| dc.description.abstract | Methyl isocyanate (MIC) is the major culprit in the Bhopal gas tragedy, which occurred due to the release of a poisonous cloud from the Union Carbide pesticide plant into the atmosphere over Bhopal on the night of December 2/3, 1984. MIC is used primarily as a chemical intermediate in the manufacture of methylcarbamate insecticides, polyurethane foams, plastics, and certain pharmaceuticals. MIC is the simplest alkyl isocyanate. It is a liquid at room temperature and pressure, but highly volatile, with a vapor pressure of 348 mm Hg at 20°C. MIC is flammable and may explode if exposed to heat, flame, or shock. It is soluble in water and reacts with water to form methylamine and N,N'-dimethyl urea. It is a highly reactive molecule and reacts with functional groups such as amino, hydroxyl, sulfhydryl, etc. In general, most reagents that attack MIC add to the N=C double bond to form N methylcarbamyl derivatives.
One of the striking features of the Bhopal disaster, in which several thousand people lost their lives, was the lack of toxicological information on MIC. Since the tragedy, MIC has been studied extensively to provide data on its toxicity following acute exposures. Such studies have shown that MIC is a potent sensory and pulmonary irritant. When inhaled, it decreases the respiratory rate by reflex sensory irritation. Exposure to higher concentrations of MIC results in extensive alveolar damage and pulmonary edema.
First, the acute LC (inhalation route) and LD (subcutaneous route) of MIC were determined. Various concentrations-0.5, 1.0, and 2.0 LC -and doses-0.5, 1.0, and 2.0 LD -were used to study its hematological and biochemical effects in rats. Irrespective of the route of administration, the hematological and biochemical changes-such as hemoconcentration, increased plasma total proteins with decreased plasma albumin, hyperglycemia, severe lactic acidosis, and uremia-were dose related and similar in rats except for differences in severity. These changes were also essentially similar in rabbits, indicating species similarity in systemic toxic effects of MIC in mammals.
The key puzzle in understanding the toxicity of such a highly reactive chemical is whether the systemic changes represent a primary effect of MIC or of its hydrolysis products.
It was established that the observed hematological and biochemical changes were due to MIC per se and not to its hydrolysis products, as both methylamine (MA) and N,N dimethylurea (DMU) failed to influence these parameters in both species.
Animals intoxicated with MIC by either route were severely gasping and died due to respiratory failure. Hence, efforts were made to delineate mechanisms leading to severe tissue hypoxia, respiratory failure, and death.
MIC was found to carbamylate the N terminal amino group of hemoglobin in vivo. However, in contrast to earlier reports (Lee, 1976), MIC interaction with normal hemoglobin did not alter its quaternary structure and did not contribute to tissue hypoxia.
Subsequently, progressive physiological effects of MIC in anaesthetised rabbits were studied after subcutaneous administration, focusing on respiratory and cardiovascular systems.
The sequence of events indicated that:
(i) the primary event was hypotension due to MIC induced generalized vasodilation, persisting longer with increasing severity-possibly due to fluid loss (hypovolemia)-leading to terminal cardiac failure; and
(ii) MIC affected respiration, possibly through central chemoreceptors, showing stimulation at lower concentrations and respiratory depression at higher concentrations.
Acid–base parameters, such as decreased arterial pH, PCO , PO , and progressive increase in arteriovenous oxygen difference after MIC intoxication, clearly demonstrated severe stagnant hypoxia, acute metabolic acidosis, and decreased ventricular function and peripheral resistance leading to hypotension and shock like state.
Electroencephalographic (EEG) recordings showed slowing and synchronization with frequent delta waves. Compressed spectral analysis revealed spreading of power to higher frequencies, and power spectral analysis indicated reductions in all four bands in frontal transverse leads. Combined with blood gas data, this showed impairment of brain function, likely due to stagnant hypoxia. These findings suggest that acute MIC toxicity is mediated by its effects on vascular beds, resulting in fluid loss from the vascular compartment and subsequent hypovolemic hypotension.
The effects of MIC on tissue respiration were investigated by studying rat liver mitochondrial respiration in vitro and in vivo. MIC stimulated state 4 respiration, decreased the ADP/O ratio, inhibited state 3 oxidation, and abolished respiratory control in isolated mitochondria-indicating its action as an “inhibitory uncoupler.” Oxidation of NAD linked substrates (glutamate + malate) was more sensitive to MIC inhibition than succinate oxidation.
Apart from inhibiting electron transport at complex I, MIC interfered with the translocation of reducing equivalents into mitochondria by inhibiting membrane bound glycerophosphate dehydrogenase. MIC also stimulated dormant ATPase activity in tightly coupled mitochondria. Similar effects were observed in vivo in rats administered 1.0 LD MIC, showing impairment of electron transport at complex I. MA and DMU had no such effects, demonstrating that MIC per se impaired tissue respiration.
MIC interaction with erythrocyte membranes increased membrane fluidity and decreased osmotic fragility both in vitro and in vivo in rabbits. In contrast, erythrocytes became more fragile after subcutaneous administration of its hydrolysis products. MIC inhibited erythrocyte AChE and ATPase in vitro but not in vivo. Subcutaneous MIC lowered plasma Na and increased plasma K levels in rabbits. Inhibition of Na /K ATPase and altered membrane permeability are likely contributors.
Histological changes in lungs-severe interseptal edema, fluid accumulation, and protein exudation into interstitial and alveolar spaces-and similar findings in other organs provided clear evidence of fluid loss from the vascular compartment leading to hypovolemic shock.
The studies in this thesis have clearly established that MIC causes specific systemic toxic effects. Apart from respiratory depression due to sensory and pulmonary irritation on inhalation, MIC affects the cardiovascular system in vivo, leading to severe hypotension, vascular fluid loss, and hypovolemic shock when animals are exposed to lethal doses. Death results from severe tissue hypoxia of both stagnant and histotoxic types and consequent respiratory failure.
The significance of the study lies in providing valuable information on MIC toxicity and in guiding future research on potential long term human effects of this industrial disaster. | |
