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British Journal of Industrial Medicine Sep 1985
Topics: Accidents, Occupational; Animals; Chemical Industry; Cyanates; Humans; Isocyanates; Lethal Dose 50; Toxicology; United Kingdom
PubMed: 4041388
DOI: 10.1136/oem.42.9.577 -
British Journal of Industrial Medicine Aug 1990A follow up study three years after exposure to methyl isocyanate in 93% of exposed survivors and "control" residents in 10 Bhopali communities showed an excess of eye...
A follow up study three years after exposure to methyl isocyanate in 93% of exposed survivors and "control" residents in 10 Bhopali communities showed an excess of eye irritation, eyelid infection, cataract, and a decrease in visual acuity among the exposed people. Breathlessness was twice as common in the heavily exposed clusters as those with lower exposure, a trend that could not be explained by different age or smoking patterns (OR 2.05, 95% CI 1.36-3.08). Case referent analysis of outpatient attendances at Bhopal Eye Hospital, considering patients with severe refractive errors and astigmatism as "controls," showed a 40% increased risk of trachoma, 36% increased risk of other lid infections, and 45% increased risk of irritant symptoms among previously exposed people. "Bhopal eye syndrome" may thus include full resolution of the initial interpalpebral superficial erosion, a subsequent increased risk of eye infections, hyperresponsive phenomena (irritation, watering, and phlyctens), and possibly cataracts. It remains to be confirmed whether this reflects a more generalised disease as a consequence of previous exposure to methyl isocyanate or whether it is only the eye that is affected.
Topics: Accidents, Occupational; Adolescent; Adult; Cataract; Child; Child, Preschool; Cohort Studies; Cyanates; Environmental Exposure; Eye Diseases; Female; Follow-Up Studies; Humans; India; Infant; Isocyanates; Male; Middle Aged; Visual Acuity
PubMed: 2393636
DOI: 10.1136/oem.47.8.553 -
Environmental Analysis, Health and... Sep 2021Methyl isocyanate (MIC), a low molecular weight synthetic aliphatic compound, having an isocyanate group (-NCO), has industrial application. In this study, the effects...
Methyl isocyanate (MIC), a low molecular weight synthetic aliphatic compound, having an isocyanate group (-NCO), has industrial application. In this study, the effects of methyl isocyanate and its mechanism on outer membrane protein of Escherichia coli were observed using experimental and computational methods. In vitro exposure of N-succinimidyl N-methylcarbamate (NSNM) a synthetic analogue of MIC on E. coli to a final concentration of 2 mM was found to affect the growth curve pattern and changes in cell morphology. Molecular docking studies of MIC and NSNM with E. coli outer membrane protein (OmpW, OmpX, OmpF OmpA), and periplasmic domain (PAL) were performed. The in-silico results revealed that outer membrane protein OmpF showed the highest negative binding energy, i.e. ∆G -4.11 kcal/mole and ∆G -3.19 kcal/mole by NSNM and MIC as compared to other proteins. Our study concludes that methyl isocyanate retains lethal toxicity which leads to cell death due to the membrane protein damage of E. coli membrane.
PubMed: 34428861
DOI: 10.5620/eaht.2021020 -
Journal of Chromatography. B,... Sep 2018Methyl isocyanate (MIC) is an important precursor for industrial synthesis, but it is highly toxic. MIC causes irritation and damage to the eyes, respiratory tract, and...
Determination of methyl isopropyl hydantoin from rat erythrocytes by gas-chromatography mass-spectrometry to determine methyl isocyanate dose following inhalation exposure.
Methyl isocyanate (MIC) is an important precursor for industrial synthesis, but it is highly toxic. MIC causes irritation and damage to the eyes, respiratory tract, and skin. While current treatment is limited to supportive care and counteracting symptoms, promising countermeasures are being evaluated. Our work focuses on understanding the inhalation toxicity of MIC to develop effective therapeutic interventions. However, in-vivo inhalation exposure studies are limited by challenges in estimating the actual respiratory dose, due to animal-to-animal variability in breathing rate, depth, etc. Therefore, a method was developed to estimate the inhaled MIC dose based on analysis of an N-terminal valine hemoglobin adduct. The method features a simple sample preparation scheme, including rapid isolation of hemoglobin, hydrolysis of the hemoglobin adduct with immediate conversion to methyl isopropyl hydantoin (MIH), rapid liquid-liquid extraction, and gas-chromatography mass-spectrometry analysis. The method produced a limit of detection of 0.05 mg MIH/kg RBC precipitate with a dynamic range from 0.05-25 mg MIH/kg. The precision, as measured by percent relative standard deviation, was <8.5%, and the accuracy was within 8% of the nominal concentration. The method was used to evaluate a potential correlation between MIH and MIC internal dose and proved promising. If successful, this method may be used to quantify the true internal dose of MIC from inhalation studies to help determine the effectiveness of MIC therapeutics.
Topics: Animals; Erythrocytes; Gas Chromatography-Mass Spectrometry; Hydantoins; Inhalation Exposure; Isocyanates; Limit of Detection; Liquid-Liquid Extraction; Rats; Reproducibility of Results; Toxicity Tests
PubMed: 30015309
DOI: 10.1016/j.jchromb.2018.07.004 -
Environmental Health Perspectives Jul 1992Of 113 methyl isocyanate (MIC)-exposed subjects studied initially at Bhopal, India, 79, 56, 68, and 87 were followed with clinical, lung function, radiographic, and...
Of 113 methyl isocyanate (MIC)-exposed subjects studied initially at Bhopal, India, 79, 56, 68, and 87 were followed with clinical, lung function, radiographic, and immunologic tests at 3, 6, 12, 18, and 24 months. Though our cohort consisted of subjects at all ages showing a varied severity of initial illness, fewer females and young subjects were seen. Initially all had eye problems, but dominant symptoms were exertional dyspnea, cough, chest pain, sputum, and muscle weakness. A large number showed persistent depression mixed with anxiety, with disturbances of personality parameters. The early radiographic changes were lung edema, overinflation, enlarged heart, pleural scars, and consolidation. The persistent changes seen were interstitial deposits. Lung functions showed mainly restrictive changes with small airway obstruction; there was impairment of oxygen exchange. Oxygen exchange improved at 3-6 months, and spirometry improved at 12 months, only to decline later. The expiratory flow rates pertaining to large and medium airway function improved, but those for small airways remained low. There were changes of alveolitis in bronchoalveolar lavage fluid on fiber optic bronchoscopy, and in 11 cases positive MIC-specific antibodies to IgM, IgG, and IgE were demonstrated. On follow up, only 48% of the subjects were clinically stable, while 50% showed fluctuations. Thirty-two percent of the subjects had lung function fluctuations. Detailed sequential behavior over 2-4 years was predicted for dyspnea, forced vital capacity, maximum expiratory flow rate (0.25-0.75), peak expiratory flow rate, VO2, and depression score. A model for clinical behavior explained a total variance of 52.4% by using the factors of cough, PCO2 and X-ray zones in addition to above five parameters. The behavior of the railway colony group (1640 patients) revealed a similar pattern of illness. When this observed pattern of changes was transferred to the affected Bhopal city sections (with an equitable age-sex distribution), our model results were again validated. Thus the picture of MIC-induced disease seems similar despite the differences for age-sex and initial severity of illness in our cohort and in the population of Bhopal city as predicted by our model.
Topics: Adult; Age Factors; Antisickling Agents; Cohort Studies; Cyanates; Environmental Exposure; Female; Follow-Up Studies; Humans; Immunoglobulin E; India; Isocyanates; Lung Diseases; Male; Middle Aged; Models, Biological; Neuromuscular Diseases; Psychophysiologic Disorders; Radiography; Sex Factors
PubMed: 1396463
DOI: 10.1289/ehp.9297241 -
Environmental Health Perspectives Jun 1987F344/N rats and B6C3F1 mice were exposed to 0, 1, 3, or 6 ppm methyl isocyanate by inhalation for 6 hr on 4 consecutive days. Deaths of rats were observed following 3...
F344/N rats and B6C3F1 mice were exposed to 0, 1, 3, or 6 ppm methyl isocyanate by inhalation for 6 hr on 4 consecutive days. Deaths of rats were observed following 3 ppm exposures, and mice died after exposures to 6 ppm. Deaths appeared to be related to severe respiratory distress. Survivors in high dose groups lost weight initially, then gained weight at rates equal to controls throughout a 91-day recovery period. Lung weights increased significantly in male and female rats exposed to 3 ppm, but no persistent changes in brain, kidney, thymus, spleen, liver, or testis weights were seen in either mice or rats. Blood and serum from male and female rats were taken for clinical pathology and hematology assessments on day 7 of postexposure, the day prior to the first observed deaths of these animals. No changes or only slight changes were seen in measures of serum alanine aminotransferase, sorbitol dehydrogenase, alkaline phosphatase, or in blood and brain cholinesterase activities. However, serum creatine kinase increased with dose in both males and females. Blood urea nitrogen, creatinine, and methemoglobin were unchanged. No changes were seen in counts of red blood cells or platelets, or in red cell indices. Hemoglobin concentrations and hematocrits were slightly elevated. No changes were noted in absolute leukocyte counts, but counts of segmented neutrophils increased and lymphocytes decreased.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Animals; Blood; Body Weight; Cyanates; Female; Isocyanates; Male; Mice; Organ Size; Rats; Rats, Inbred F344; Respiratory System; Time Factors
PubMed: 3622427
DOI: 10.1289/ehp.8772133 -
Environmental Health : a Global Access... May 2005On December 3 1984, more than 40 tons of methyl isocyanate gas leaked from a pesticide plant in Bhopal, India, immediately killing at least 3,800 people and causing...
On December 3 1984, more than 40 tons of methyl isocyanate gas leaked from a pesticide plant in Bhopal, India, immediately killing at least 3,800 people and causing significant morbidity and premature death for many thousands more. The company involved in what became the worst industrial accident in history immediately tried to dissociate itself from legal responsibility. Eventually it reached a settlement with the Indian Government through mediation of that country's Supreme Court and accepted moral responsibility. It paid $470 million in compensation, a relatively small amount of based on significant underestimations of the long-term health consequences of exposure and the number of people exposed. The disaster indicated a need for enforceable international standards for environmental safety, preventative strategies to avoid similar accidents and industrial disaster preparedness. Since the disaster, India has experienced rapid industrialization. While some positive changes in government policy and behavior of a few industries have taken place, major threats to the environment from rapid and poorly regulated industrial growth remain. Widespread environmental degradation with significant adverse human health consequences continues to occur throughout India.
Topics: Accidents, Occupational; Chemical Industry; Deception; Developing Countries; Disasters; Environmental Exposure; Explosions; Gas Poisoning; Humans; India; Industry; Isocyanates; Liability, Legal; Urban Population
PubMed: 15882472
DOI: 10.1186/1476-069X-4-6 -
Environmental Health Perspectives Jun 1987Male 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...
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.
Topics: Animals; Cyanates; Epithelium; Isocyanates; Male; Mice; Microscopy, Electron; Nasal Mucosa; Necrosis; Olfactory Mucosa; Rats; Rats, Inbred F344; Regeneration; Time Factors
PubMed: 3622447
DOI: 10.1289/ehp.877277 -
PloS One 2014The anticancer agent 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(methylamino)carbonyl]hydrazine (laromustine), upon decomposition in situ, yields methyl isocyanate and...
The anticancer agent 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(methylamino)carbonyl]hydrazine (laromustine), upon decomposition in situ, yields methyl isocyanate and the chloroethylating species 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (90CE). 90CE has been shown to kill tumor cells via a proposed mechanism that involves interstrand DNA cross-linking. However, the role of methyl isocyanate in the antineoplastic function of laromustine has not been delineated. Herein, we show that 1,2-bis(methylsulfonyl)-1-[(methylamino)carbonyl]hydrazine (101MDCE), an analog of laromustine that generates only methyl isocyanate, activates ASK1-JNK/p38 signaling in endothelial cells (EC). We have previously shown that ASK1 forms a complex with reduced thioredoxin (Trx1) in resting EC, and that the Cys residues in ASK1 and Trx1 are critical for their interaction. 101MDCE dissociated ASK1 from Trx1, but not from the phosphoserine-binding inhibitor 14-3-3, in whole cells and in cell lysates, consistent with the known ability of methyl isocyanate to carbamoylate free thiol groups of proteins. 101MDCE had no effect on the kinase activity of purified ASK1, JNK, or the catalytic activity of Trx1. However, 101MDCE, but not 90CE, significantly decreased the activity of Trx reductase-1 (TrxR1). We conclude that methyl isocyanate induces dissociation of ASK1 from Trx1 either directly by carbamoylating the critical Cys groups in the ASK1-Trx1 complex or indirectly by inhibiting TrxR1. Furthermore, 101MDCE (but not 90CE) induced EC death through a non-apoptotic (necroptotic) pathway leading to inhibition of angiogenesis in vitro. Our study has identified methyl isocyanates may contribute to the anticancer activity in part by interfering with tumor angiogenesis.
Topics: Animals; Antineoplastic Agents; Biocatalysis; Carbamates; Cattle; Cell Death; Cells, Cultured; Endothelial Cells; Humans; Hydrazines; Immunoblotting; Isocyanates; MAP Kinase Kinase Kinase 5; Mitogen-Activated Protein Kinase 8; Neovascularization, Physiologic; Signal Transduction; Sulfonamides; Thioredoxin Reductase 1; Thioredoxins
PubMed: 25068797
DOI: 10.1371/journal.pone.0103224