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Asian Pacific Journal of Cancer... 2012Methyl isocyanate may have a role in cancer etiology, although the link is unclear. There is evidence in the literature that it can induce cancer in animals but the... (Review)
Review
Methyl isocyanate may have a role in cancer etiology, although the link is unclear. There is evidence in the literature that it can induce cancer in animals but the carcinogenic potency is weak. Pheochromocytoma of adrenal medulla and acinar cell tumors of pancreas have been observed in methyl isocyanate exposed animals. Conversely, emerging data from population-based epidemiological studies are contradictory since there is no evidence of such cancers in methyl isocyanate exposed humans. Recently, we reported a high prevalence of breast and lung cancers in such a population in Bhopal. In vitro findings appearing in the latest scientific literature suggest that genomic instability is caused by methyl isocyanate analogs in lung, colon, kidney, ovary epithelial cells, and that hepatocytes may undergo oncogenic transformation, have obvious implications. The conflicting information prompted us to present this update over the last three decades on methyl isocyanate-induced cancers after an extensive literature search using PubMed. While the pertinent literature remains limited, with a scarcity of strong laboratory analyses and field-epidemiological investigations, our succinct review of animal and human epidemiological data including in vitro evidences, should hopefully provide more insight to researchers, toxicologists, and public health professionals concerned with validation of the carcinogenicity of methyl isocyanate in humans.
Topics: Animals; Breast Neoplasms; Carcinoma, Acinar Cell; Cell Transformation, Neoplastic; Female; Genomic Instability; Humans; Isocyanates; Lung Neoplasms; Male; Neoplasms; Pheochromocytoma; Rats
PubMed: 22938400
DOI: 10.7314/apjcp.2012.13.6.2429 -
Antimicrobial Agents and Chemotherapy May 2023Fosmanogepix (FMGX), a novel antifungal available in intravenous (IV) and oral formulations, has broad-spectrum activity against pathogenic yeasts and molds, including...
Fosmanogepix (FMGX), a novel antifungal available in intravenous (IV) and oral formulations, has broad-spectrum activity against pathogenic yeasts and molds, including fungi resistant to standard of care antifungals. This multicenter, open-label, single-arm study evaluated FMGX safety and efficacy for treatment of candidemia and/or invasive candidiasis caused by Candida auris. Eligible participants were ≥18 years, with established candidemia and/or invasive candidiasis caused by C. auris, (cultured within 120 h [for candidemia] or 168 h [for invasive candidiasis without candidemia] with accompanying clinical signs) and limited treatment options. Participants were treated with FMGX (≤42 days; loading dose: 1000 mg IV twice daily [Day 1], followed by 600 mg IV once daily [QD]). Switching to oral FMGX 800 mg QD was permitted from Day 4. Primary endpoint was treatment success (survival and clearance of C. auris from blood/tissue cultures without additional antifungals) at the end of the study treatment (EOST), assessed by an independent data review committee (DRC). Day 30 survival was a secondary endpoint. susceptibility of isolates was assessed. Nine participants with candidemia (male:6, female:3; 21 to 76 years) in intensive care units in South Africa were enrolled; all received IV FMGX only. DRC-assessed treatment success at EOST and Day 30 survival were 89% (8/9). No treatment related adverse events or study drug discontinuations were reported. FMGX demonstrated potent activity against all C. auris isolates (MIC range: 0.008 to 0.015 μg/mL [CLSI]; 0.004-0.03 μg/mL [EUCAST]), with the lowest MICs compared to other antifungals tested. Thus, the results showed that FMGX was safe, well-tolerated, and efficacious in participants with candidemia caused by C. auris.
Topics: Humans; Male; Female; Antifungal Agents; Candidemia; Candida auris; Candidiasis, Invasive; Treatment Outcome; Microbial Sensitivity Tests
PubMed: 37022196
DOI: 10.1128/aac.01419-22 -
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 -
Environmental Science and Pollution... Apr 2021Methylcarbamoyl mercapturic acid (MCAMA, N-acetyl-S-(N-methylcarbamoyl)-L-cysteine) is a urinary metabolite of N,N-dimethylformamide and methyl isocyanate, which are...
Characterization of US population levels of urinary methylcarbamoyl mercapturic acid, a metabolite of N,N-dimethylformamide and methyl isocyanate, in the National Health and Nutrition Examination Survey (NHANES) 2005-2006 and 2011-2016.
Methylcarbamoyl mercapturic acid (MCAMA, N-acetyl-S-(N-methylcarbamoyl)-L-cysteine) is a urinary metabolite of N,N-dimethylformamide and methyl isocyanate, which are volatile organic compounds that are harmful to humans. N,N-dimethylformamide exposure causes liver damage, and methyl isocyanate inhalation damages the lining of the respiratory tract, which can increase risk of chronic obstructive pulmonary disease and asthma. This study characterizes urinary MCAMA levels in the US population and explores associations of MCAMA concentrations with select demographic and environmental factors. We used liquid chromatography tandem mass spectrometry to measure MCAMA in urine collected from study participants ≥ 12 years old (N = 8272) as part of the National Health and Nutrition Examination Survey 2005-2006 and 2011-2016. We produced multiple regression models with MCAMA concentrations as the dependent variable and sex, age, fasting time, race/ethnicity, diet, and cigarette smoking as independent variables. Cigarette smokers and nonsmokers had median urinary MCAMA concentrations of 517 μg/g creatinine and 127 μg/g creatinine, respectively. Sample-weighted multiple regression analysis showed that MCAMA was positively associated with serum cotinine (p < 0.0001). Compared to non-exposed participants (serum cotinine ≤ 0.015 ng/mL), presumptive exposure to second-hand tobacco smoke (serum cotinine > 0.015-≤ 10 ng/mL and 0 cigarettes smoked per day) was associated with 20% higher MCAMA (p < 0.0001). Additionally, smoking 1-10 cigarettes per day was associated with 261% higher MCAMA (p < 0.0001), smoking 11-20 cigarettes per day was associated with 357% higher MCAMA (p < 0.0001), and smoking > 20 cigarettes per day was associated with 416% higher MCAMA (p < 0.0001). These findings underscore the strong association of tobacco smoke exposure with urinary MCAMA biomarker levels.
Topics: Acetylcysteine; Biomarkers; Child; Cotinine; Dimethylformamide; Humans; Isocyanates; Nutrition Surveys; Tobacco Smoke Pollution
PubMed: 33398732
DOI: 10.1007/s11356-020-12135-7 -
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 -
International Journal of Occupational... 2015December 2014 marked the 30th year anniversary of Bhopal gas tragedy. This sudden and accidental leakage of deadly poisonous methyl isocyanate (MIC) gas instigated... (Review)
Review
December 2014 marked the 30th year anniversary of Bhopal gas tragedy. This sudden and accidental leakage of deadly poisonous methyl isocyanate (MIC) gas instigated research efforts to understand the nature, severity of health damage and sufferings of 570 000 ailing survivors of this tragedy. In a decade-long period, our systematic laboratory investigations coupled with long-term molecular surveillance studies have comprehensively demonstrated that the risk of developing an environmental associated aberrant disease phenotype, including cancer, involves complex interplay of genomic and epigenetic reprogramming. These findings poised us to translate this knowledge into an investigative framework of "molecular biodosimetry" in a strictly selected cohort of MIC exposed individuals. A pragmatic cancer risk-assessment strategy pursued in concert with a large-scale epidemiological study might unfold molecular underpinnings of host-susceptibility and exposureresponse relationship. The challenges are enormous, but we postulate that the study will be necessary to establish a direct initiation-promotion paradigm of environmental carcinogenesis. Given that mitochondrial retrograde signaling-induced epigenetic reprogramming is apparently linked to neoplasticity, a cutting-edge tailored approach by an expert pool of biomedical researchers will be fundamental to drive these strategies from planning to execution. Validating the epigenomic signatures will hopefully result in the development of biomarkers to better protect human lives in an overburdened ecosystem, such as India, which is continuously challenged to meet population demands. Besides, delineating the mechanistic links between MIC exposure and cancer morbidity, our investigative strategy might help to formulate suitable regulatory policies and measures to reduce the overall burden of occupational and environmental carcinogenesis.
Topics: Antisickling Agents; Bhopal Accidental Release; Carcinogens; Disasters; Humans; Incidence; India; Isocyanates; Neoplasms; Radiometry; Risk Assessment; Survival Rate; Survivors
PubMed: 26294196
DOI: 10.13075/ijomeh.1896.00313 -
Organic Process Research & Development Dec 2020The cyclic azodicarbonyl 4-methyl-1,2,4-triazoline-3,5-dione (MTAD) is a versatile and powerful reagent used mainly in cycloaddition chemistry. Though known for more...
The cyclic azodicarbonyl 4-methyl-1,2,4-triazoline-3,5-dione (MTAD) is a versatile and powerful reagent used mainly in cycloaddition chemistry. Though known for more than 50 years, its unsafe preparation, as well as purification by sublimation, hampered its widespread applicability on a larger scale. Herein we report a scalable and safe route to MTAD, which avoids the generation of methyl isocyanate. Moreover, we demonstrate that sublimation can be circumvented by the application of judicious oxidation conditions, followed by simple filtration. Overall, up to 25 g of MTAD was prepared in a single batch from commercial starting materials in three steps, with recrystallization serving as the only purification in the sequence. When employed in dearomative methodologies, the MTAD obtained by this protocol displayed synthetic efficiency equivalent to that of MTAD purified by sublimation.
PubMed: 33958851
DOI: 10.1021/acs.oprd.0c00470 -
The Indian Journal of Medical Research Nov 2014Stress induced premature senescence (SIPS) is a relative extension to the concept of exogenous cellular insult. Besides persistent double strand (ds) DNA breaks and... (Review)
Review
Stress induced premature senescence (SIPS) is a relative extension to the concept of exogenous cellular insult. Besides persistent double strand (ds) DNA breaks and increased β-galactosidase activity, biological significance of telomeric attrition in conjunction with senescence associated secretory phenotype (SASP) has been highlighted in SIPS. To gain insight on the potential role of this unique phenomenon invoked upon environmental stress, we sequentially validated the molecular repercussions of this event in ovarian epithelial cells after exposure to methyl isocyanate, an elegant regulator of cellular biotransformation. Persistent accumulation of DNA damage response factors phospho-ATM/γ-H2AX, morphological changes with increased cell size and early yet incremental β-gal staining, imply the inception of premature senescence. Advent of SASP is attributed by prolonged secretion of pro-inflammatory cytokines along with untimely but significant G1/S cell cycle arrest. Telomeric dysfunction associated with premature senescence is indicative of early loss of TRF2 (telomeric repeat binding factor 2) protein and resultant multiple translocations. Induction of senescence-associated heterochromatic foci formation showcases the chromatin alterations in form of trimethylated H3K9me3 in conjunction with H4 hypoacetylation and altered miRNA expression. Anchorage-independent neoplastic growth observed in treated cells reaffirms the oncogenic transformation following the exposure. Collectively, we infer the possible role of SIPS, as a central phenomenon, to perturbed genomic integrity in ovarian surface epithelium, orchestrated through SASP and chromatin level alterations, a hitherto unknown molecular paradigm. Although translational utility of SIPS as a biomarker for estimating ovarian cancer risk seems evident, further investigations will be imperative to provide a tangible way for its precise validation in clinical settings.
Topics: Biomarkers; Carcinogenesis; Cell Transformation, Neoplastic; Cellular Senescence; Epithelial Cells; Female; Histones; Humans; Isocyanates; Ovarian Neoplasms; Ovary; Stress, Physiological; Telomere Shortening; Telomeric Repeat Binding Protein 2
PubMed: 25673532
DOI: No ID Found -
Proceedings of the American Thoracic... Jul 2010The inhalation of reactive gases and vapors can lead to severe damage of the airways and lung, compromising the function of the respiratory system. Exposures to... (Review)
Review
The inhalation of reactive gases and vapors can lead to severe damage of the airways and lung, compromising the function of the respiratory system. Exposures to oxidizing, electrophilic, acidic, or basic gases frequently occur in occupational and ambient environments. Corrosive gases and vapors such as chlorine, phosgene, and chloropicrin were used as warfare agents and in terrorist acts. Chemical airway exposures are detected by the olfactory, gustatory, and nociceptive sensory systems that initiate protective physiological and behavioral responses. This review focuses on the role of airway nociceptive sensory neurons in chemical sensing and discusses the recent discovery of neuronal receptors for reactive chemicals. Using physiological, imaging, and genetic approaches, Transient Receptor Potential (TRP) ion channels in sensory neurons were shown to respond to a wide range of noxious chemical stimuli, initiating pain, respiratory depression, cough, glandular secretions, and other protective responses. TRPA1, a TRP ion channel expressed in chemosensory C-fibers, is activated by almost all oxidizing and electrophilic chemicals, including chlorine, acrolein, tear gas agents, and methyl isocyanate, the highly noxious chemical released in the Bhopal disaster. Chemicals likely activate TRPA1 through covalent protein modification. Animal studies using TRPA1 antagonists or TRPA1-deficient mice confirmed the role of TRPA1 in chemically induced respiratory reflexes, pain, and inflammation in vivo. New research shows that sensory neurons are not merely passive sensors of chemical exposures. Sensory channels such as TRPA1 are essential for maintenance of airway inflammation in asthma and may contribute to the progression of airway injury following high-level chemical exposures.
Topics: Acids; Animals; Chemical Warfare Agents; Chemoreceptor Cells; Environmental Exposure; Gases; Humans; Inhalation Exposure; Irritants; Mice; Nociceptors; Occupational Exposure; Respiratory System; Sensory Receptor Cells; Transient Receptor Potential Channels
PubMed: 20601631
DOI: 10.1513/pats.201001-004SM -
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