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Scientific Reports Jun 2018Development of effective rescue countermeasures for toxic inhalational industrial chemicals, such as methyl isocyanate (MIC), has been an emerging interest. Nonetheless,...
Development of effective rescue countermeasures for toxic inhalational industrial chemicals, such as methyl isocyanate (MIC), has been an emerging interest. Nonetheless, current methods for studying toxin-induced airway injuries are limited by cost, labor time, or accuracy, and only provide indirect or localized information. Optical Coherence Tomography (OCT) endoscopic probes have previously been used to visualize the 3-D airway structure. However, gathering such information in small animal models, such as rat airways after toxic gas exposure, remains a challenge due to the required probe size necessary for accessing the small, narrow, and partially obstructed tracheas. In this study, we have designed a 0.4 mm miniature endoscopic probe and investigated the structural changes in rat trachea after MIC inhalation. An automated 3D segmentation algorithm was implemented so that anatomical changes, such as tracheal lumen volume and cross-sectional areas, could be quantified. The tracheal region of rats exposed to MIC by inhalation showed significant airway narrowing, especially within the upper trachea, as a result of epithelial detachment and extravascular coagulation within the airway. This imaging and automated reconstruction technique is capable of rapid and minimally-invasive identification of airway obstruction. This method can be applied to large-scale quantitative analysis of in vivo animal models.
Topics: Algorithms; Animals; Endoscopy; Imaging, Three-Dimensional; Isocyanates; Male; Rats; Rats, Sprague-Dawley; Tomography, Optical Coherence; Trachea
PubMed: 29880863
DOI: 10.1038/s41598-018-26389-2 -
Monthly Notices of the Royal... Oct 2017Methyl isocyanate has been recently detected in comet 67P/ Churyumov-Gerasimenko (67P/CG) and in the interstellar medium. New physicochemical studies on this species are...
Methyl isocyanate has been recently detected in comet 67P/ Churyumov-Gerasimenko (67P/CG) and in the interstellar medium. New physicochemical studies on this species are now necessary as tools for subsequent studies in astrophysics. In this work, infrared spectra of solid CHNCO have been obtained at temperatures of relevance for astronomical environments. The spectra are dominated by a strong, characteristic multiplet feature at 2350-2250 cm, which can be attributed to the antisymmetric stretching of the NCO group. A phase transition from amorphous to crystalline methyl isocyanate is observed at ~ 90 K. The band strengths for the absorptions of CHNCO in ice at 20 K have been measured. Deuterated methyl isocyanate is used to help with the spectral assignment. No X-ray structure has been reported for crystalline CHNCO. Here we advance a tentative theoretical structure, based on Density Functional Theory (DFT) calculations, derived taking as a starting point the crystal of isocyanic acid. A harmonic theoretical spectrum is calculated then for the proposed structure, and compared with the experimental data. A mixed ice of HO and CHNCO was formed by simultaneous deposition of water and methyl isocyanate at 20 K. The absence of new spectral features indicates that methyl isocyanate and water do not react appreciably at 20 K, but form a stable mixture. The high CHNCO/HO ratio reported for comet 67P/CG, and the characteristic structure of the 2350-2250 cm band, make of it a very good candidate for future astronomical searches.
PubMed: 29861511
DOI: 10.1093/mnras/stx1461 -
Mutation Research May 2018Follow-up cytogenetic study was carried out on 145 individuals from areas stratified by Indian Council of Medical Research, for evaluation of the effect of... (Clinical Trial)
Clinical Trial
Follow-up cytogenetic study was carried out on 145 individuals from areas stratified by Indian Council of Medical Research, for evaluation of the effect of age-at-exposure and its interaction with exposure status on chromosomal aberrations (CA) in blood-lymphocytes. CA was presented as abnormal cell (Abc), aberrations (Abn) and number of aberration/abnormal cell (Abn/Abc), and correlated with age-at-exposure (childhood: <1-10 years; young: 11-26 years; adult: >27 years). Age related increase in abnormalities (Abc, Abn, Abn/Abc) was observed in all exposure strata, except moderately exposed adult-group, which has exhibited lower Abn/Abc than similarly exposed childhood and young age-groups. Elevation of CA was also related to exposure status. Abn/Abc frequency was significantly higher in the severely exposed young and adult groups compared to the controls of the same age. Two-way ANOVA revealed significant abnormalities between the exposed groups; however, interaction of age and exposure was not statistically significant. Significant difference in group-means of Abc and Abn was also observed between adult and childhood in Tukey HSD test. Altogether, a significant interaction of age and MIC-exposure on CA could not be established due to inter-individual variation and lack of baseline information on CA. Significantly higher Abn was observed in people consuming tobacco; however, interaction of lifestyle with additional environmental/occupational exposures during last 30 years against a background exposure to MIC remained un-elucidated. Nevertheless, the study was important for demonstration of the correlation of the current status of CA in circulating lymphocytes with age and exposure status of the MIC-exposed survivors.
Topics: Adult; Age Factors; Chemical Hazard Release; Child; Child, Preschool; Chromosome Aberrations; Disasters; Environmental Exposure; Female; Follow-Up Studies; Humans; India; Infant; Isocyanates; Male
PubMed: 29684722
DOI: 10.1016/j.mrfmmm.2018.03.005 -
Environmental Science and Pollution... Feb 2018Health effects of methyl isocyanate (MIC) exposure were mostly reported on the one-time acute exposure in Bhopal population. Epidemiological survey conducted by the...
Health effects of methyl isocyanate (MIC) exposure were mostly reported on the one-time acute exposure in Bhopal population. Epidemiological survey conducted by the Indian apex body of health research has been reported as Technical Reports, which were lacking in peer review by the expert epidemiologic scientists. The present pilot survey was aimed to measure the health effects 30 years post disaster in MIC-exposed survivors. Questionnaire-based survey has captured every health complaint in 168 individuals and grouped as systemic functions for interpreting the long-term effects of MIC. Key health parameters, including reproductive outcome and respiratory/orthopedic/general morbidity, were prevalent among the severely exposed population compared to control and moderately exposed groups. The collective incidence of diabetes, hypertension, and cancer also was prevalent in the severely exposed group. Ophthalmic morbidity was almost similar in the three groups, rather with higher incidence in the control group, though not statistically significant. Among all health parameters, reproductive, ophthalmic, and respiratory effects were prevalent over others. Although the incidence of health problems has been declined among the survivors, long-term effect is apparent as scars of one-time acute exposure might trigger sequel of long-term effects. Additionally, acquisition of genetic rearrangements, survival of T cell sub-populations, variable latency of chemical effect on DNA nucleosides, nutritional status, occupational exposure, living environment, lifestyle, and overall gene-environment interaction might perturb individual immunity and favor onset of long-term illness in a scenario of background exposure to MIC. However, the exercise should be continued on a larger sample size for drawing a conclusive result on long-term MIC effect on survivors' health.
Topics: Bhopal Accidental Release; Disasters; Environmental Exposure; Female; Health Status Indicators; Humans; Incidence; India; Isocyanates; Life Style; Male; Middle Aged; Morbidity; Neoplasms; Prevalence; Reproduction; Survivors
PubMed: 29204942
DOI: 10.1007/s11356-017-0865-6 -
Mutation Research. Genetic Toxicology... Dec 2017Following the 1984 Bhopal methyl isocyanate (MIC) gas disaster, genetic alterations were sporadically reported on small cohorts. However, the outcome of the multi-center... (Clinical Trial)
Clinical Trial
Following the 1984 Bhopal methyl isocyanate (MIC) gas disaster, genetic alterations were sporadically reported on small cohorts. However, the outcome of the multi-center cytogenetic screening conducted at that time remains unknown and no follow-up studies on the long-term effects of MIC exposure have been published. The present work examines genetic changes in the exposed population,with the aim of identifying any long-term effects of MIC. G-Banded metaphases were studied in lymphocytes of 130 individuals. Chromosomal aberrations (CA) were broadly grouped as abnormal cells (Abc), aberrations (Abn), and aberration/abnormal cell (Abn/Abc). From the previous multi-center screening, 946 records were retrieved, from which CA, sister chromatid exchanges (SCE), and cell-cycle kinetics (RI) were computed. In our analysis of the previous study, Abc and Abn were higher in the moderately and severely exposed groups than in the unexposed population. Abc appeared uniform in all groups of the present study, although Abn and Abn/Abc were higher in the exposed groups. Aberrations were now significantly higher in the unexposed and moderately exposed groups than in the previous screening. Although Abn and Abc now appeared lower in severely exposed subjects, the Abn/Abc ratio was higher, perhaps due to more rearrangements and damage in a smaller number of Abc. This result may be attributed to differences between the methods used in the studies, then and now. Elevated SCEs and reduced RI were seen in the severely exposed population shortly after exposure, and stable/clonal rearrangements were seen 30 y later. Follow-up of index cases and their progenies is needed.
Topics: Bhopal Accidental Release; Chromosome Aberrations; Female; Follow-Up Studies; Humans; India; Isocyanates; Male; Middle Aged
PubMed: 29150050
DOI: 10.1016/j.mrgentox.2017.10.004 -
Chemical Biology & Drug Design Jan 2018Laromustine (also known as cloretazine, onrigin, VNP40101M, 101M) is a prodrug of 90CE, a short-lived chloroethylating agent with anticancer activity. The short...
pH-dependent general base catalyzed activation rather than isocyanate liberation may explain the superior anticancer efficacy of laromustine compared to related 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine prodrugs.
Laromustine (also known as cloretazine, onrigin, VNP40101M, 101M) is a prodrug of 90CE, a short-lived chloroethylating agent with anticancer activity. The short half-life of 90CE necessitates the use of latentiated prodrug forms for in vivo treatments. Alkylaminocarbonyl-based prodrugs such as laromustine exhibit significantly superior in vivo activity in several murine tumor models compared to analogs utilizing acyl, and alkoxycarbonyl latentiating groups. The alkylaminocarbonyl prodrugs possess two exclusive characteristics: (i) They are primarily unmasked by spontaneous base catalyzed elimination; and (ii) they liberate a reactive carbamoylating species. Previous speculations as to the therapeutic superiority of laromustine have focused upon the inhibition of enzymes by carbamoylation. We have investigated the therapeutic interactions of analogs with segregated chloroethylating and carbamoylating activities (singly and in combination) in the in vivo murine L1210 leukemia model. The combined treatment with chloroethylating and carbamoylating prodrugs failed to result in any synergism and produced a reduction in the therapeutic efficacy compared to the chloroethylating prodrug alone. Evidence supporting an alternative explanation for the superior tumor selectivity of laromustine is presented that is centered upon the high pH sensitivity of its base catalyzed activation, and the more alkaline intracellular pH values commonly found within tumor cells.
Topics: Animals; Antineoplastic Agents; Catalysis; Cell Line, Tumor; DNA; Drug Design; Female; Half-Life; Humans; Hydrazines; Hydrogen-Ion Concentration; Isocyanates; Leukemia; Mice; Prodrugs; Protein Carbamylation; Sulfonamides; Transplantation, Homologous
PubMed: 28636806
DOI: 10.1111/cbdd.13057 -
The Journal of Chemical Physics Sep 2016Various astrophysical relevant molecules obeying the empirical formula CHNO are characterized using explicitly correlated coupled cluster methods (CCSD(T)-F12)....
Various astrophysical relevant molecules obeying the empirical formula CHNO are characterized using explicitly correlated coupled cluster methods (CCSD(T)-F12). Rotational and rovibrational parameters are provided for four isomers: methyl isocyanate (CHNCO), methyl cyanate (CHOCN), methyl fulminate (CHONC), and acetonitrile N-oxide (CHCNO). A CHCON transition state is inspected. A variational procedure is employed to explore the far infrared region because some species present non-rigidity. Second order perturbation theory is used for the determination of anharmonic frequencies, rovibrational constants, and to predict Fermi resonances. Three species, methyl cyanate, methyl fulminate, and CHCON, show a unique methyl torsion hindered by energy barriers. In methyl isocyanate, the methyl group barrier is so low that the internal top can be considered a free rotor. On the other hand, acetonitrile N-oxide presents a linear skeleton, C symmetry, and free internal rotation. Its equilibrium geometry depends strongly on electron correlation. The remaining isomers present a bend skeleton. Divergences between theoretical rotational constants and previous parameters fitted from observed lines for methyl isocyanate are discussed on the basis of the relevant rovibrational interaction and the quasi-linearity of the molecular skeleton.
PubMed: 27782665
DOI: 10.1063/1.4963186 -
The millimeter wave spectrum of methyl cyanate: a laboratory study and astronomical search in space.Astronomy and Astrophysics Jul 2016The recent discovery of methyl isocyanate (CHNCO) in Sgr B2(N) and Orion KL makes methyl cyanate (CHOCN) a potential molecule in the interstellar medium. The aim of this...
AIMS
The recent discovery of methyl isocyanate (CHNCO) in Sgr B2(N) and Orion KL makes methyl cyanate (CHOCN) a potential molecule in the interstellar medium. The aim of this work is to fulfill the first requirement for its unequivocal identification in space, i.e. the availability of transition frequencies with high accuracy.
METHODS
The room-temperature rotational spectrum of methyl cyanate was recorded in the millimeter wave domain from 130 to 350 GHz. All rotational transitions revealed - splitting owing to methyl internal rotation and were globally analyzed using the ERHAM program.
RESULTS
The data set for the ground torsional state of methyl cyanate exceeds 700 transitions within = 10 - 35 and [Formula: see text] and newly derived spectroscopic constants reproduce the spectrum close to the experimental uncertainty. Spectral features of methyl cyanate were then searched for in Orion KL, Sgr B2(N), B1-b, and TMC-1 molecular clouds. Upper limits to the column density of methyl cyanate are provided.
PubMed: 27721514
DOI: 10.1051/0004-6361/201628140 -
Drug Metabolism and Disposition: the... Aug 2016This review highlights the recent research into the biotransformations and rearrangement of the sulfonylhydrazine-alkylating agent laromustine. Incubation of... (Review)
Review
This review highlights the recent research into the biotransformations and rearrangement of the sulfonylhydrazine-alkylating agent laromustine. Incubation of [(14)C]laromustine with rat, dog, monkey, and human liver microsomes produced eight radioactive components (C-1 to C-8). There was little difference in the metabolite profile among the species examined, partly because NADPH was not required for the formation of most components, which instead involved decomposition and/or hydrolysis. The exception was C-7, a hydroxylated metabolite, largely formed by CYP2B6 and CYP3A4/5. Liquid chromatography-multistage mass spectrometry (LC-MS(n)) studies determined that collision-induced dissociation, and not biotransformation or enzyme catalysis, produced the unique mass spectral rearrangement. Accurate mass measurements performed with a Fourier-transform ion cyclotron resonance mass spectrometer (FTICR-MS) significantly aided determination of the elemental compositions of the fragments and in the case of laromustine revealed the possibility of rearrangement. Further, collision-induced dissociation produced the loss of nitrogen (N2) and methylsulfonyl and methyl isocyanate moieties. The rearrangement, metabolite/decomposition products, and conjugation reactions were analyzed utilizing hydrogen-deuterium exchange, exact mass, (13)C-labeled laromustine, nuclear magnetic resonance spectroscopy (NMR), and LC-MS(n) experiments to assist with the assignments of these fragments and possible mechanistic rearrangement. Such techniques produced valuable insights into these functions: 1) Cytochrome P450 is involved in C-7 formation but plays little or no role in the conversion of [(14)C]laromustine to C-1 through C-6 and C-8; 2) the relative abundance of individual degradation/metabolite products was not species-dependent; and 3) laromustine produces several reactive intermediates that may produce the toxicities seen in the clinical trials.
Topics: Animals; Antineoplastic Agents, Alkylating; Biotransformation; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP3A; Dogs; Haplorhini; Humans; Hydrazines; Hydroxylation; Microsomes, Liver; Molecular Structure; Rats; Substrate Specificity; Sulfonamides
PubMed: 27278961
DOI: 10.1124/dmd.116.069823 -
Astronomy and Astrophysics Mar 2016The recent analysis of the composition of the frozen surface of comet 67P/Churyumov-Gerasimenko has revealed a significant number of complex organic molecules. Methyl...
The recent analysis of the composition of the frozen surface of comet 67P/Churyumov-Gerasimenko has revealed a significant number of complex organic molecules. Methyl isocyanate (CHNCO) is one of the more abundant species detected on the comet surface. In this work we report extensive characterization of its rotational spectrum resulting in a list of 1269 confidently assigned laboratory lines and its detection in space towards the Orion clouds where 399 lines of the molecule have been unambiguously identified. We find that the limited mm-wave laboratory data reported prior to our work require some revision. The abundance of CHNCO in Orion is only a factor of ten below those of HNCO and CHCN. Unlike the molecular abundances in the coma of comets, which correlate with those of warm molecular clouds, molecular abundances in the gas phase in Orion are only weakly correlated with those measured on the comet surface. We also compare our abundances with those derived recently for this molecule towards Sgr B2 (Halfen et al. 2015). A more accurate abundance of CHNCO is provided for this cloud based on our extensive laboratory work.
PubMed: 27274565
DOI: 10.1051/0004-6361/201527531