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PubMed1986

Sensory and pulmonary irritation with exposure to methyl isocyanate.

Methyl isocyanate (MIC) was tested for its potency as a sensory irritant and as a pulmonary irritant in mice. To evaluate sensory irritation, animals were exposed to MIC at concentrations between 0.5 and 7.6 ppm for a period of 90 min. A characteristic reflex decrease in respiratory rate indicating sensory irritation was observed. The concentration evoking a 50% decrease in respiratory rate (RD50) was found to be 1.3 ppm. To evaluate pulmonary irritation, animals were first anesthetized and fitted with a tracheal cannula. Following recovery from anesthesia, they were exposed to MIC at concentrations between 0.4 and 7.3 ppm for a period of 90 min. A characteristic decrease in respiratory rate indicating pulmonary irritation in tracheally cannulated (TC) mice was observed. The concentration evoking a 50% decrease in respiratory rate (RD50TC) was found to be 1.9 ppm. Thus, MIC was found to be a potent sensory and pulmonary irritant.

Animals↗
PubMed1986

Immunotoxicity studies in mice exposed to methyl isocyanate.

The effects of methyl isocyanate (MIC) on systemic immunity were evaluated in female B6C3F1 mice exposed via inhalation to 0, 1, or 3 ppm for 6 hr per day on four consecutive days. Humoral immunity, measured as the antibody response to sheep erythrocytes, and natural killer cell activity were not affected by MIC. Furthermore, resistance to the infectious agents Listeria monocytogenes, mouse malaria parasite, and influenza virus, or to B16F10 transplantable tumor cells, was not compromised by MIC exposure. Although lymphoproliferative responses to mitogens were not significantly suppressed, the response of splenic lymphocytes to allogeneic leukocytes in a mixed leukocyte response (MLR) was suppressed in a dose-related fashion and differed significantly from the control response at the 3-ppm level. These studies indicate that MIC exposure in mice does not severely alter systemic immunity. The moderate changes detected in immune function may be a secondary consequence of respiratory toxicity which occurred in these animals.

Animals↗
PubMed1987

Evaluating the potential for genotoxic carcinogenicity of methyl isocyanate.

The carcinogenicity prediction and battery selection method was used to predict the probability of carcinogenicity of methyl isocyanate (MIC) based upon the results of short-term tests. The analysis predicts that MIC has a significant potential for inducing cancer in rodents. However, the pattern of response suggests that the carcinogenic potency would be low. Obviously, the realization of the identified risk would be dependent upon level, duration, and mode of exposure.

Animals↗
PubMed1988

Uptake and distribution of 14C during and following exposure to [14C]methyl isocyanate.

Guinea pigs were exposed to [14C]methyl isocyanate (14CH3-NCO, 14C MIC) for periods of 1 to 6 hr at concentrations of 0.5 to 15 ppm. Arterial blood samples taken during exposure revealed immediate and rapid uptake of 14C. Clearance of 14C was then gradual over a period of 3 days. Similarly 14C was present in urine and bile immediately following exposure, and clearance paralleled that observed in blood. Guinea pigs fitted with a tracheal cannula and exposed while under anesthesia showed a reduced 14C uptake in blood indicating that most of the 14C MIC uptake in normal guinea pigs occurred from retention of this agent in the upper respiratory tract passages. In exposed guinea pigs 14C was distributed to all examined tissues. In pregnant female mice similarly exposed to 14C MIC, 14C was observed in all tissues examined following exposure including the uterus, placenta, and fetus. While the form of 14C distributed in blood and tissues has not yet been identified, these findings may help to explain the toxicity of MIC or MIC reaction products on organs other than the respiratory tract, as noted by several investigators.

Animals↗
PubMed1991

Long term pulmonary impairment following a single exposure to methyl isocyanate.

Groups of guinea pigs were exposed for 3 hr to 6, 13, 19, 27, or 37 ppm of methyl isocyanate (MIC). Pulmonary performance was evaluated immediately postexposure and for a period of 1 year in the animals surviving 19 or 37 ppm of MIC. At 6 and 13 ppm deterioration of pulmonary performance was observed but complete recovery occurred within a few weeks. In those animals surviving 19 or 37 ppm some recovery occurred but a long lasting impairment of pulmonary performance was observed. One year after a single exposure to MIC these animals presented a condition best described as chronic obstructive lung disease. Using flow-volume measurements during air breathing and during CO2 challenge, animals surviving at 19 or 37 ppm presented typical abnormalities associated with airflow limitation along the conducting airways. One year after exposure lung hyperinflation was also present. At this time the poor ventilatory response to CO2 was due to mechanical limitation of lung expansion during inspiration and airflow limitation during expiration. The findings were similar to humans with severe obstructive lung disease. Microscopic examination substantiated the flow-volume measurements in that the main bronchi, small bronchi, and bronchioles were found to have an increase in dense fibrous tissue, while the alveolar level was characterized by destruction of alveolar walls and an increase in septal thickness. Thus a single exposure to MIC, if the concentration is high enough, is sufficient to induce permanent pulmonary toxicity.

Administration, Inhalation↗
PubMed1992

In vitro and in vivo effect of methyl isocyanate on rat liver mitochondrial respiration.

Previous work has shown that irrespective of the route of exposure methyl isocyanate (MIC) caused acute lactic acidosis in rats (Jeevaratnam et al., Arch. Environ. Contam. Toxicol. 19, 314-319, 1990) and the hypoxia was of stagnant type due to tissue hypoperfusion resulting from hypovolemic hypotension in rabbits administered MIC subcutaneously (Jeevarathinam et al., Toxicology 51, 223-240, 1988). The present study was designed to investigate whether MIC could induce histotoxic hyperoxia through its effects on mitochondrial respiration. Male Wistar rats were used for liver mitochondrial and submitochondrial particle (SMP) preparation. Addition of MIC to tightly coupled mitochondria in vitro resulted in stimulation of state 4 respiration, abolition of respiratory control, decrease in ADP/O ratio, and inhibition of state 3 oxidation. The oxidation of NAD(+)-linked substrates (glutamate + malate) was more sensitive (five- to sixfold) to the inhibitory action of MIC than succinate while cytochrome oxidase remained unaffected. MIC induced twofold delay in the onset of anerobiosis, and cytochrome b reduction in SMP with NADH in vitro confirms inhibition of electron transport at complex I region. MIC also stimulated the ATPase activity in tightly coupled mitochondria while lipid peroxidation remained unaffected. As its hydrolysis products, methylamine and N,N'-dimethylurea failed to elicit any change in vitro; these effects reveal that MIC per se acts as an inhibitor of electron transport and a weak uncoupler. Administration of MIC sc at lethal dose caused a similar change only with NAD(+)-linked substrates, reflecting impairment of mitochondrial respiration at complex I region and thereby induction of histotoxic hypoxia in vivo.

Adenosine Diphosphate↗
PubMed1989

Acute and subacute toxicity study of inhaled methyl isocyanate in Charles Foster rats.

Charles Foster male and female rats were exposed only once to 3.52 and 35.32 ppm doses of methyl isocyanate in separate experiments for 10 min each in an acute toxicity study, while in subacute toxicity experiments, they were exposed to 0.212, 0.265, and 0.349 ppm doses for 30 min daily, for 6 days, by inhalation. Clinical signs, mortality, body and organ weights, and changes in hematology and clinical pathology were routinely monitored to determine the principal organ sites damaged on exposure to the gas. During exposure, animals were observed to have congestion in eyes, lachrymation, nasal secretion and dyspnea, progressively increasing ataxia, and immobility. Uncoordinated movements were also observed, indicating effects on the nervous system. Upon microscopic examination of the viscera, pathological findings confined to bronchial tree, lung parenchyma, liver, and kidneys were observed.

Administration, Inhalation↗
PubMed1988

Mutagenicity of methyl isocyanate in the modified test conditions of Ames Salmonella/microsome liquid-preincubation procedure.

Methyl isocyanate (MIC) was tested for mutagenicity using the Ames Salmonella/microsome liquid-preincubation procedure with slight modification of test conditions. In the modification the preincubation mixture was incubated at 10 degrees C for 60 min. MIC was assayed both in the presence and absence of Aroclor-1254-induced S9, using 5 tester strains of Salmonella typhimurium, TA97a, TA98, TA100, TA102 and TA104. MIC induced mutagenic response in two base-pair substitution strains, TA100 and TA104, in the presence and absence of S9. However, mutagenic response in the presence of S9 was low as compared to that in the absence of S9. In the comparative mutagenic activity at 3 different preincubation test conditions (37 degrees C for 20 min, 20 degrees C for 40 min and 10 degrees C for 60 min), optimum mutagenic response was observed at 10 degrees C for the 60-min test condition. However, no mutagenic response was observed at 37 degrees C for the 20-min test condition.

Animals↗
PubMed1986

Acute inhalation studies with methyl isocyanate vapor. I. Methodology and LC50 determinations in guinea pigs, rats, and mice.

Groups of male and female Fischer 344 rats, B6C3F1 mice, and Hartley guinea pigs were exposed once for 6 hr to mean concentrations of 10.5, 5.4, 2.4, 1.0, or 0 (control) ppm of methyl isocyanate (MIC) vapor. Rats and mice were also exposed to 20.4 ppm of MIC. No deaths occurred in animals exposed to 2.4 or 1.0 ppm. The majority of deaths for the 20.4- and 10.5-ppm groups occurred during postexposure Days 1 through 3, while at 5.4 ppm deaths were observed throughout the 14-day postexposure period. The 6-hr LC50 values (with 95% confidence limits) were 6.1 (4.6 to 8.2) ppm for rats, 12.2 (8.4 to 17.5) ppm for mice, and 5.4 (4.4 to 6.7) ppm for guinea pigs. Notable clinical observations during and immediately following MIC exposure were lacrimation, perinasal/perioral wetness, respiratory difficulty (e.g., mouth breathing), decreased activity, ataxia, and hypothermia. The frequency of clinical signs decreased during the second postexposure week. Body weight losses were common in all species following MIC exposures of 2.4 ppm or greater. At 1.0 ppm, only female mice had body weight depression. Recovery of body weight loss was observed in the 5.4- (guinea pigs only), 2.4- and 1.0-ppm concentration groups. The lungs of all animals that died were discolored. Following microscopic examination of the respiratory tract, deaths were attributed to pulmonary edema and congestion. In a separate study, Fischer 344 rats and Hartley guinea pigs were exposed once for 4 hr to mean concentrations of 36.1, 25.6, 15.2, or 5.2 ppm of MIC vapor. In general, the results were similar to those of the single 6-hr exposure study.

Animals↗
PubMed1986

Acute inhalation studies with methyl isocyanate vapor. II. Respiratory tract changes in guinea pigs, rats, and mice.

Hartley guinea pigs, Fischer-344 rats, and B6C3F1 mice of both sexes were exposed to varying concentrations of methyl isocyanate (MIC) vapor with the highest concentration being 20.4 ppm for rats and mice and 10.5 ppm for guinea pigs. A control group for each species was exposed to air only. All animals were exposed for a duration of 6 hr, and survivors were sacrificed 14 days following exposure. The respiratory tract was removed and examined microscopically from all animals. Guinea pigs were more sensitive to the MIC vapor than were rats which were in turn more sensitive than mice. Gross lesions encountered in many of the animals that died consisted of nasal discharge, often blood tinged, and discoloration of the lungs. Microscopic lesions included acute necrosis of epithelial lining throughout the respiratory tract in animals that died shortly after exposure coupled with congestion, edema, and inflammation. A microscopic lesion which appeared unique to guinea pigs was bronchiolitis obliterans where the necrosis and inflammation had completely closed the bronchioles. Additional microscopic lesions observed in some animals that died or were sacrificed at the end of the study (postexposure Day 14) consisted of squamous metaplasia of respiratory epithelium in the nasal cavity, which extended into the larynx, trachea, and, in some cases, the bronchi. In addition, epithelial regeneration throughout the tract and submucosal fibroplasia in the trachea, bronchi, and bronchioles were observed, the latter lesion being primarily confined to rodents. No animals exposed to 2.4 or 1.0 ppm of MIC vapor died following exposure. There were minimal microscopic lesions at sacrifice in the 2.4 ppm-exposed animals from all three species. Only in guinea pigs were there lesions in the 1.0-ppm group attributed to MIC vapor exposure.

Animals↗
PubMed1987

Four-day repeated inhalation and recovery study of methyl isocyanate in F344 rats and B6C3F1 mice.

F344 rats and B6C3F1 mice of both sexes were exposed by inhalation to 0, 1, and 3 ppm methyl isocyanate (MIC) for 4 consecutive days (6 hr/day) followed by a recovery period of 91 days. Five mice and rats/sex/group except the 3 ppm group (5 rats/sex on Day 7 and 2 males on Day 28) were killed on Days 7, 28, 49, and 91 after the exposure and examined histopathologically. Forty-nine of 56 male rats, 51 of 56 female rats, and 1 of 56 male mice in the 3 ppm group died by 28 days; early death animals were also examined histologically. Exposure-related changes occurred in rats and mice of both sexes in the 3 ppm group only. Lesions of the nasal cavity in rats and mice were characterized by regeneration of the olfactory and respiratory epithelia secondary to epithelial erosion. By Day 28 the olfactory and respiratory epithelia in mice appeared normal, while in rats incomplete regeneration of the olfactory epithelium was still present. Regeneration of the respiratory epithelium in the trachea of rats occurred in the 3 ppm group and the epithelium appeared to return to normal by Day 28. Lung lesions in rats consisted of mural and/or intraluminal fibrosis secondary to extensive erosion of the respiratory epithelium in the major bronchi to the terminal bronchioles. Acute inflammation of the small airways, occasional hyaline membranes of alveolar walls, and pulmonary atelectasis were also seen. Alveolar fibrosis was observed in rats found dead from Day 14 on and in male rats killed on Day 28. Atrophy of the thymus and spleen, atrial thrombosis of the heart, and hepatocellular necrosis were frequently seen in rats dying following MIC exposure. The lung lesions in mice were qualitatively similar to those in rats, but were restricted to the major bronchi. Minimal intraluminal or mural fibrosis was still present in mice on Day 91. In a separate study, a single 6-hr exposure of five male rats to 3 ppm MIC was followed by a recovery period of 7 days. The lesions of the respiratory system were essentially the same as those in the 3 ppm group killed on Day 7 after the 4-day repeated exposure of MIC, but the alveolar lesions were more severe.

Administration, Inhalation↗
PubMed1988

Acute toxicity of methyl isocyanate, administered subcutaneously in rabbits: changes in physiological, clinico-chemical and histological parameters.

Subcutaneous administration of methyl isocyanate (MIC) in 0.5 LD50 and 1 LD50 doses in female rabbits resulted in significant changes in physiological, clinico-chemical and histological parameters. There was a fall in arterial blood pressure and cardioacceleration in both the 0.5 LD50 and 1 LD50 groups, while the respiration showed a differential response in these groups with the former showing hyperpnoea and the latter showing respiratory inhibition. A significant increase in the arterial blood lactic acid, lactate/pyruvate ratio and 2,3-diphosphoglycerate levels, and the significant changes in acid-base status of both arterial and venous blood indicated tissue hypoxia of a stagnant type. Histopathological observations revealed a mild to moderate degree of congestion, focal lymphocytic infiltrations and necrosis in all visceral organs examined. These findings suggest that acute toxicity of MIC in vivo may be mediated by its effects on vascular beds.

2,3-Diphosphoglycerate↗
PubMed1987

Inhibition of rat brain cytochrome oxidase activity by pyrolysed products of methyl isocyanate.

The effects were studied of methyl isocyanate (MIC) and its thermally degraded products (dMIC) on rat brain cytochrome oxidase activity. Pure MIC did not inhibit brain cytochrome oxidase activity. A significant inhibition of brain cytochrome oxidase activity by dMIC was observed both in vivo and in vitro. The presence of cyanide in pyrolysed products of MIC has also been confirmed by chemical methods.

Animals↗
PubMed1988

Cytogenetic activity of methyl isocyanate in vivo in the mouse micronucleus test.

The ability of methyl isocyanate (MIC) to induce mutagenic and cytotoxic effects in vivo in the mouse micronucleus test was evaluated by assessing the induction of micronuclei and depression of polychromatic erythrocytes in bone marrow and peripheral blood smears. Animals were exposed to MIC through intraperitoneal injection for 2 and 5 days in separate experiments, and bone marrow and peripheral blood were sampled 6 and 48 h after the last injection, respectively. MIC did not significantly increase the frequencies of micronucleated polychromatic erythrocytes (MN-PCE) and micronucleated normochromatic erythrocytes (MN-NCE) in bone marrow and peripheral blood samples respectively in either twice or multiply treated mice. However, a dose-dependent depression in percentage PCE observed was significant. This indicates that MIC exposure led to the cytotoxic effect by inhibition of bone marrow cell proliferation.

Animals↗
PubMed2004

The formation of poly(ester-urea) networks in the absence of isocyanate monomers.

The polymerization of N,N' carbonylbis (caprolactam) (CBC) and polyol in the presence of alcoholate as catalyst produced cross-linked poly(ester-urea)s via ring opening addition reaction. In contrast to conventional synthetic routes, the use of non-toxic CBC eliminates the need for toxic isocyanate-based monomers. The structure of the molecules resulting from model reactions was confirmed using FT-IR and (1)H- and (13)C-NMR spectroscopy. Poly(ester-urea) networks exhibit rubber-like mechanical properties and high-temperature stability. Cell adhesion and cell growth on the polymers evidenced the high biocompatibility of the material. Degradation of the poly(ester-urea)s was investigated at 70 degrees C in neutral and basic aqueous solution. The degradation depends on the swelling behavior of the samples. Mechanical properties, good biocompatibility, and degradation behavior of the CBC/polyol-based polymers make them interesting materials for biomedical applications.

Absorbable Implants↗
PubMed2006

Modification of the biopolymer castor oil with free isocyanate groups to be applied as bioadhesive.

Surgical adhesives have been used for several applications, including haemostasis, sealing air leakages and tissue adhesion. The aim of this work was to develop a biodegradable urethane-based bioadhesive containing free isocyanate groups. This material presents the advantage of being biodegradable, biocompatible and having the capacity of reacting with amino groups present in the biological molecules. A urethane based on castor oil (CO) was synthesized by reaction of the molecule with isophorone diisocyanate (IPD). The characterization of the material was accomplished by different techniques: ATR-FT-IR (attenuated transmittance reflection-Fourier transform infrared), swelling capacity determination, evaluation of the moisture curing kinetics, reaction with aminated substrates and determination of surface energy by contact angle measurement. The study of the urethane thermal properties was performed by DMTA (dynamical mechanical thermal analysis) and TGA (thermogravimetric analysis). The haemocompatibility of the urethane was also evaluated by thrombosis and haemolysis tests.

Biopolymers↗
PubMed2006

Thermal characteristics of lysine tri-isocyanate and its mixture with water.

The thermal reactivity of lysine tri-isocyanate (LTI, 2-isocyanatoethyl-2,6-diisocyanato caproylate) and its mixture with 1% water was investigated after the occurrence of a runaway reaction at a plant. By using a sensitive thermal calorimeter, C80, and an adiabatic calorimeter, ARC, an onset reaction of LTI was observed at 70-100 degrees C and it became vigorous at 175-200 degrees C. The reaction is considered as co-polymerization at this stage, which causes a second decomposition reaction at 200 degrees C if the heat generation is accumulated in the vessel. On the other hand, the presence of water can catalyze LTI at much lower onset temperature and lead to a moderate reaction at 50 degrees C since carbamine is produced and in turn it induces decarbonization of the LTI molecule with significant release of CO2 gas which was detected by a gas chromatography and an FT-IR gas analyzer.

Calorimetry↗
PubMed2005

Conformational analysis and comparison between theoretical and experimental vibration spectra for isocyanate species on Ag/Al2O3 catalyst.

Density functional theory (DFT) calculations were performed to study the structure and vibrational frequencies of the intermediate for the isocyanate (NCO) surface species on Ag/Al(2)O(3) catalyst using the GAUSSIAN 98 suite of programs. Thermal decomposition of adsorbed CH(3)NO(2) species leads to the formation of two types of NCO species (NCO on Ag and NCO on Al(2)O(3)) above 298K. In order to investigate the reaction mechanism, we have designed the calculated models (a-g) for the NCO intermediate. Through the analysis of the vibration mode and the vibration frequency of the calculated models (a-g), we conclude that there is an excellent agreement between the calculated vibration spectrum of the model (e) containing the -AgNCO group or model (g) containing the -AlNCO group and the experimental vibration spectrum.

Aluminum Oxide↗