Atomic Defence

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explosion centre, since those within this radius are likely to die anyhow of radiation sickness, unless shielded by, say, buildings. Extensive provision will have to be made for decontaminating casualties ; and the necessary buildings, with good water-supply and ventilation, and the protective arrangements for workers, cannot easily be improvised. After decontamination, the casualty can go to hospital. Here his wounds, and almost certainly his burns, will be the

THE LANCET L011TDONSATURDAY, FEB. 11, 1950

Atomic Defence FROM the studies made at Hiroshima and Nagasaki have a fair idea of the medical problems likely to arise after an atomic explosion in a populous area. PARK1 points out that the explosion may cause injuries in three ways : (1) by its actual force, which may hurt people up to z2 miles away ; (2) by heat, with a range of 21/2 miles ; and (3) by radiation, with a range of 2-3 miles. The direct injuries may be caused either by blast, or by flying fragments of material or falling debris ; blast injuries are relatively few, but 70% of casualties are likely to be injured by fragments or debris. Burns are also of two types : there are flash burns, which may affect people in the open as far as 21/2 miles away, and then there are secondary burns from fires caused by the explosion. Various estimates put the proportion of casualties who have burns-usually in addition to injuries-at from 65% to 90%. About 35% of casualties have radiation injuries. These are mostly due to direct exposure to y-rays, but they may also be caused by exposure to substances rendered radioactive by the explosion ; and there is a further unknown proportion who have inhaled radioactive dust or who have ingested substances ’contaminated by such dust or have even been rendered radioactive themselves. This spreading of radioactive dust and possibly waterwind is droplets by the explosion and by one of the main and most incalculable dangers that any system of atomic defence would have to face, because it is so insidious ; and obviously it may lead to contamination of water, food, clothing, and we

subsequent

medical supplies. To avoid contamination, the rescue services would have to be at least 3 miles from the explosion, and on the leeward side perhaps even further away. All rescue workers would have to be provided with and a complete change, including Their underclothing. duty would be simply rescue and first-aid in the contaminated area-stopping haemorrhage, immobilising broken limbs, and so on -and they would concentrate on getting the casualty to the decontamination centre and the " base " hospital as soon as possible. Forward blood and plasma transfusion, so well exploited in the late war, is no use in atomic work ; nor must hypodermic injections be given : morphine, if given at all, must be given by mouth. PARK holds that rescue-workers should concentrate on casualties beyond a 2-mile radius from

protective clothing

1. Park, W. E.

Canad. med. Ass. J. 1949, 61, 473.

treated on established lines. The many cases of burns will call for good laboratory facilities and ample blood and plasma for infusion. In addition, radiation sickness will have to be watched for, and here the important criterion is the white blood-cell count. PARK thinks that if the count is less than 2000 per c.mm. treatment is a waste of time and material ; if the count is over 2000 per c.mm. a transfusion of 500 ml. of whole blood is given, and if it remains above this figure twenty-four hours later the full supportive treatment for radiation sickness can be undertaken with a good chance of success. One of the peculiarities of atomic warfare is that, when the immediate casualties have been dealt with, the defence planners must prepare for a fresh wave of radiation-sickness cases 8-14 days after the explosion. Those affected may have had some sickness on the first day. Thereafter they are quite well until symptoms associated with granulopenia appear ; then follow haemorrhages due to thrombocytopenia and increased heparin in the blood ; and after about three weeks-if the patient survives-comes an aplastic type of anemia. This syndrome requires intensive treatment by repeated blood-transfusion, penicillin against infection, and intravenous toluidine-blue to control the hyperheparineemia. In each case a large amount of laboratory work is clearly needed for proper control. The later effects of radiation on the blood have so far not been conspicuous. SNELL, NEEL, and ISHIBASHI2 carefully examined the blood of some 900 people in Hiroshima who had had epilation of the scalp after exposure to the atom-bomb explosion two years before. Compared with the population of a nearby town, their red-cell count was 1’6% lower and their hoemoglobin 2-1% lower ; the white-cell counts were not significantly different. Here, then, in brief outline, are the problems. On what scale must the defence services be provided ? Some guiding figures are known. The Hiroshima bomb devastated 4 square miles, killed about 60,000 people, and injured some 69,000; the Nagasaki bomb blew up P/2 square miles, killed 39,000, and injured 25,000. PEARSE and PAYNE 3 estimate that at Hiroshima there were probably 34,000 severely burned casualties, and calculate that to cope with this number of burns 170,000 professional persons " (doctors, nurses, technicians) would be needed, eight thousand tons of medical supplies (enough to fill a Liberty ship) would be used, and the cost would be about 10 million dollars. And all this is for only PERRIN LONG4 believes one aspect of treatment. that the explosion of a single bomb of the Hiroshima type would create within the first twenty-four hours the need for 300 first-aid teams, 500 stretcher-bearer ’’

2. 3. 4.

Snell, F. M., Neel, J. V., Ishibashi, K. Arch. intern. Med. 1949, 84, 569. Pearse, H. E., Payne, J. T. New Engl. J. Med. 1949, 241, 647. Quoted by Snyder, L. T. Med. Ann. Distr. Columbia, 1949, 18, 505.

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and 24 neuroNo wonder PARK says that it is psychiatric to handle all the cases ; we can probably impossible to save some. And these only try grim estimates to the atomic-bomb apply only original explosions. Bombs capable of causing ten times this destruction are reputed to be a practical possibility, if not already made-, and the proposed hydrogen bomb is said to be many times more powerful and destructive than even these. Will any defence system be able to do more than rescue those at the fringe of the affected area ? And if both sides in a war use these engines of obliteration, who will call himself the victor ? It is of course suggested that fear of retaliation may prevent resort to atomic bombs and biological warfare.5 But those who start wars are prepared to take risk ;-, and it is as well that everyone should realise what is involved in the ’’ atomic defence " of which some politicians

teams, 400

casualty-collection points,

centres.

speak

so

glibly.

Thiosemicarbazone in Tuberculosis HERE and in the United States the only chemotherapeutic agents that have shown much promise in the treatment of tuberculosis have been the sulphones, streptomycin, and p-aminosalicylic acid. But a fourth group, the thiosemicarbazones, has now appeared on the scene from Germany, where these drugs have been developed by DoMAGK and the workers of the Farbenfabriken Bayer Laboratories at Elberfeld6 and clinical trials have been made. These compounds were developed through a study of the sulphonamides, sulphones, and sulphathiodiazoles, all of which show some antituberculosis activity. DoMAGK found that this activity depended not on the presence of sulphonamide or sulphone groups or thiazole or thiodiazole rings but on an open-chain arrangement of nitrogen and sulphur atoms, as in the thiosemicarbazones. Of the large number of substances tested the most active was found to be 4-acetyl-aminobenzaldehyde thiosemi-

carbazone,

CH3CONH->CH.N.NH.CS.NH2’ This has been submitted to extensive clinical investigation in Germany under the names ’ Conteben’ and TBI-698. The sulphur atom in the thiosemicarbazones is essential for activity, and compounds derived from aldehydes are more active than those derived from ketones. The aromatic aldehydes appear to be more active than the aliphatic, and activity is increased by introducing substituents into the aromatic ring.7 HOGGARTH and his co-workers8 of the I.C.I. Research Laboratories have recently examined a number of thiosemicarbazones and find that the thiosemicarbazone of p-ethylsulphonylbenzaldehyde is more active than TBI-698 in the mouse. TBI-698 is effective bv mouth and parenterally ; it is only sparingly soluble in water, but can be 5.

Kingston-McCloughrey, E. J. War in Three Dimensions. London,

1949. 6. Domagk,

G., Behnisch, R., Mietzsch, F., Schmidt, H. Naturwissenschaften, 1946, 10, 315. Behnisch, R., Mietzsch, F., Schmidt, H. Angew. Chem. 1948, 5, 113. 7. Behnisch, R., Mietzsch, F., Schmidt, H. Amer. Rev. Tuberc. 1950, 61, 1. 8. Hoggarth, E., Martin, A. R.. Storey, N. E., Young, E. H. P. Brit. J. Pharmacol. 1949. 4, 248.

rendered suitable for injection by solubilising agents such as antipyrin, propylene glycol, and some acid amides. LEVADITI,9 at the Institut Pasteur, and DOMAGK 10 have investigated the antituberculosis activity of TBI-698 in vivo. According to LEVADITI its effect in the experimentally infected mouse is comparable to that of p-aminosalicylic acid, though inferior to that of streptomycin. On the other hand, DoMAGK reports that in the guineapig TBI-698 is a hundred times as active as p-aminosalicylic acid, weight for weight, and its activity is of the order of that of streptomycin. TBI-698 inhibits the growth of M yc. tuberculosis on an eggs, culture medium containing p-aminobenzoic acid at a dilution of 1 : 300,000 ; the comparable dilutions for p-aminosalicylic acid and streptomycin are 1 : 5000 and 1 : 50,000-100,000. Besides inhibiting the growth of tubercle bacilli TBI-698 produces morphological changes-abnormal size, granular disintegration, and thread formation -in the bacilli. It also changes their staining properties ; the bacilli losing their capacity for taking first the Ziehl stain and then Gram’s stain. The mode of action of the drug is not yet clear ; it may act directly on the tubercle bacillus itself rather than indirectly via the host. DoAGK believes that a combination of TBI-698 and streptomycin is likely to be more effective than either drug alone. The clinical trials with TBI-698 in Germany have been reviewed by MERTENS and BUNGE,l1: in 1949 HINSHAW and McDERMOTT of the Mayo Clinic visited the various centres in Germany where tlie drug has been tried and they have now 12 reported on their observations to the National Tuberculosis Association of America. These American workers did much of the pioneer work with the sulphones and streptomycin and so are fully aware of the pitfalls likely to arise in the clinical evaluation of new drugs in tuberculosis. Over sixty German papers on this subject have either been published or are in the press, covering observations on some 10,000 patients in more than 300 hospitals and sanatoria. The report of HINSHAW and McDERMOTT is based on a survey of 10 of the larger German centres where TBI-698 has been in use since 1947. The dosage of TBI-698 is much lower than that of streptomycin or p-aminosalicylic acid. In general, an initial dose of 25-50 mg. daily for one or two weeks is suggested, with a gradual increase to 200-300 mg. if the drug is well tolerated. All observers agree that very prolonged treatment is desirable, the average recommendation being at least six months, though many patients have been treated continuously for more than a year. Unfortunately the drug potential toxicity which is greater in many respects than that of streptomycin. Among the’ minor manifestations of toxicity are anorexia, malaise, headache, and occasional vomiting ; the more serious, which occurred in 4 patients per 1000, include ansemia, toxic erythema, conjunctivitis, cerebral oedema, and granulocytopenia. There is some difference of opinion on whether TBI-698 is hepatoxic : jaundice is certainly common among patients treated with it. It apparently produces a diminution in the

has a

9. Levaditi, C. 10. Domagk, G. 11. Mertens, A., 12. Hinshaw, H.

Pr. méd. 1949, 57, 519. Amer. Rev. Tuberc. 1950, 61, 8. Bunge, R. Ibid. p. 20. C., McDermott, W. Ibid, p. 145.