SECTION II
CLINICAL FEATURES
CHAPTER V
PHYSIOLOGICAL ACTION OF WAR GASES
TOXICITY
The first outstanding feature of the war gases is their very high toxicity. They kill where substances measuring up to our former ideas of high toxicity fail to injure. Thus prussic or hydrocyanic acid, which has usually stood at the head of toxic gases in the minds of scientists and laymen alike, is no more toxic, as a matter of fact, than a dozen other gases which were investigated or tried out in the war. In the field it proved practically harmless. The toxicity figure for chlorine is about 2.5 mg. per liter; that of phosgene 0.35; for mustard gas, hydrocyanic acid, and a considerable number of others, 0.2 or less.
The peculiar requirements for field use, as contrasted with controlled laboratory administration, was responsible, of course, for the fact that hydrocyanic acid was found almost useless as a war gas, while the commonly handled chlorine, produced industrially in such large amounts every day without accident, proved so very potent in war and the insidious phosgene ten times more so.
Experience showed that, to be valuable as a war gas, a poison must meet certain requirements. It should be a liquid or be easily liquefied, or it might be a solid, though the solids did not prove as effective as liquids. It must be readily volatilized at ordinary temperatures, and the vapor must have sufficient density to remain near the ground and to maintain its concentration for some time. It must be fairly stable in the presence of moisture and under the molecular shock of the detonating charge of the shell. In addition, it must compare favorably with the most toxic compounds known to science. Hydrocyanic acid fails as a war gas because of the low density of its vapor and the fact that the human organism can withstand the gas below certain concentrations without apparent injury. To kill, then, it requires a concentration which it is not practicable to obtain in the field. Gases like chlorine or phosgene injure in proportion to the amount encountered, so that, while a lethal concentration may not be attained at a given point, nevertheless they will cause casualties of greater or lesser extent, depending upon the concentration and time of exposure.
ORGANIC HALOGEN DERIVATIVES
The second outstanding feature of the war gases is the fact that they are practically all organic halogen derivatives. With the exception of hydrocyanic acid, acrolein, and a very few others, all of the gases which appeared to be of even possible value in the field contain chlorine, bromine, iodine, or fluorine in organic combination. The organic groupings impart the necessary volatility;
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the halogens give added weight to the molecule, increasing the vapor density, in many cases giving an instability in the presence of water sufficient to account for the final toxicity. The organic groups also give to a large number of the war gases their characteristic lipoid solubility. Of the three or four most effective compounds used, all are soluble in alcohol, acetone, fats, and oils, and so are able to penetrate the cells of the body with the facility of the anesthetics an(l for the same reason.
SPECIFICITY
The third outstanding feature of the war gases is their specificity. This is more apparent than real, perhaps, but it is sufficiently striking to allow of a rough classification based on the physiological attack. All the gases are irritating to all tissues with which they come in sufficient contact, but under field conditions certain tissues and organs are more quickly or obviously injured by a given gas than are others.
I. Eye irritants:
1. Brombenzyl cvanide.
2. Benzyl bromide.
3. Bromacetone.
4. Chloracetophenone.
5. Chloropirin.
6. Xilyl bromide.
7. Dichlorethylsulphide (mustard gas).
II. Lung irritants:
1. Chlorine, bromine.
2. Phosgene.
3. Triclorimethylchlorformate.
4. Chloropicrin.
5. Mustard.
III. Nasal irritants:
1. Diphenylchlorarsine.
2. Mustard.
IV. Skin irritants:
1. Mustard.
EYE IRRITANTS
Taking up the groups in their order, the lacrymators, are characterized by their instantaneous effect on the corneal nerves. Sudden contact with a very moderate concentration of a good lacrymator is as painful as a sharp blow on the eves, and, indeed, feels very much like it. Such a concentration is immediately unbearable, the eyes are kept shut and the lacrymatory glands are stimulated to a copious secretion of tears. At very low concentrations the lacrymators are felt as a slight irritation of the eye, causing frequent winking and increased flow of tears. Such concentrations are not detectable by the nerves of taste or smell, and do not produce irritation of the respiratory tract except after exceedingly long exposure. Some substances, even with prolonged exposures, fail to show injury to the respiratory mechanism, while they are (distinctly and immediately felt in the eve. For example, a concentration of chloropicrin which is perceptible to the eye in time will injure the lung epi-
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thelium, but several days of continuous exposure are required before there is evidence of the development of lung edema. The effect on the eyes, however, is instantaneous, suggests a physical or a molecular effect, and is at striking example of specificity. The time element precludes the possibility of hydrolysis or other decomposition, and suggests that this compound is itself a protoplasmic poison with a particular chemical relation to the compounds of the corneal nerve filaments, so that these are stimulated long before other nerve endings or other types of tissue cells are affected. After prolonged exposure, recognizable only in the eye, the respiratory mucosa shows definite injury. and rhinitis, bronchitis, pneumonia, and lung edema develop. At a still later period the kidney also shows injury. Chloropicrin is evidently toxic, therefore, to many tissues. As is well known, it is quite stable chemically, and hydrolyzes only very slowly in water. It is soluble in the fat solvents and the fats. Like chloroform, it is picked up by the blood stream from the lungs, and because of a certain degree of tissue specificity it reaches and damages the kidney more perceptibly than the liver, muscles, nerve cells, or other types of tissues. In this it resembles its chemical relative, chloroform, whose specific action on the liver is well known.
Mustard gas, on the other hand, produces no instantaneous effect on the eve. The individual is usually entirely unaware of its presence unless he detects its odor and recognizes it. Hours after exposure the typical injury to the exposed corneal area appears, with conjunctivitis. There is nothing resembling the instantaneous action of the true lacrymators. It may be concluded that mustard gas has no special affinity for the corneal nerve filaments, and that it is not, itself, in the same sense or degree as are chlorine and chloropicrin. a protoplasmic poison.
LUNG IRRITANTS
A large number of casualties and some the most severe injuries produced by the war gases are to be credited to the lung irritants.
Chlorine is interesting chiefly because of its historic position as the first war gas used, and because of the dramatic sufferings of the first, unprotected victims. It is a highly reactive element, combining with protoplasm in a very great variety of ways, irritating and killing tissues, therefore, wherever it comes in contact with it. Chlorine gives evidence of instantaneous reactivity along the respiratory tract and in the eyes. Its effect on the nerve endings of the upper respiratory tract is so intense that in high concentrations it causes immediate spasms of the glottis or violent coughing and vomiting. The lungs later develop the usual reaction to injury of the lining epithelium, namely, edema and necrosis.
Chlorine may replace hydrogen in its organic combinations, incidentally producing hydrochloric acid; it may add directly on to unsaturated molecules or form more stable compounds; it may remove hydrogen from water, causing destructive oxidations, with the formation of hydrochloric acid; it may remove metallic ions from protein combination and thus alter the distribution of electric charges and so change the physical properties of the protoplasm; it may combine with the basic organic groups. These are some of the more obvious ways in which chlorine reacts with and alters protoplasm. These alterations are probablv irreversible, chemically or physically, and any such change is assumed to be injurious or, if extensive enough. fatal.
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The action of chloropicrin on the respiratory tract has already been touched upon. At moderate concentrations it produces lung edema, intense irritation of the whole tract, violent coughing, and retching. The edema comes on with considerable dclay after exposure. Chloropicrin hydrolyzes very slowly in water, so that its eflect on the respiratory mucosa can hardly be attributed to a production of hydrochloric acid within the cells, though this factor may contribute in the lelaved action. A very general injury to the whole organism is suggested in the fact that men exposed to this gas are described as aging quickly, though the kidney lesions may account for part of this general deterioration. Nothing at all definite is known concerning the chemical action of this gas on protoplasm.
Phosgene and its relative, superpalite, are the most effective of the lung- irritant group. Phosgene is quite reactive chemically. It dissolves and quickly hydrolyzes in water thus:
FORMULA
It is readily soluble in oils and fats and the fat solvents. While phosgene may react in a large number of ways, its lipoid solubility and its production of acid in contact with water would appear to be sufficient to account for its great toxicity. The former carries it into the cells like an anesthetic, the latter breaks it up when inside them, with the production of acidity. There is no strong evidence that it is immediately toxic. It produces no striking irritation of the corneal nerves nor, at medium concentrations, of those in the respiratory tract. Diluted, it may be inhaled without discomfort and has, at such times, a rather pleasant odor reminiscent of muscat grapes or of fermenting cornstalks. In more concentrated form the gas produces a sense of shock and a gripping of the chest, but even this immediate sensation passes off and leaves no well-defined sense of injury. Some time later the developing injury to the lung tissues and the resulting edema become sufficient to make the patient aware of his condition, and the feeling of malaise rapidly intensifies. Phosgene itself probably gets as far as the lung capillaries. The packing of the corpuscles in these capillaries during the early stages of phosgene gassing has been established and is probably due to the production of acid in the corpuscle membranes. There is no evidence of action to a greater distance, and from the rate of hydrolysis of phosgene it is improbable on theoretical grounds.
Superpalite behaves like phosgene but is still more toxic.
Mustard gas must be classed as a lung irritant. It has no immediate effect hut, like phosgene, is absorbed and hydrolyzes within the cell to produce an acid. It produces, however, a type of reaction in the respiratory tract quite different from that of phosgene, with the formation of a tenacious membrane in the upper portion of the trachea andl bronchial tree instead of the excessive edema of the alveoli.
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NASAL IRRITANTS
The nasal irritants, as a rule, are not, strictly speaking, gases. They are solids which are highly dispersed in the form of smokes, and which are therefore more apt to collect in the upper respiratory passages rather than in the alveoli. Sufficient concentration or deep breathing incident to heavy work, however, will carry the particles into the deeper portions of the respiratory tract. The phenylchlorarsines are the typical examples of this group. These compounds irritate the nerve endings in the nose and throat, producing violent sneezing or vomiting and coughing. The mode of action of these smokes is not known definitely, though they are probably protoplasmic poisons per se, and on decomposition yield phenyl and arsenic groups as well as acid. The fact that they are not gaseous prevents their affecting tissues to any large extent and so limits their field of importance. They can be rather easily removed from the inspired air by a filtering device attached to the mask.
SKIN IRRITANTS
Next to the lung irritants the skin irritants have proved most effective.
Of these, mustard(FORMULA)is typical.
It acts on all the tissues with which it comes in contact-eyes, respiratory tract, and skin. It is a heavy, oily liquid, volatilizing slowly. It dissolves in the ordinary fat solvents, fats, and lipoids, but only to a very small extent in water. It penetrates the cells with considerable rapidity and by virtue of its lipoid solubility, tends to collect in the fat droplets and lipoids of the cell. In the watery phase of the cell it hydrolyzes to produce hydrochloric acid. The passage from oil solution to water solution, and finally to hydrochloric acid, is slow and may continue for several days in the cells of a tissue exposed to mustard gas. This leads to a slowly developing injury to skin, eye, and respiratory tract, which increases in intensity, at times, for a period of two to three days and is then followed by the removal of the necrotic tissue and the very slow process of repair. There is very little evidence that mustard gas owes its tremendous toxicity to anything more than its ability to penetrate cells and there to produce acidity. Mustard gas has no immediate irritating action on nerve endings or tissues. Its toxicity develops slowly and is presumably the result of its decomposition products. One of these is hydrochloric acid, and while it is quite possible that other toxic fragments are developed in its breakdown, the acid alone can easily account for much of the injury. One of its hydrolytic products, dihydroxethyl sulphide, has been shown by Marshall to be practically nontoxic.
In concluding this chapter it seems appropriate to emphasize again the injury which results from the development of acidity within cells. Aside from the well-known action of phosphorus and perhaps chloroform on the liver cells, few clean-cut examples of this type of reaction had been described prior to the war. It may prove, however, that many types of cell intoxicants owe their action to an indirect development of acidity, which becomes the immediate cause of the injury.
There is considerable evidence to show that acid outside of the cell (toes verv little harm. For example, very large amounts of hydrochloric acid
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may be injected into the veins of all animal Without producing noticeable physiological effects. In this case the acidity is immediately taken care of by the effective buffer system of the circulating medium andl the injected acid never reaches the interior of the tissue cells. The mucosa of the stomach is regularly bathed with 0.2 to 0.4 per cent hydrochloric acid, with a hydrogen ion concentration sufficient to indicate with Congo Red, but without damage to the mucosa cells. The neutrality of the cell interior is maintained by the impermeability of its membranes to acid. In the same way the skin resists damage from dilute acids for long periods.
On the other hand, the appearance of acidity within the cell instantly sets in motion the autolytic machinery of the cell, and in direct proportion to the amount of acid developed. Cell proteins are not digested by the cell proteases in the normal reaction of its fluids. When this reaction shifts toward the acid side these proteins become digestible by the enzymes always present. The more acid produced the more protein is rendered available for digestion. These available proteins liquefy and digest away, the structure of the cell is obliterated, the products diffuse out and are transported elsewhere by the blood and lymph, and the cell shrinks or dies and is completely autolyzed. All tissues which have been studied behave in this way toward acidity, but they differ very markedly in the extent of the reaction. Muscle and connective tissues are only slightly digested by their own enzymes, even under the most favorable conditions. They contain relatively large proportions of stroma or skeletal proteins which are not rendered digestible by a physiological or pathological rise in the hydrogen ion concentration. The epithelial tissues. on the other hand, are exceedingly sensitive to increased hydrogen ion concentration. They respond by very rapid and complete autolysis to the optimum increase of acidity. Anything, therefore, which can reach and penetrate epithelial structures and produce acidity within these tissue cells will do the maximum amount of tissue injury. If injury is done to a particularly vital gland or structure, the conditions are right for the maximum disablement of the organism as at whole.
Phosgene, superpalite, and "mustard" combine the properties of the anesthetics with rapid hydrolysis to acids. By the strategy of the war they were applied directly to epithelial tissues. With phosgene and superpiilite contact is made with the alveolar epithelium, a vital link in the fundamental functions of tissue respiration. Injury to it is like injury to the heart or blood vessels or the blood. It makes precarious the maintenance of the proper oxygen supply to the body as a whole. With mustard gas the skin epithelium is injured, or the upper respiratory tract. While the former injury is not necessarily fatal unless of large extent, it effectually eliminates the man from active service until the wounds are healed.
When such a combination is effected--of a penetrating, acid-forming substance coming in contact with epithelial organs--there is a lethal toxicity quite equal to that of hydrocyanic acid anld, in addition, injuries grading all the way down to zero, in proportion to the amount of gas received by the epithelium. In spite of its chemical reactivity, chlorine hats only a tenth the toxic power of these gases (phosgene, superpalite, and “mustard”) because it penetrates only slightly, and in the many combinations which it makes with protoplasm only a few lead to the production of acid.
