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Annals of the New York Academy of... Nov 2020Methyl isocyanate (MIC, "Bhopal agent") is a highly reactive, toxic industrial chemical. Inhalation of high levels (500-1000 ppm) of MIC vapor is almost uniformly fatal....
Methyl isocyanate (MIC, "Bhopal agent") is a highly reactive, toxic industrial chemical. Inhalation of high levels (500-1000 ppm) of MIC vapor is almost uniformly fatal. No therapeutic interventions other than supportive care have been described that can delay the onset of illness or death due to MIC. Recently, we found that inhalation of MIC caused the appearance of activated tissue factor in circulation with subsequent activation of the coagulation cascade. Herein, we report that MIC exposure (500 ppm for 30 min, nose-only) caused deposition of fibrin-rich casts in the conducting airways resulting in respiratory failure and death within 24 h in a rat model (LC ). We thus investigated the effect of airway delivery of the fibrinolytic agent tissue plasminogen activator (tPA) on mortality and morbidity in this model. Intratracheal administration of tPA was initiated 11 h post MIC exposure and repeated every 4 h for the duration of the study. Treatment with tPA afforded nearly 60% survival at 24 h post MIC exposure and was associated with decreased airway fibrin casts, stabilization of hypoxemia and respiratory distress, and improved acidosis. This work supports the potential of airway-delivered tPA therapy as a useful countermeasure in stabilizing victims of high-level MIC exposure.
Topics: Airway Obstruction; Animals; Disease Models, Animal; Isocyanates; Male; Rats; Rats, Sprague-Dawley; Tissue Plasminogen Activator
PubMed: 32233099
DOI: 10.1111/nyas.14344 -
Toxicology in Vitro : An International... Jun 2020Human exposure to carbamates and organophosphates poses a serious threat to society and current pharmacological treatment is solely targeting the compounds' inhibitory...
Human exposure to carbamates and organophosphates poses a serious threat to society and current pharmacological treatment is solely targeting the compounds' inhibitory effect on acetylcholinesterase. This toxicological pathway, responsible for acute symptom presentation, can be counteracted with currently available therapies such as atropine and oximes. However, there is still significant long-term morbidity and mortality. We propose mitochondrial dysfunction as an additional cellular mechanism of carbamate toxicity and suggest pharmacological targeting of mitochondria to overcome acute metabolic decompensation. Here, we investigated the effects on mitochondrial respiratory function of N-succinimidyl N-methylcarbamate (NSNM), a surrogate for carbamate insecticides, ex vivo in human platelets. Characterization of the mitochondrial toxicity of NSNM in platelets revealed a dose-dependent decrease in mitochondral oxygen consumption linked to respiratory chain complex I while the pathway through complex II was unaffected. In intact platelets, an increase in lactate production was seen, due to a compensatory shift towards anaerobic metabolism. Treatment with a cell-permeable succinate prodrug restored the NSNM-induced (100 μM) decrease in mitochondrial oxygen consumption and normalized lactate production to the level of control. We have demonstrated that carbamate-induced mitochondrial complex I dysfunction can be alleviated with a mitochondrial targeted countermeasure: a cell-permeable prodrug of the mitochondrial complex II substrate succinate.
Topics: Blood Platelets; Carbamates; Cell Membrane Permeability; Cell Respiration; Cells, Cultured; Electron Transport Complex I; Humans; Insecticides; Lactic Acid; Mitochondria; Oxygen Consumption; Prodrugs; Succinic Acid
PubMed: 32057835
DOI: 10.1016/j.tiv.2020.104794 -
Environmental Science and Pollution... Jun 2019Severity of clinical expression and high mortality could not facilitate establishing exposure index/association following MIC disaster in Bhopal. Mortality-based...
Severity of clinical expression and high mortality could not facilitate establishing exposure index/association following MIC disaster in Bhopal. Mortality-based exposure stratification was critiqued by the International Medical Commission on Bhopal (IMCB). IMCB stratified exposure considering distance as surrogate at 2 km intervals after 10 years. The first follow-up cytogenetic screening of the pre-screened survivors after 30 years has demonstrated chromosome abnormalities (CA). Exposure stratification was attempted considering cytogenetic screening conducted during 1986-1988. Elevation of CA appeared proportional to exposure status and authenticated the initial mortality-based stratification. The one-on-one comparison of the previous and present cytogenetics has described the individual response to MIC exposure over 30 years. Chi-square test has been carried out for checking the cytogenetic changes at the individual level statistically, which revealed that differences of chromosomal aberrations collected immediately post-disaster and 30 years later are nonsignificant. The prominence of interindividual variation was noticed in general. The impact of overall exposure was higher in males. Constitutional abnormalities in 8.5% of the study population, including translocation, inversion, deletion, fragile sites, etc., necessitate screening of blood-linked members. The incidence of acrocentric association was prominent in the study population. Normal karyotype in children born to severely exposed parents with congenital anomalies indicates necessity of molecular karyotyping and/or screening of mutations. The study highlights follow-up of the health of the index cases at shorter (3-6 months) intervals. This comprehensive spectrum of cytogenetic report highlights immediate post-disaster chromosomal aberrations, the changes that occurred over 30 years in conjunction with other environmental factors at the individual level, constitutive genomic aberrations, polymorphic variations, and chromosomal patterns in congenitally malformed children of the survivors, which collectively indicate the possibility of acquisition/persistence of stable aberrations in MIC-exposed lymphocytes through interaction with environmental/biological confounders.
Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Chromosome Aberrations; Cytogenetic Analysis; Disasters; Environmental Exposure; Female; Follow-Up Studies; Humans; India; Isocyanates; Lymphocytes; Male; Middle Aged; Mutagens; Sex Factors
PubMed: 31041706
DOI: 10.1007/s11356-019-04439-0 -
Indoor Air Mar 2019Toxic compounds in cooking fumes could cause respiratory problems. In the present study, the formation of isocyanic acid (ICA), methyl isocyanate (MIC), and hydrogen...
Toxic compounds in cooking fumes could cause respiratory problems. In the present study, the formation of isocyanic acid (ICA), methyl isocyanate (MIC), and hydrogen cyanide (HCN) was studied during the heating of proteins or frying of protein-rich foods. Heating was performed in an experimental setup using a tube oven set at 200-500°C and in a kitchen when foods with different protein content were fried at a temperature around 300°C. ICA, MIC, and HCN were all generated when protein or meat was heated. Individual amino acids were also heated, and there was a significant positive correlation between their respective nitrogen content and the formation of the measured compounds. Gas from heated protein or meat also caused carbamylation in albumin. ICA, MIC, and HCN were also present in fumes generated when meat, egg, and halloumi were fried in a kitchen pan. The levels of ICA were here twice that of the Swedish occupational exposure limit. If ICA, MIC, and HCN in fumes from heated protein-rich foods could contribute to the risk of airway dysfunction among those exposed is not clear, but it is important to avoid inhaling frying and grilling fumes and to equip kitchens with good exhaust ventilation.
Topics: Air Pollution, Indoor; Albumins; Cooking; Environmental Monitoring; Food; Hot Temperature; Humans; Hydrogen Cyanide; Isocyanates; Meat; Occupational Exposure; Proteins; Sweden
PubMed: 30548495
DOI: 10.1111/ina.12526 -
Drug and Chemical Toxicology May 2019Methyl isocyanate (MIC) is a highly toxic industrial chemical causing acute lethality after inhalation. The objective of this study was to determine whether alterations...
Methyl isocyanate (MIC) is a highly toxic industrial chemical causing acute lethality after inhalation. The objective of this study was to determine whether alterations in hemostasis also occur in the immediate hours after exposure. Male rats were exposed to MIC (125-500 ppm) by nose-only vapor inhalation for 30 min. Arterial O saturation was monitored prior to exposure, and hourly thereafter. Rats were euthanized at 1, 2, 4, and 8 hr and plasma analyzed for recalcification clotting time, tissue factor (TF) activity, and protein levels. Hypoxemia, as assessed by pulse oximetry, was an early feature of MIC inhalation. In contrast to sham or low (125 ppm) concentrations, 250 and 500 ppm MIC caused significant declines in blood oxygen saturation (% SpO) at 1 hr, which remained at deficit during the postexposure period. Commensurate with hypoxemia, plasma clotting time was significantly accelerated 1 hr after MIC inhalation (sham treatment: 955 ± 62.8 s; 125 ppm MIC: 790 ± 62 s; 250 ppm: 676 ± 28.0 s; 500 ppm: 581 ± 175 s). This procoagulant effect was transient, with no difference observed between sham and all MIC groups by 8 hr. Similarly, elevated TF activity and protein were detected in plasma 1 hr after MIC inhalation, each of which showed a progressive decline back to control levels at later timepoints. This study demonstrates that MIC inhalation resulted in hypoxemia and transient hypercoagulability of blood. Accelerated clotting occurred rapidly and was likely due to intravascular TF, which initiates the extrinsic coagulation pathway.
Topics: Animals; Blood Coagulation; Dose-Response Relationship, Drug; Hypoxia; Inhalation Exposure; Isocyanates; Male; Oxygen; Rats; Rats, Sprague-Dawley; Thromboplastin
PubMed: 30426789
DOI: 10.1080/01480545.2018.1517773 -
Astronomy and Astrophysics Aug 2018Relatively high abundances of methyl isocyanate (CHNCO), a methyl derivative of isocyanic acid (HNCO), found in the Orion KL and Sgr B2 molecular clouds suggest that its...
CONTEXT
Relatively high abundances of methyl isocyanate (CHNCO), a methyl derivative of isocyanic acid (HNCO), found in the Orion KL and Sgr B2 molecular clouds suggest that its ethyl derivative, ethyl isocyanate (CHCHNCO), may also be present.
AIMS
The aim of this work is to provide accurate experimental frequencies of ethyl isocyanate in its ground and excited vibrational states in the millimeter wave region to support searches for it in the interstellar medium.
METHODS
The rotational spectrum of ethyl isocyanate was recorded at room temperature from 80 to 340 GHz using the millimeter wave spectrometer in Valladolid. Assigned rotational transitions were analyzed using the -reduced semirigid-rotor Hamiltonian.
RESULTS
More than 1100 distinct frequency lines were analyzed for the ground vibrational state of the conformer as well as for three vibrational satellites corresponding to successive excitation of the lowest-energy C-N torsional mode. Newly determined rotational and centrifugal distortion constants were used for searches of spectral features of ethyl isocyanate in Orion KL and Sgr B2 clouds. Upper limits to CHCHNCO in these high-mass star-forming regions were obtained.
PubMed: 30369619
DOI: 10.1051/0004-6361/201833223 -
The Astrophysical Journal Jul 2018Methyl isocyanate (CHNCO) was recently found in hot cores and suggested on comet 67P/CG. The incorporation of this molecule into astrochemical networks requires data on...
Methyl isocyanate (CHNCO) was recently found in hot cores and suggested on comet 67P/CG. The incorporation of this molecule into astrochemical networks requires data on its formation and destruction. In this work, ices of pure CHNCO and of CHNCO(4-5%)/HO mixtures deposited at 20 K were irradiated with a UV D lamp (120-400 nm) and bombarded by 5 keV electrons to mimic the secondary electrons produced by cosmic rays (CRs). The destruction of CHNCO was studied using IR spectroscopy. After processing, the ν-NCO band of CHNCO disappeared and IR bands corresponding to CO, CO, OCN and HCN/CN appeared instead. The products of photon and electron processing were very similar. Destruction cross sections and half-life doses were derived from the measurements. Water ice provides a good shield against UV irradiation (half-life dose of ~ 64 eV molecule for CHNCO in water-ice), but not so good against high-energy electrons (half-life dose ~ 18 eV molecule). It was also found that CHNCO does not react with HO over the 20-200 K temperature range. These results indicate that hypothetical CHNCO in the ices of dense clouds should be stable against UV photons and relatively stable against CRs over the lifetime of a cloud (~ 10 yr), and could sublime in the hot core phase. On the surface of a Kuiper belt object (the original location of comet 67P/CG) the molecule would be swiftly destroyed, both by photons and CRs, but embedded below just 10 μm of water-ice, the molecule could survive for ~ 10 yr.
PubMed: 30185993
DOI: 10.3847/1538-4357/aac826 -
Journal of Radioanalytical and Nuclear... 2018-Methyl carbamoylimidazole is a safe and practical alternative to methyl isocyanate for carbamoylation reactions. We have developed a new chemical route for its...
-Methyl carbamoylimidazole is a safe and practical alternative to methyl isocyanate for carbamoylation reactions. We have developed a new chemical route for its synthesis from methyl iodide and applied this to the synthesis of -[C]methyl carbamoylimidazole as a new [C]synthon to radiolabel biomolecules for PET imaging research. -[C]methyl carbamoylimidazole was prepared from [C]methyl iodide in 70-74% radiochemical yield (decay corrected) and can be used in situ for further reaction without purification. The reactivity of -[C]methyl carbamoylimidazole was demonstrated in a series of [C]carbamoylation reactions.
PubMed: 30100651
DOI: 10.1007/s10967-018-5948-4 -
Nature Communications Jul 2018The 6,6-quinolone scaffolds on which viridicatin-type fungal alkaloids are built are frequently found in metabolites that display useful biological activities. Here we...
The 6,6-quinolone scaffolds on which viridicatin-type fungal alkaloids are built are frequently found in metabolites that display useful biological activities. Here we report in vitro and computational analyses leading to the discovery of a hemocyanin-like protein AsqI from the Aspergillus nidulans aspoquinolone biosynthetic pathway that forms viridicatins via a conversion of the cyclopenin-type 6,7-bicyclic system into the viridicatin-type 6,6-bicyclic core through elimination of carbon dioxide and methylamine through methyl isocyanate.
Topics: Alkaloids; Aspergillus nidulans; Binding Sites; Biosynthetic Pathways; Carbon Dioxide; Cloning, Molecular; Crystallography, X-Ray; Cyclization; Escherichia coli; Fungal Proteins; Gene Expression; Genetic Vectors; Hemocyanins; Hydroxyquinolines; Isocyanates; Kinetics; Methylamines; Models, Molecular; Protein Binding; Protein Conformation, alpha-Helical; Protein Interaction Domains and Motifs; Quinolones; Recombinant Proteins; Substrate Specificity; Zinc
PubMed: 30026518
DOI: 10.1038/s41467-018-05221-5 -
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