SCIENCE
Questions Persist About Cyanide Poisoning in Bhopal Disaster Researchers in India, North America puzzle over apparent success of treating victims with sodium thiosulfate, usual antidote for cyanide poisoning Wil Lepkowski, C&EN Washington
Treatment was immediately stopped and Daunderer was sent home. But thiosulfate treatment was resumed soon after the Indian Council for Medical Research (ICMR)—roughly the equivalent of the U.S/s National Institutes of Health—began monitoring the treatment and observing positive effects. The ICMR report, issued in March, recommended continued use of thiosulfate. It concluded: "At least in the survivors there is evidence of chronic cyanide poisoning operating as a result of either inhalation of hydrocyanic acid or more probably subsequent generation of cyanide radical from the cyanogen pool in gas-afflicted victims. The changes in the urinary thiocyanate and in the blood gas before and after thiosulfate treatment substantiated the findings. While further work on the nature of abnormalities in hemoglobin brought about by exposure to MIC gas is in progress, the rationale for the use of sodium thiosul-
One of the most fascinating, confusing, and politically explosive issues surrounding the methyl isocyanate (MIC) disaster that occurred at Bhopal, India, last December revolves around whether cyanide, or some chemical impersonator, was present in the gas mixture that escaped from the MIC tank. Union Carbide, whose Indian subsidiary operated the now-closed plant, insists that cyanide was not present, but the bitter debate persists. Demonstrations, beatings by police, and jailings have taken place in Bhopal over the issue, and trust is minimal on all sides. The controversy persists because the usual antidote for cyanide poisoning, sodium thiosulfate (Na2S203), has been reported to be effective in alleviating the breathing difficulties and neurological problems of victims. Thiosulfate is being given r o u t i n e l y to p a t i e n t s in clinics around Bhopal with government approval and apparent success. Large numbers of local Bhopal physicians, however, still oppose such treatment. The p h e n o m e n o n represents a maddening conundrum that ultimately will have to be settled, both in laboratories and in the courts. For right after the lethal leakage in Bhopal, Carbide and local physicians vehemently recommended against sodium thiosulfate treatment that was begun by a German toxicologist, Max Daunderer of Munich. Karol: no evidence of cyanide exposure 42
October 14, 1985 C&EN
fate as an antidote has been established to ameliorate the lingering sickness of gas-affected victims in Bhopal." But instead of diminishing the controversy, the ICMR findings caused it to grow. Hitavada, Bhopal's daily newspaper, reported in August that some voluntary clinics were closed, their staff members beaten, and their physicians jailed for administering thiosulfate. Days later, however, the Indian Supreme Court ordered the local state government to allow the treatment to continue and instructed ICMR to develop a scheme for distributing thiosulfate to the victims. ICMR is also performing double-blind studies of effects of sodium thiosulfate treatment at a temporary hospital near the site of the now-closed plant. Meanwhile, ICMR is performing other studies of MIC toxicity and treatment. It has not shared its findings with many foreign researchers yet, but has invited selected foreign scientists to come to India to help in the investigations. The National Institute of Environmental Health Sciences in Durham, N.C., is performing extensive studies of MIC toxicity and thiosulfate treatment. Those studies are headed by chemical pathologist Ernest E. McConnell. Other North American researchers active in MIC research in connection with Bhopal include Roy E. Albert, professor of environmental medicine at New York University Medical Center; Dayan Varma, a pharmacologist at McGill University in Montreal; Meryl H. Karol and Yves Alarie of the University of Pittsburgh's department of industrial environmental health sciences; and William E. Brown of CarnegieMellon University's department of biological sciences. In some studies, Carbide scientists, who are doing
their own work on isocyanate toxicity, are consulted regularly. Karol, Alarie, and Brown have been examining serum and tissue samples Indian researchers brought them this past summer. Karol, in a paper delivered at the recent national meeting of the American Chemical Society in Chicago, reported that in laboratory animals MIC produced strong antibody responses and injured the immune systems (C&EN, Sept. 16, page 5). But her information, Karol insists, shows no evidence of cyanide exposure. As to whether antibodies could be detected to indicate whether Bhopal patients were exposed to cyanide, Karol says she knows of no past immunological research about such exposure. "I doubt if anyone has ever looked for any [antibodies]," she comments. Chronic cyanide poisoning is well known to industrial hygienists and public health workers. Smokers are known to carry small amounts of cyanide in their blood, and some industrial workers are continuously exposed to low levels of cyanide. Both Karol and Brown are puzzled by the thiosulfate findings. But Brown has acknowledged that, if thiosulfate has indeed been effective, either some new biochemical reactions are involved in MIC toxicity, or molecules formed as a result of the MIC runaway reaction at Bhopal could be at work. Thiosulfate has never been suggested as a chemical treatment for MIC exposure. But then, not many treatments have been reported, because before the Bhopal accident, MIC had been the least studied of the isocyanates. As for thiosulfate involvement as the cyanide antidote, the mechanism works roughly this way: Cyanide poisons by binding to the zinc or iron portions of the enzyme cytochrome oxidase. The action inactivates the enzyme, and thereby cuts off oxygen metabolism. Thiosulfate treatment involves first stimulating the production of methemoglobin, which like a scavenger picks the cyanide off the enzyme. The thiosulfate, via the enzyme rhodanese, then removes the cyanide from the methemoglobin, and converts it to sodium isocyanate, in which form it is excreted in urine.
Brown: long-term effects key question It is difficult to account chemically for how cyanide could have been formed in any large amounts during the runaway, heat-generating MIC reaction. Carbide's report on the accident, issued in March, indicated formation of isocyanic acid during the reaction. But that compound, though toxic, is not fatal. However, the literature says cyanide can easily form in the absence of water when MIC degrades at temperatures over 400 °C. But the reaction at Bhopal involved water, and the temperatures were likely lower. Temperatures much above 400 °C, Carbide points out, would have destroyed the tank. Still, sodium thiosulfate is probably doing something beyond acting as a placebo, as many physicians have suggested. McGill's Varma, who first reported damage to fetuses and to female reproductive systems after the disaster, says that he observed alleviation of headaches and weakness after thiosulfate treatment, but that those conditions returned in a short time. So he is one authority who believes thiosulfate treatment is only marginally useful. He last visited Bhopal in July. However, Carnegie-Mellon's Brown offered C&EN some ideas on how thiosulfate might be alleviating the MIC toxicity symptoms. Some of his research on MIC biochemical toxicology leads into that explanation. Brown has determined that MIC—
or some metabolite of it—binds reversibly to cholinesterase, most likely covalently at the enzyme's hydroxyl, amino, or sulfhydryl groups on the protein chain. Such groups are found on proteins, he says, especially the cholinergic enzymes. The key is reversibility of the binding. That would mean that the harm it does in binding to cholinesterase is not permanent and, if so, the reversibility could be enhanced perhaps by some agents. Brown suggests sodium thiosulfate could act in that role. Strong nucleop>hiles, he says, can displace those sorts of reactions. And thiosulfate, being nucleophilic, could perform that function. "But we don't have any data either to support or deny that," he comments. To Brown, one of the key questions has to do with the long-term biochemical effects of MIC exposure. "The kind of thing that I would like to do, now that we've characterized the MIC as a slowly reversible reaction with the cholinergic protein, is to put things like sodium thiosulfate in the system and see if that accelerates the recovery process. We've got a student looking at the relationship between isocyanate exposure and clouding of the eyes." "The question we keep coming up with," says Brown, "is how we do these studies. It will be very important, if there are these chronic kinds of things, to really have a look at the Bhopal patients—look at the history of these people and follow them for as long as we can. One of the things that there's less emphasis on, in the research effort we know about, is the toxic potential of methylamine [formed from MIC in a moist environment] and methyl isocyanate. If you have those two together, you can get an adduct of the two. If there was something like cyanide in the air and in combination with the other two, what would be the effects? It's opening up a whole new area of research." So the mystery continues. Carbide, through a spokesman, says the company is pursuing work on the subject but isn't discussing it with the press. "But if they are achieving good results with thiosulfate treatment, we think that's fine," the spokesman commented. D October 14, 1985 C&EN
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