the preparation of [11C-carbonyl]isocyanates have been developed. Reaction of N-organo-sulfinylamines; RNSO, (R = Me, Et, allyl, cyclohexyl and phenyl) with [11C]phosgene gave the corresponding [11C-carbonyl]isocyanates in good radiochemical yield (53-68%) from [11C]phosgene (decay corrected) in ca 16 min from EOB. Alternatively, the reaction of [11C]phosgene with N,N'-organo-ureas; (RNH)(2)CO, (R = Me, Et, Pr and phenyl) also gave the corresponding [11C-carbonyl]isocyanates in moderate radiochemical yield (9-37%) from [11C]phosgene (decay corrected) in ca 16 min from EOB. For identification, the [11C-carbonyl]organo-isocyanates were derivatized with 1-(2-methoxyphenyl)piperazine in situ to [11C-carbonyl]carboxamides and the position of radiolabelling in the carbonyl group confirmed by [11/13C]co-labeling and subsequent carbon-13 NMR spectroscopy.

Carbon Radioisotopes↗

PubMed1997

Determination of complex mixtures of airborne isocyanates and amines. Part 3. Methylenediphenyl diisocyanate, methylenediphenylamino isocyanate and methylenediphenyldiamine and structural analogues after thermal degradation of polyurethane.

A method is presented for the determination of isocyanates in polymeric methylenediphenyl diisocyanate (MDI) and related compounds formed during the thermal decomposition of polyurethane (PUR). Derivatization of isocyanates was performed in impinger flasks containing dibutylamine (DBA) with the formation of urea derivatives. Compounds containing amine groups were then derivatized with ethyl chloroformate (ET to give urethane derivatives. Reversed-phase liquid chromatography, with a gradient flow rate of 40 milligrams min-1 and mass spectrometry in the electrospray mode monitoring positive ions was studied. Injection volumes of up to 10 milligrams of the sample were made possible by using column focusing. 1,5-Naphthyldiisocyanate-DBA and 1,5-naphthyldiamine-ET derivatives were used as internal standards. Virtually linear calibration curves were obtained for 4,4'-MDI-DBA and 4,4'-methylenediphenyldiamine-ET (MDA-ET) and the correlation coefficients were 0.9952-0.9964 (n = 14). The precision for five injections of samples spiked with 4,4'-MDA-ET, and 4,4'-MDI-DBA ar concentrations of 50 nmol ml-1 was 2.76 and 2.55%, respectively. The instrumental detection limit, defined as three times the noise, was 4 fmol of MDI-DBA and 50 fmol of MDA-ET injected. In chromatograms of polymeric MDI derivatized with diethylamine, dipropylamine and DBA, the presence of several structural isomers and analogues in polymeric MDI was demonstrated. In the chromatograms of thermal decomposition products of MDI-PUR, in addition to isocyanates, related amino isocyanates and amines were also observed.

Air Pollutants, Occupational↗

PubMed1989

The use of isocyanate paints in auto refinishing--a survey of isocyanate exposures and related work practices in South Australia.

A survey of 45 crash repair workshops where two-pack polyurethane spray paints are used has been carried out. Painters were interviewed using a combined health-work practice questionnaire. Monitoring for airborne isocyanate was undertaken in 14 spray shops. Health data from the questionnaire were compared with corresponding data for control groups of mechanics and industrial spray painters, not exposed to isocyanates. Compared with the other two groups, the isocyanate spray painters generally reported more respiratory and skin problems. Airborne isocyanate concentrations associated with various operations were monitored with both impinger and paper tape methods. A direct comparison of the two methods is presented.

Air Pollutants, Occupational↗

PubMed1993

Exposure to TMXDI (meta) aliphatic isocyanate and TMI (meta) unsaturated aliphatic isocyanate. Clinical and immunological evaluation of 96 workers.

We evaluated 96 workers employed at facilities that manufacture or use TMXDI (meta) aliphatic isocyanate and TMI (meta) unsaturated aliphatic isocyanate. We used immunoglobulin (Ig) and IgG serum antibody enzyme-linked immunosorbent assay (ELISA) studies and a questionnaire designed to identify symptoms compatible with work-related syndromes such as asthma and hypersensitivity pneumonitis. There were no workers with immunologically induced disease due to TMI isocyanate or TMXDI isocyanate nor were there any workers whose questionnaires suggested new onset of asthma. Approximately 40% of workers experienced some irritant symptoms, mostly upper respiratory or ocular. One worker had low level IgE antibody against TMXDI-HSA but had no work-related respiratory symptoms. Very low-level IgG against TMI-HSA or TMXDI-HSA was present in 7% of workers, all of whom were in the high-exposure category.

Air Pollutants, Occupational↗

PubMed2006

Biomarkers for isocyanate exposure: Synthesis of isocyanate DNA adducts.

Isocyanates are important intermediates in industrial manufacturing. DNA adducts and protein adducts are important tools to biomonitor people exposed to xenobiotics. In the present work, the formation of DNA adducts deriving from 4-chlorophenyl isocyanate (4CPI) and 4-methylphenyl isocyanate (4MPI) were explored. The adducts of 4CPI and/or 4MPI with 2'-deoxyadenosine, 2'-deoxyguanosine, and 2'-deoxycytidine were synthesized and characterized by NMR and MS. For low level detection, an LC-MS/MS method was developed. The formation of DNA adducts was confirmed in in vitro reactions with DNA.

Biomarkers↗

PubMed2002

Evaluation of the NIOSH draft method 5525 for determination of the total reactive isocyanate group (TRIG) for aliphatic isocyanates in autobody repair shops. National Institute for Occupational Safety and Health.

This paper evaluates the performance of the NIOSH draft method 5525 for analysis of monomeric and TRIG aliphatic isocyanates in autobody repair shops. It was found that an optimized pH gradient enhanced noticeably the resolution and, therefore, identification of aliphatic isocyanates. Samples proved to be very stable for at least a year when stored at -13 degrees C in the freezer, and no major stability problems were found for the MAP reagent. The detector response factor RSD for selected MAP ureas was 40% in the fluorescence (FLD), 3% in the UV at 254 nm (UV254), and 1% in the UV at 370 nm (UV370). The mean FLD/UV254 and UV254/UV370 detector response ratios of standards were 31.7 (RSD = 37.8) and 17.1 (RSD = 5.4), respectively. The FLD/UV254 ratio in bulks varied from 0.41 to 1.97 times the HDI monomer ratio. The mean UV254/UV370 ratio in bulks was 16.1 (range 14.1 to 19.2, N = 38). Mean (range) recovery of 92 (91.2-93.2)% was found for the N3300 (isocyanurate) spiked on 25 mm quartz fiber filters in the range 0.07 to 2.2 microg NCO ml(-1). Mean (range) recovery for impingers was 100.7 (91.7-106.0)% for N3300 in the concentration range of 0.018 to 2.5 microg NCO ml(-1) and 81.0 (76.1-89.1)% for IPDI in the concentration range of 0.016 to 1.87 microg NCO ml(-1). Analytical method precision was 3.4% and mean bias 7.4% (range = 0-25%). The NIOSH draft method 5525 provides flexibility, enhanced sensitivity and specificity, powerful resolution, and very small compound-to-compound variability in the UV254, resulting in a more reliable identification and quantification of aliphatic isocyanates.

Air Pollution, Indoor↗

PubMed2005

Lewis acid-promoted reactions of zirconacyclopentadienes with isocyanates. A one-pot three-component synthesis of multiply-substituted iminocyclopentadienes from one isocyanate and two alkynes.

Multiply-substituted iminocyclopentadienes were formed from Lewis acid-promoted reactions of zirconacyclopentadienes and isocyanates via a one-pot three-component coupling process; the C=O double bond of the RN=C=O moiety in the isocyanate was cleaved, and the isocyanates behaved formally as a one-carbon unit with Lewis acid-dependent and substituent-dependent reactions being realized.

Alkynes↗

PubMed1979

Isocyanate asthma: respiratory symptoms due to 1,5-naphthylene di-isocyanate.

Occupationally related asthma developing in three patients due specifically to exposure to 1,5-naphthylene di-isocyanate (NDI), a hot curing agent used in manufacturing rubber, has been confirmed for the first time using bronchial provocation testing. This substance has been thought to be safer than toluene di-isocyanate (TDI) and diphenylmethane di-isocyanate (MDI) because of its relatively high melting point (120 degrees C). Each patient worked in the same factory and the circumstances of exposure were similar. Provocation testing was also performed with TDI in concentrations up to 0.018 parts per million (ppm) and MDI in concentrations up to 0.02 ppm, to which the patients had been exposed in the past, but no reactions were elicited. None of the patients had increased bronchial reactivity judged by histamine lability and exercise testing. Each patient was advised to give up his job, but two of the three could not find alternative employment and remained exposed. Three-year follow-up shows that airways narrowing has persisted in those who have remained exposed.

Adult↗

PubMed1989

Investigations on the acute toxic, cytogenetic, and embryotoxic activity of phenyl isocyanate and diethoxyphosphoryl isocyanate.

Phenyl isocyanate (I) and diethoxyphosphoryl isocyanate (II), used as intermediates in organic chemical syntheses, were tested for their acute toxic, cytogenetic, and embryotoxic activity on mice of different strains. The oral LD50 values for male CFLP mice were determined to be 196 mg/kg for I and 4080 mg/kg for II. Single oral doses of 1/40 and 1/20, respectively, of the LD50 of I (4.9 and 9.8 mg/kg) and II (102 and 204 mg/kg) did not cause any significant enhancement in the percentage of chromosome aberrations in bone marrow cells of CFLP mice. After oral administration of 9.8 mg/kg I and 204 mg/kg II to pregnant Halle-AB-Jena and Halle-DBA mice at various days of gestation (4, 7, 11, or 15), none of the compounds tested were embryotoxic.

Animals↗

PubMedDate not supplied

Biotransformation of methyl isocyanate in the rat. Evidence for glutathione conjugation as a major pathway of metabolism and implications for isocyanate-mediated toxicities.

S-(N-Methylcarbamoyl)-N-acetylcysteine (AMCC), a chemically labile mercapturic acid conjugate, was identified by liquid chromatography-mass spectrometry (LC-MS) in the urine of rats dosed intraperitoneally with methyl isocyanate (MIC; 45.2 mumol). The corresponding cysteine conjugate, however, was not detected in urine. Following methylation, urine extracts were analyzed by thermospray LC-MS and the AMCC methyl ester was quantified by means of a stable isotope dilution assay procedure which utilized S-(N-methylcarbamoyl)-N-[2H3]-acetylcysteine [( 2H3]AMCC) as internal standard. The results showed that the fraction of the injected dose of MIC which appeared in 24-h urine collections as AMCC was 24.8 +/- 1.9% (mean +/- SD, N = 4). Thus, conjugation of MIC with glutathione (GSH), followed by metabolism of the resulting adduct to AMCC, appears to represent a quantitatively important pathway of biotransformation of MIC in the rat. However, in view of the known carbamoylating properties and in vitro cytotoxicity of S-linked conjugates of MIC, it seems unlikely that the GSH pathway of metabolism fulfills a conventional detoxification role in the case of MIC. In contrast, it is proposed that carbamate thioester conjugates of MIC, which can revert spontaneously to free MIC under physiological conditions, may actually contribute to the multisystem adverse effects of this highly toxic isocyanate in vivo.

Acetylcysteine↗

PubMed2003

(S)-2-chloro-2-fluoroethanoyl isocyanate, a chiral derivative of trichloroacetyl isocyanate.

Carbamate diastereomers 3b-18b were prepared from easily accessible (S)-2-chloro-2-fluoroethanoyl isocyanate (1) and various secondary chiral alcohols. Compound 1 as a chiral analog of trichloroacetyl isocyanate undergoes the reaction with alcohols very fast, thus blocking the hydroxyl group for the purposes of NMR investigation. Moreover, the correlation of stereochemistry of 3b-18b with their (1)H NMR spectra revealed that the constitution as well as configuration influences regularly the values of chemical shift difference (deltadelta = delta(R) - delta(S)) except for those diastereomers bearing simple alkyl groups in the molecule. Spectral as well as crystallographic data manifest the predominant planar conformation of the central part of the molecule. Due to the good accessibility and high reactivity in particular, the acylisocyanate 1 might be considered, to some extent, an alternative for TAI giving additional information on a compound's spatial structure.

Journal Article↗

PubMed1992

Application of tryptamine as a derivatizing agent for the determination of airborne isocyanates. Part 5. Investigation of tryptamine-coated XAD-2 personal sampler for airborne isocyanates in workplaces.

The development of an efficient solid sorbent personal sampler with increased convenience for sample collection in workplaces is described. Several solid sorbents were coated with tryptamine, and sampling tubes were prepared with the coated sorbents. These tubes were evaluated for the collection of phenyl isocyanate vapour generated in a commercial test atmosphere generation system that permits the simultaneous collection of up to 12 uniformly loaded samples. Tryptamine-coated XAD-2 resin was shown to be the most efficient solid sorbent for the collection of airborne phenyl isocyanate. The optimum amount of tryptamine needed for coating XAD-2 resin was investigated.

Air Pollutants, Occupational↗