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PubMed1993

The Bhopal accident and methyl isocyanate toxicity.

The Bhopal accident, the world's worst industrial disaster, in which nearly 40 metric tons of methyl isocyanate (MIC) was released from the Union Carbide pesticide plant, occurred nearly 10 yr ago during the night of December 2 and 3, 1984. Over 3000 people residing in areas adjacent to the plant died of pulmonary edema within 3 d of the accident. Follow-up studies revealed pulmonary, ophthalmic, reproductive, immunologic, neurological, and hematologic toxicity among the survivors. Despite high reactivity, MIC can traverse cell membranes and reach distant organs, perhaps as a reversible conjugate with glutathione, which may explain some of the systemic effects of MIC. MIC can be degraded as a result of pyrolysis and interaction with water, but none of the breakdown products can duplicate the toxicity observed in Bhopal and in animal models. MIC may be the most toxic of all isocyanates because of its very high vapor pressure relative to other isocyanates and because of its ability to exert toxic effects on numerous organ systems.

Accidents, Occupational↗
PubMed2004

Determinants of isocyanate exposures in auto body repair and refinishing shops.

As part of the Survey of Painters and Repairers of Auto bodies by Yale (SPRAY), the determinants of isocyanate exposure in auto body repair shops were evaluated. Measurements (n = 380) of hexamethylene diisocyanate-based monomer and polyisocyanate and isophorone diisocyanate-based polyisocyanate were collected from 33 auto body shops. The median total reactive isocyanate concentrations expressed as mass concentration of the NCO functional group were: 206 microg NCO/m3 for spray operations; 0.93 microg NCO/m3 for samples collected in the vicinity of spray operations done on the shop floor (near spray); 0.05 microg NCO/m3 for office or other shop areas adjacent to spray areas (workplace background); 0.17 microg NCO/m3 for paint mixing and gun cleaning operations (mixing); 0.27 microg NCO/m3 for sanding operations. Exposure determinants for the sample NCO mass load were identified using linear regression, tobit regression and logistic regression models. For spray samples in a spray booth the significant determinants were the number of milliliters of NCO applied, the gallons of clear coat used by the shop each month and the type of spray booth used (custom built crossdraft, prefabricated crossdraft or downdraft/semi-downdraft). For near spray (bystander) samples, outdoor temperature >65 degrees F (18 degrees C) and shop size >5000 feet2 (465 m2) were significant determinants of exposure levels. For workplace background samples the shop annual income was the most important determinant. For sanding samples, the shop annual income and outdoor temperature >65 degrees F (18 degrees C) were the most significant determinants. Identification of these key exposure determinants will be useful in targeting exposure evaluation and control efforts to reduce isocyanate exposures.

Air Pollutants, Occupational↗
PubMed2005

Exposure to low molecular weight isocyanates and formaldehyde in foundries using hot box core binders.

Emissions from a chemical core binder system (Hot Box) based on a formaldehyde-carbamide resin have been investigated. The binder is used in some Swedish die-casting foundries. During core-making and casting, low molecular monoisocyanates, in particular methyl isocyanate (MIC) and isocyanic acid (ICA), were identified. Exposure to air concentrations of MIC, ICA and formaldehyde were subsequently determined in all Swedish foundries using the Hot Box binder, and involved three brass and one grey iron foundry. The survey was carried out in the winter period of 2001, and involved core-makers, casters and fettlers in the brass foundries, whereas only core-makers were included in the grey iron foundry. For each worker, four to five short-term samples of isocyanates (n = 298) and one 8 h sample of formaldehyde (n = 64) were collected during one shift for 15 die-casters, 39 core-makers and 10 other workers in the foundry. The air concentrations of the MIC short-term samples varied between <4 and 68 microg m(-3), with corresponding ICA levels between <4 and 280 microg m(-3). Calculated 8 h time weighted average air concentrations of MIC, based on short-term samples for each individual, varied between <4 and 31 microg m(-3); for ICA the corresponding levels varied from <4 to 190 microg m(-3). The formaldehyde time weighted average concentration levels ranged from 14 to 1600 microg m(-3), and the Swedish occupational exposure limit (600 microg m(-3)) was exceeded only in 3% of the samples. In general, the core-makers were exposed to higher average formaldehyde levels compared to the casters, the latter being more exposed to monoisocyanates. During core-making and die-casting, low molecular monoisocyanates, in particular MIC and ICA, were identified. Compared to the American Conference of Governmental Industrial Hygienists (ACGIH) threshold limit value-time weighted average (TLV-TWA) for MIC, the exposures were low. The lack of toxicological and human data for ICA and the relatively high air concentrations call for medical examination and preventive measures in production, ventilation and the use of personal safety equipment in the investigated foundries.

Air Pollutants, Occupational↗
PubMed1999

Prevalence of self-reported respiratory symptoms in workers exposed to isocyanates.

Until now, no survey had been conducted to assess the prevalence of respiratory symptoms in a large population that had been occupationally exposed to isocyanates, compared with that in a control group. We performed such a survey, using questionnaires administered by occupational physicians. Overall, 1114 workers' questionnaires (585 exposed and 529 control) were analyzed. Exposed workers, primarily painters from small factories, reported significantly (P < 0.05) more wheezing (8.6% vs 3.6%), more breathlessness with wheezing (3.4% vs 0.6%) in the last year, and more rhinitis (33.1% vs 19.1%) than did control workers. A trend for more asthma (2.1% vs 0.8%; P < or = 0.07) was also observed. Furthermore, 16.4%, 16.2%, and 10.6% of exposed workers reported (respectively) cough, rhinitis, and chest tightness when working in contact with isocyanates. We conclude that isocyanate-exposed workers demonstrate significantly higher prevalence rates of rhinitic and asthmatic symptoms than do control subjects.

Adult↗
PubMed2002

Investigation of pulmonary function among employees exposed to low levels of monomeric isocyanates and solvents at an automobile finishings plant.

There have been reports in the literature of decrements in pulmonary function associated with long-term, low-level monomeric isocyanate exposure combined with solvent exposure. This cross-sectional study examines the relationship between these exposures and pulmonary function in an automobile paint and coating (finishes) plant. A job exposure matrix was developed for isocyanate and solvent exposure; years in a work task were used as a surrogate for exposure. Recent pulmonary function tests were used as the outcome variables; specifically the difference between predicted and actual FEV1 and FVC. The results of the analysis demonstrated no statistically significant relationship between combined isocyanate and solvent exposure and decline in pulmonary function. There was a statistically significant negative correlation between solvent exposure and FEV1 and FVC.

Adult↗
PubMed2006

Impairment in workers with isocyanate-induced occupational asthma and removed from exposure in the province of Québec between 1985 and 2002.

OBJECTIVE: The objective of this project was to assess both the outcome for patients diagnosed with proven isocyanate-induced occupational asthma (IIOA) by specific inhalation challenge (SIC) and the functional impairment, 2 years after cessation of exposure to isocyanates, using the compensation insurance scale proposed in the province of Quebec. METHODS: We used a retrospective cohort of 233 patients diagnosed in the province of Quebec between 1985 and 2002 and randomly chose 105 of those patients. We kept 89 subjects with complete data at T0 (the time of diagnosis) and 79 were reevaluated at T2, approximately 2 years after their removal from exposure, for final impairment-disability assessment. At each evaluation (T0 and T2), a clinical examination and lung function tests, including spirometry and methacholine challenge, were performed. RESULTS: At T2, 79 of 89 patients were reassessed (89%). The remaining patients were lost to follow up (8) or too unstable to be reassessed for final impairment-disability settlement (2). No statistical difference was observed for spirometry data and antiasthmatic medication use between T0 and T2 (P = 0.11). At T2, 73% of patients were still using short-acting beta2 agonists and 39% inhaled glucocorticoids. A forced expiratory volume in 1 second variation of +/-10% from T0 to T2 occurred in 31 subjects (40%). Forced expiratory volume in 1 second worsened in 14 (18%), remained significantly unchanged in 51 (64%), and improved in 14 (18%). Nonspecific bronchial hyperresponsiveness (BHR) improved in significantly in 19 (24%); the others remained unchanged. Both were not associated with smoking status (P > 0.05). Nonspecific BHR was normalized in nine of 79 (11%) patients. Clinical remission occurred in only four (5%) subjects. The mean impairment-disability score was 21% +/- 13% at 2 years according to the scale used by the Workers' Compensation Board. CONCLUSIONS: These results show the generally poor medical outcome of IIOA and suggest the importance of early detection and withdrawal of the workers from exposure to isocyanates. They also emphasize the need for medical surveillance program and adequate treatment of patients with IIOA.

Adult↗
PubMed1987

Inhibition of yeast respiration and fermentation by benomyl, carbendazim, isocyanates, and other fungicidal chemicals.

The inhibition of yeast (Saccharomyces cerevesiae) metabolism by fungicidal chemicals was investigated. Glucose- or ethanol-dependent yeast respiration was measured with an oxygen electrode, and manometric determination of carbon dioxide release was used to measure fermentation. Both respiration and fermentation were inhibited more by benomyl than by identical molar concentrations of its breakdown product, carbendazim. Butyl isocyanate, another benomyl breakdown product, inhibited respiration more but inhibited fermentation less than the parent compound. Of the isocyanates tested, hexyl isocyanate was the most inhibitory towards both activities. Captan was more active and iprodione less active than benomyl. Because benomyl rapidly broke down to carbendazim when it was prepared in 80% ethanol, only 59% of the dissolved benomyl was intact when it was added to yeast to determine its effect on respiration or fermentation.

Benomyl↗
PubMed1994

HLA class II alleles in isocyanate-induced asthma.

Studying genetic factors that control human immune responsiveness may further our understanding of specific types of asthma in which the role of immune factors is uncertain to date. HLA Class II gene products are involved in the control of immune responses. Therefore, we investigated whether HLA Class II genetic markers contribute to susceptibility or resistance to isocyanate-induced asthma (IAA) in exposed workers. We collected venous blood samples from two groups of unrelated white adults: (1) patients with isocyanate-induced asthma documented by a positive inhalation challenge; and (2) exposed individuals with no history of IAA. The second exon of DQA1, DQB1, DPB1, and DRB genes was selectively amplified by the polymerase chain reaction (PCR) method. HLA typing was carried out by the PCR-RFLP method, which allowed discrimination of most HLA DQA1, DQB1, DPB1, and DRB alleles. No significant difference was found in the distribution of DPB1 alleles between patients and control subjects. Allele DQB1*0503 and allelic combination DQB1*0201/0301 were associated with susceptibility to the disease. Conversely, allele DQB1*0501 and the DQA1*0101-DQB1*0501-DR1 haplotype conferred significant protection to exposed healthy control subjects. Our results are consistent with the hypothesis that immune mechanisms are involved in isocyanate-induced asthma and that specific genetic factors may increase or decrease the risk of developing IAA in exposed workers.

Adult↗
PubMed1997

Human leukocyte antigen associations in occupational asthma induced by isocyanates.

Exposure to diisocyanates is recognized as a leading cause of occupational asthma. Occupational asthma induced by isocyanates shares many characteristics with immunoglobulin E (IgE)-mediated asthma: in both, the responsible agent is known, and the clinical presentation, response to inhalation challenge in the laboratory, and response to antiasthma drugs are similar. Although asthma mediated by an IgE mechanism occurs in atopic subjects, occupational asthma induced by isocyanates occurs mostly in nonatopic asthmatics, and an IgE-mediated mechanism has not been consistently demonstrated. However, activated T lymphocytes, methacromatic cells, and eosinophils are increased in the bronchial mucosa of allergic and nonallergic asthmatics and subjects with occupational asthma induced by isocyanates, suggesting similar, probably immunologically mediated mechanisms for both nonoccupational and occupational asthma. Occupational asthma occurs in up to 5-10% of the exposed subjects. Evaluation of major histocompatibility complex (MHC) class II genes in exposed subjects who develop toluene diisocyanate (TDI) asthma has shown a negative association with HLA-DQB1*0501 and a positive association with HLA-DQB1*0503 alleles. In addition, a high proportion of TDI asthmatics express the HLA-DQB1*0503-associated aspartic acid at residue 57, suggesting that HLA-DQ may have a key role in conferring susceptibility. Thus, asthma induced by the low-molecular-weight agent TDI may result from an immunologic reaction due to the interaction of genetic susceptibility with exposure in the workplace.

Antibodies↗
PubMed2005

Allyl cyanate-to-isocyanate rearrangement for the synthesis of quaternary stereocenter with nitrogen substituent.

The stereochemistry and efficiency of an allyl cyanate-to-isocyanate rearrangement for the construction of quaternary stereocenter with nitrogen substituent was investigated by the synthesis of (R)-alpha-methylphenylalanine. The rearrangement was found to be stereospecific, and the chirality of allyl carbamate was transferred to that of the quaternary carbon bearing isocyanate group. These results establish that an allyl cyanate-to-isocyanate rearrangement is a useful method for the synthesis of natural products, that contain the quaternary carbon with nitrogen substituent.

Allyl Compounds↗
PubMed1987

Results of in vitro and in vivo genetic toxicity tests on methyl isocyanate.

Methyl isocyanate (MIC) was tested for genetic toxicity in a variety of in vitro and in vivo assays. Negative results were obtained in the Salmonella/mammalian microsome assay using five bacterial strains in a preincubation protocol. The Drosophila sex-linked recessive lethal test also gave negative results in studies that involved three routes of administration: inhalation, feeding, and injection. Positive results were obtained for three endpoints in cultured mammalian cells. Reproducible, dose-related increases in trifluorothymidine-resistant clones were induced in L5178Y mouse lymphoma cells, and the frequencies of both SCE and chromosomal aberrations increased in Chinese hamster ovary cells. These effects were independent of exogenous metabolism. In mice exposed to methyl isocyanate by inhalation, cytogenetic analyses were carried out on bone marrow, blood, and lung cells. A single, 2-hr exposure to concentrations of 0, 3, 10, and 30 ppm MIC produced no evidence of chromosomal effects in the bone marrow, although significant cell cycle delay was observed. In four experiments involving exposures on 4 consecutive days to 0, 1, 3, or 6 ppm, delays in bone marrow cell cycle were again observed. Increases in SCE and chromosomal aberrations were observed in bone marrow cells, and a dose-related increase in SCE occurred in lung cells but not in peripheral blood lymphocytes. A significant increase in micronucleated polychromatic erythrocytes in the peripheral blood was observed in male mice in one experiment. From these results, it appears that methyl isocyanate has the capacity to affect chromosome structure but not to induce gene mutations.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Ultrastructural changes in the nasal mucosa of Fischer 344 rats and B6C3F1 mice following an acute exposure to methyl isocyanate.

Male rats and male mice received a single 2-hr exposure to 0 (control), 10, or 30 ppm of methyl isocyanate and were sacrificed after 1, 3, 14, or 90 days to assess the ultrastructural changes in the nasal mucosa by transmission electron microscopy. One day after exposure to methyl isocyanate, there were widespread areas of necrosis and degeneration of the respiratory and olfactory epithelium of rats and mice in the 10 ppm and 30 ppm groups. Qualitatively the ultrastructural findings were similar for both exposure groups and species. Degeneration followed by rapid regeneration was observed for both respiratory and olfactory epithelia but was most striking for olfactory epithelium in the dorsal meatus. Three days after the exposure, the olfactory epithelium was two to three cell layers thick due to a loss of supporting cells, olfactory neurons, and basal cells. By 14 days after exposure, the olfactory epithelium was composed of a heterogeneous cell population three to five cell layers thick. At 90 days following exposure, the epithelium was of normal thickness (eight to ten cell layers), with normal architectural arrangement, and composed of well-differentiated cells that appeared similar to those of controls. There were several findings that suggested the epithelial cells of Bowman's glands were the progenitor for the regenerating supporting cells of the olfactory epithelium. This study demonstrated that the respiratory and olfactory epithelium is capable of complete structural regeneration after an acute destruction by methyl isocyanate.

Animals↗
PubMed1987

Functional evidence of persistent airway obstruction in rats following a two-hour inhalation exposure to methyl isocyanate.

Pulmonary function was assessed in male, F344 rats 1,2,4,7, and 13 weeks after a single 2-hr exposure to 0, 3, 10, or 30 ppm methyl isocyanate. No significant changes were observed in the rats exposed to 3 ppm through 13 weeks. Diffusing capacity (DLco), quasistatic lung compliance, and homogeneity of ventilation, as determined by multibreath nitrogen washout, were depressed in the rats exposed to 10 and 30 ppm by 1 week after exposure. None of the rats exposed to 30 ppm survived beyond 1 week. By 13 weeks, dramatic increases in lung volumes were observed in the rats exposed to 10 ppm, while DLco and lung compliance were only mildly affected. However, volume-specific DLco and compliance were depressed in the rats exposed to 10 ppm, suggesting that lung hyperinflation or other compensatory means of increasing lung size occurred in response to the methyl isocyanate-induced lung lesion. This group also exhibited increased expiratory times during tidal breathing and severely impaired distribution of ventilated air. Collectively, these results suggest the development and likely progression of a severe, obstructive airway lesion with associated gas trapping, and the existence of a pronounced concentration-response relationship between 3 and 10 ppm methyl isocyanate exposures.

Airway Obstruction↗
PubMed1994

Oxidative conversion of isothiocyanates to isocyanates by rat liver.

This report describes the oxidative metabolism of isothiocyanates to isocyanates catalyzed by rat liver microsomes. Incubation of 2-naphthylisothiocyanate, microsomes, and NADPH yielded either N,N'-di-naphthylurea or, on inclusion of 2-aminofluorene in the incubations, N-2-naphthyl-N'-2-fluorenylurea. These ureas were formed by the production of the known genotoxicant, 2-naphthylisocyanate, which reacted with its hydrolysis product, 2-aminonaphthalene, to yield the symmetrical urea, or with 2-aminofluorene to form the mixed urea. Formation of N,N'-di-2-naphthylthiourea was also observed because 2-aminonaphthalene reacted with the substrate. Urea formation was dependent on the microsomes, NADPH, and oxygen. Use of microsomes from rats previously treated with Aroclor 1254 increased urea formation greater than 10-fold. The enzyme activity was inhibited by alpha-napthoflavone, flavone, or CO, and slightly inhibited by metyrapone, 7-ethoxycoumarin, or SKF-525A. It was not inhibited by methimazole or paraoxon, suggesting that neither flavin-containing monooxygenase nor hydrolytic enzyme was involved. These data are consistent with a cytochrome P450-dependent, oxidative desulfuration of 2-naphthylisothiocyanate to yield 2-naphthylisocyanate. Further studies with the isomeric 1-naphthylisothiocyanate and the dietary benzylisothiocyanate showed that they can also be metabolized to their isocyanates, as evidenced by the trapping of isocyanates with 2-aminofluorene to form the mixed ureas.

1-Naphthylisothiocyanate↗
PubMed2001

[A case of pneumonitis possibly due to isocyanate associated with high levels of serum KL-6].

A 47-year-old automobile painter developed dry cough, chills and dyspnea after four months of painting work. The spray contained isocyanates (HDI). A chest radiograph showed bilateral ground-glass shadows. The serum KL-6 level was very high: 11,100 U/ml. Marked lymphocytosis and a striking decrease in the CD4/CD8 ratio were observed in the bronchoalveolar lavage fluid. Transbronchial lung biopsy specimens showed alveolitis and bronchiolitis. Cessation of exposure to isocyanates improved the symptoms and laboratory data. We suspected that the patient was suffering from hypersensitivity pneumonitis induced by isocyanates. Specific IgG antibodies for TDI, MDI, and HDI were not demonstrated by enzyme-linked immunosorbent assay. Because abnormal shadows in the chest radiograph did not improve quickly after admission, we administered glucocorticoids which improved the symptoms, the chest radiograph findings, and the serum KL-6 level.

Alveolitis, Extrinsic Allergic↗
PubMed1992

[A case of hypersensitivity pneumonitis due to isocyanate exposure showing progression even two months after removal of the antigen].

A 68-year-old male developed dry cough and exertional dyspnea after handling paint spray containing isocyanates (TDI, MDI) for three months. Initially, the symptoms fluctuated according to whether he was at work or not. He was admitted to our hospital on February 7, 1990, because of progressive worsening of symptoms. In spite of admission to hospital and cessation of exposure to isocyanates, there was no improvement of symptoms. His chest X-ray film showed diffuse small nodular and reticular shadows. Transbronchial lung biopsy revealed thickening of the alveolar walls and formation of Masson's bodies associated with mononuclear cell infiltration in alveolar spaces. High titers of TDI-HSA and MDI-HSA specific IgG antibodies were detected by ELISA, and a high level of serum soluble IL2 receptor was also detected. From these results, we diagnosed hypersensitivity pneumonitis due to exposure to isocyanates. One week administration of prednisolone caused dramatic improvement of his symptoms, chest X-ray findings, and laboratory data. His clinical course and response to prednisolone therapy indicated that long-term steroid administration could not be avoided. The prolonged symptoms and the necessity for long-term steroid therapy are discussed.

Aged↗
PubMedDate not supplied

[Isocyanates: adverse effects on health].

The paper describes the main adverse biological effects of isocyanates, particularly toluene di-isocyanate (TDI). It is not intended to be simply a review of the literature but a stimulus for further investigations on the mechanism of action, chemical characterization, environmental release, exposure, fate, health effects, carcinogenicity and mutagenicity of isocyanates.

Animals↗
PubMed1984

Acute airway obstruction followed by hypersensitivity pneumonitis in an isocyanate (MDI) worker.

A rare combination of an acute asthmatic reaction followed by hypersensitivity pneumonitis after exposure to diphenylmethane diisocyanate (MDI) is described. The patient, who was nonatopic and did not show bronchial hyperreactivity to metacholine, was occasionally engaged at the workplace in spraying a mixture of MDI and polyol to produce a polyurethane foam for use as a packing material. Challenge testing by MDI resulted first in a significant immediate bronchial obstruction indicated by decreases in specific airway conductance and forced expiratory volume at 1 s, and then in a significant decrease in vital capacity and diffusing capacity, associated with systemic reactions such as anorexia, malaise, fever, and leukocytosis three to eight hours after challenge. Challenge testing by toluene diisocyanate produced a mild systemic reaction. This finding, as well as the detection of specific IgG antibodies to various isocyanate-human serum albumin conjugates, suggests immunologic cross-reactivity between different isocyanates. Neither skin testing nor the radioallergosorbent test indicated a type I sensitization. After contact with isocyanates was terminated, the disease did not recur.

Acute Disease↗