Contents

CHAPTER XVII

THE INFLUENCE OF SOLVENTS, ADSORBENTS, AND CHEMICAL ANTI-DOTES ON THE SEVERITY OF HUMAN SKIN LESIONS CAUSED BY MUSTARD GAS ^a

NORMAL COURSE OF LESIONS

The following sketch of the course of the main clinical phenomena of dichlorethylsulphide lesions is given to serve as a "normal" for judging the modifications produced by experimental measures. Further details of the skin phenomena are contained in Chapter XVI.

Dichlorethylsulphide, as is now generally known, is a very powerful and peculiar irritant. It produces successively simple erythema, cutaneous edema, extensive vesication with coagulated contents, ulceration, and superficial sloughing. The effects, although severe, do not extend beyond the skin or mucous membranes.

Very small doses are effective. The substance is very rapidly absorbed and fixed in the skin. Solvents prevent the effects only if they are applied almost immediately after contact; they are practically useless after ten or fifteen minutes. On the other hand, the effects develop quite slowly. In the human skin they become perceptible only after from one hour to two days, according to the dosage. Histologic changes, however, start much earlier, probably soon after the entrance of the poison.

With severe burns the destructive effects grow worse for several days. In any case the healing is a very slow process, very much slower than with ordinary burns. Even when healed the burned skin remains abnormal at least for months.

Another striking peculiarity is the entire absence of pain or sensitiveness during the first two days. At this time even extensive blisters cause absolutely no discomfort. This is not due to a true anesthesia, for the sensitiveness to touch is unimpaired. Apparently, the nerves are in some way protected against the poison. A little later (on the third to fifth day), when the necrotic changes develop and the epidermis is more or less destroyed, the lesions become exquisitely sensitive to mechanical and chemical irritation. In milder cases the edema of the skin leads to intolerable itching.

The hypersensitivity increases until the lesion has reached its acme--between 5 to 13 days, according to the severity. During this time the wound tends to become covered by a sloughing pseudomembrane. This condition persists for about a week.

The turn toward improvement generally sets in rather abruptly between the seventh and nineteenth day, so that within two or three days the wound
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^a These investigations, which were undertaken in collaboration with the Medical Advisory Board of the Medical Warfare Service, were carried out in the pharmacological laboratory of the Medical School of Western Reserve University, Cleveland, Ohio. They were reported in the Journal of Pharmacology and Experimental Therapeutic, Baltimore, Md.. 1918, xi, No. 3, 229, and 1919, xii, 303.

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presents a healthy looking granulating surface and the hypersensitiveness is practically gone. This spontaneous change must be taken into consideration in judging the success of methods of treatment.

From here on improvement is steady, but slow and tedious, and likely to be somewhat complicated by furunculosis.

Table 63 gives the average time relations of the experimental burns. They also hold good for clinical burns.

METHODS OF EXPERIMENTATION

The investigation upon the results of which this section is based had the purpose of studying the conditions that might affect the penetration and the toxicity of the dichlorethylsulphide.

Experiments on animals were abandoned after a few trials, since their skin did not react in the same manner as human skin and the effects that did occur were not easily graded.

TABLE 63.- Mean course of experimental lesions

The urgency of the problem at the time appeared to justify direct experimentation on human subject.^b Six students volunteered for what were often quite painful experiments. Other experiments were, made on the author of this chapter.

APPLICATION

The poison w as applied in the form of liquid and vapor. The vapor tests were preferred were, whenever possible, since the results are very uniform and milder.

VAPOR TEST

In a l-dram heomeopathic vial (about 5 cm. long and 8 mm. internal diameter) was placed a very small piece of cotton wool. On this was dropped 0.01 c.c. of the poison, then another small piece of cotton, carefully wiping the mouth of the vial. This was packed down with a glass rod and the vial left corked for an hour to one day.
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^b W. P. Bowser, W. D. Cassel, S. J. A. Foerstner, S. H Lesinger, H. H. Loucks, N. C. Wetzel.

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In applying, the open vial was held firmly against the skin by the thumb and forefinger for five minutes. The very uniform results on blank tests, and marked difference in the presence of efficient protectives, showed that a more complicated technique was not necessary.

The normal reaction was an erythematous papule that did not go on to vesication.

ALCOHOL SOLUTION

Dichlorethylsulphide, 0.1 c.c., was diluted with 20 c.c. of alcohol (the solution must be used within an hour, as it hydrolyzes fairly rapidly). Of this dilution 0.005 c.c. was blown from a pipette onto the skin and spread with the point of the pipette over an area of about one-half inch diameter. Air was then blown through the pipette over the area, thus evaporating the alcohol, and leaving a thin film of the poison.

The normal reaction of this dosage was a distinct vesicle which healed slowly. This was generally a disadvantage of the method, since it limited the number of experiments that could be made on a subject. It was also difficult to spread the liquid evenly over a painted or powdered skin area.

At first stronger doses were used (0.01 c.c. of 1 percent), but these sometimes gave rise to excessive reactions.

FILTER-PAPER TEST

In this, 0.1 c. c. of dichlorethylsulphide was spread on filter paper so as make an even stain, about 1 by 5 cm. This was then cut into 10 squares of 5 mm. each, so that each square represented about 0.001 c. c. of dichlorethylsulphide. These were laid on the skin and kept in place by a bandage for one or two hours.

The reaction was altogether too severe, and this method was tried only in connection with fairly efficient protectives.

The lesions were inspected at suitable intervals and frequently photographed.

EFFECTS OF SOLVENTS

The first line of experimentation concerned the effects of water and oil. Dichlorethylsulplhide is readily soluble in oil, and very little soluble in water. It therefore seemed probable that these solvents would affect its penetration and the irritation in the same way as they do phenol or true mustard oil. For these it was found that the irritant distributes itself between the solvent and the skin, according to its partition coefficient; the greater its affinity for the solvent the slower will be its penetration into the tissues, and the smaller the irritation, and vice versa.

The results and experiments showed that the same principles apply to dichlorethylsulphide. Waiter increases the irritation (Fig. 223) and oils render it less irritant (Fig. 224).

Unfortunately, however, the absorption is still very rapid, even in the presence of oils, and the ultimate injury is not very much reduced. The importance of the delayed absorption is further minimized by the fact that the irritation is proportional to the absolute quantity rather than to the concentration of the poison. This difference from most other irritants is explainable on the

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assumption that the toxic effects are not due to the dichlorethylsulphide itself, but to its intracellular decomposition, resulting in the liberation of hydrochloric acid within the cells. The degree of this intracellular acidosis would, of course, depend upon the absolute quantity of the dichlorethylsulphide that had penetrated into the cell. Since the poison probably does not leave the cells after its absorption, the rate of absorption would have little effect on the absolute quantity absorbed.

Notwithstanding these restrictions, however, the influence of the solvents is quite distinct, within certain limits. The protection by oils is especially efficient in prolonging the time during which removal treatment remains effective. (Fig. 225.)

The efficiency also increases with the thickness of the oily layer on the skin; and this depends largely on the stiffness of the oil or ointment. The efficiency is therefore increased by the addition of powders or "fillers."

FIG. 223.- Detrimental effects of water (vapor tests). Dichlorethylsulphide vapor was applied to the skin; 62. bare skin; 63, skin coated with water; 64, skin coated with sodium bicarbonate water paste; CZ, skin coated with soap; 66, skin coated with kaolin water paste. The photograph was taken 7 days after the application. Note the lesion is greatest on the moistened skin (63), as compared with the bare skin (62). Kaolin restrains this somewhat (66). Sodium bicarbonate paste (64) is useless. soap paste (65) is fairly efficient. (The figures in parentheses refer to experiments)

This effect appears to be purely mechanical, for no material differences exist between the various substances that were tried.

There are, however, differences between the oils themselves that are not explainable on a physical and mechanical basis, and must therefore presumably be chemical. Linseed oil, raw as well as boiled, and cod liver oil furnish considerably more protection than do other oils. (Fig. 226.) This is perhaps due to unsaturated fatty acids. The efficiency, however, is also limited. (Fig. 227.)

Under certain conditions, the fats apparently may increase the toxicity: namely, when they facilitate the contact with the poison. This occurs, for instance, when cloth saturated with the oil is laid loosely on the skin. (See fig. 224.)

The following gives a more detailed outline of the experiments and results:

WATER

The effects of dichlorethylsulphide are more severe in the presence of moisture on the skin. This is shown very convincingly by the vapor test, in experiment No. 63. (See fig. 223.)

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This action of water is reflected in the attempt to use protective substances as watery solutions or pastes. These are uniformly less effective than the dry substances, and in nearly all cases they are also less effective than the oily solutions or pastes.

Because of their water content, the following rendered the skin hypersusceptible, so that the lesions were more severe than on the bare skin: 50 percent glycerin (experiment No. 15); sodium bicarbonate-water paste (experiment No. 64); kaolin-water paste (experiment No. 66); fuller's earth-water paste (experiment No. 68).

The deleterious effects of moistening the skin do not contradict the beneficial effects of washing and scrubbing the skin, after exposure, with soapy solution.

FIG. 224.- Protective action of petrolatum when dichlorethylsulphide is applied as "splash," and when applied through fabric. In experiments No. 10 and No. 11, the alcoholic dichlorethylsulphide was applied directly to the skin; No. II was previously vaselined. The protective value of the petrolatum in No. 11 is apparent. In No. 12 and No. 13 the alcoholic dichlorethylsulphide was dropped on a small square of cloth and this was applied to the skin; No. 13 was frst oiled with petrolatum. Note that the two lesions are practically alike. The photograph was taken 19 days after the application

On the other hand, it is evident that the skin should be protected against moisture during exposure by keeping it covered with absorbent dusting powders; or better, by keeping it oiled, if that is practical.

SIMPLE OILS AND FATS

All oils restrain the effects of dichlorethylsulphide. They differ quantitatively, however.

The relative protective efficiency can be seen when the vapor or alcoholic solutions are applied to the oiled skin; but they are especially striking if equal doses of a 3 percent solution of dichlorethylsulphide in various oils is applied to the skin. The protective efficiency in the different series is in the following order, the most effective protection being at the top, the least effective at the bottom of the list.

VAPOR TESTS ^C

(Sollmann)  (Loucks)
Boiled linseed oil (53).   Castor oil (90).
Liquid petrolatum (47).
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^c The numbers in parentheses refer to experiments.

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LIQUID DICHLORETHYLSULPHIDE APPLIED TO OILED SKIN ^d

(Small dose)(Large doses)
Petrolatum (11).  Raw linseed oil (117).
Liquid petrolatum (2, 6, 7). Solid paraffin (122).
Olive oil (3).
Lanolin (4).

DICHLORETHYLSUIPHIDE DISSOLVED IN OILS (3 PERCENT)

Raw and boiled linseed oil (111 and 112) Olive oil (113).
Castor oil (114)
Cod-liver oil (115).  (See Fig. 226.)
Liquid petrolatum (110).

FIG. 225.- Value of protective oiling. In No. 8 the dichlorethylsuliphide was applied to the hare skin, in No. 9 to oiled skin. Both were washed with oil after 15 minutes. Observe the much greater effect on the unprotected skin in No. 8. The photograph was taken 24 days after the application

From these data the general order of efficiency is: Linseed oil, raw or boiled, cod-liver oil, solid paraffin, petrolatum, liquid petrolatum, olive oil, castor oil, lanolin.

The oiling of the skin is decidedly protective against slight exposure (experiments 47, 53, 90) to the vapor and fairly effective against small doses of the liquid (2, 3, 4, 11). Its usefulness, however, is not unlimited. Even the most effective oils do not prevent blisters if the strong dichlorethylsulphide is left in prolonged contact (117 to 122). (See fig. 227.)

FILLED OINTMENTS

Many of the substances that were tried as chemical antidotes really acted merely as fillers. The tabulations are again arranged in the order of efficiency, those giving the most complete protection are at the top; the least protection at the bottom. Some of the plain oil are given in brackets for comparison.

VAPOR TEST (SOLLMANN)

Zinc oleate (50).   Liquid petrolatum stiffened with charcoal (50), kaolin (49), or fuller's
Linseed oil (53).earth (48).
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^d The numbers in parentheses refer to experiments.

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VAPOR TEST (CASSEL)

Zinc oleate (97) and solid petrolatum pastes made with:
Collargol (94).   Silver abietate (resinate) (101).
Zinc stearate (95).Boric acid (99).
Zinc oxide (96).Solid petrolatum (100).
Manganese dioxide (98).

LIQUID ALCOHOLIC DICHLORETHYLSULPHIDE

Zinc in. liquid petrolatum (21).
Hexamethylamin in liquid petrolatum (20), (petrolatum, 11).

When the dichlorethylsulphide is concentrated, even the filled ointments have only slight values. This is shown by the series 116 to 122, which also includes solid paraffin. (Fig. 227.) In such cases only the chlorine preparations are promising.

FIG. 226.- Comparison of oils. Observe the degree of effect. Each area received 0.01 c. c. of 3 percent solution of dichlorethylsuiphide in the oil, spread over a surface of about one-half inch diameter. The photograph was taken 2 days alter application. The solvent oils were as follows: 110, liquid petrolatum; ill, raw linseed oil; 112, boiled linseed oil; 113, oilve oil; 114, castor oil; 115, codliver oil. (The figures refer to experiments.)

PROTECTIVE VARNISHES ^e

These may be supposed to act like the fats. They would remain longer on the skin, but they can only be applied in a very thin coat, and this is likely to furnish only an incomplete protection. A thicker coating might soon become harmful.

The actual tests by the vapor method, although not complete, were not encouraging.

Aluminum paint (83) actually increased the irritation; asphalt-ether varnish (80) was no better than bare skin. Collodion (85) furnished a very slight protection.

The following protected, but it was not determined whether the protection was greater than that of simple oiling: Rosin-ether varnish; also with zinc stearate and with fuller's earth; shellac varnish.
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^e The numbers in parentheses refer to experiments

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ADSORBENT POWDERS

These were found highly effective, just as they are in the masks. A layer of 1 mm. thick protects completely against the vapor test (Fig. 228) and quite effectively against the alcoholic solution. The results were as follows:

Vapor tests on dry powders (Sollmann). Bare skin erythematous papule. No lesion followed on cocoanut charcoal (29). Slight and inconstant erythema (less than linseed oil 53): Kaolin (27, 73), fuller's earth (28, 74). Slight papular erythema: Zinc stearate (30) (about like liquid petrolatum 47).

Vapor tests on dry powders (Loucks) .-Bare skin erythematous papule. No lesions followed on: Manganese dioxide (103), talcum (108), zinc oxide (105). Slight erythema: Silver abietate (107); reduced iron (104), litharge (106). Moderate erythema: Zinc stearate (107).

Liquid test with alcoholic dichlorethylsulphide.- Fuller's earth protected most; talcum, intermediate protection; calcium carbonate, least protection.

FIG. 227- Protective value of dichloramine-T. Pieces of filter paper about 5 mm. square, and containing about 0.001 c.c. of 95 percent dichlorethylsulphide were applied to the center of a square of skin, covered with the protectives. The coatings were as follows: 117, raw linseed oil; 118, linseed oil and kaolin, I to 3; 119, same with 3 percent of soft soap; 120, petrolatum kaolin, I to 1; 121, dichloramine-T, 10 percent in chlorcosane; 122, solid paraffin. The photographs were made I day after the application. Note that the reaction is less in 121 than in the others; 26 and 30 are recrudescences of lesions 25 days old. (The figures refer to experiments.)

These results show that the general efficiency of the powders is as follows, the most effective being at the beginning, the least effective at the end of the list: Cocoanut charcoal; fuller's earth, kaolin; talcum, manganese dioxide, zinc oxid; silver abietate, reduced iron, litharge; zinc stearate; calcium carbonate.

Practically the usefulness of the adsorbent powders is limited by the difficulty of keeping them on the skin in sufficient thickness.

The above tabulation of relative efficiency indicates plainly that the following act only mechanically, and not chemically, and that this efficiency is actually lower than that of the cheaper charcoal, kaolin, or fuller's earth, namely, metallic soaps (zinc stearate), metallic resinate (silver abietate), metallic oxids (zinc oxid and litharge), and free metals (reduced iron).

ADSORBENT WATER PASTE

The attempt was made to secure a better adhesion of the adsorbents to the skin by using them in the form of pastes. These pastes are not nearly as efficient as the dry powders. This is explainable partly by the deleterious effects of water itself, and partly by the watery film, preventing ready access of the nearly insoluble dichlorethylsulphide to the adsorbent.

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The following experiments were made, the results again being presented in order, the most efficient abcove, the least effective below.

Vapor tests (Sollmann).- Bare skin gives erythematous papule.
Inconstant slight erythema: Cocoa-charcoal paste (67) (about like dry kaolin).
Papular erythema, rather less than on bare skin: Powdered zinc paste (71).
About as on bare skin: Fuller's earth paste (68).
Slightly more severe than on bare skin: Kaolin paste (66).
Complete vesication: Sodium bicarbonate paste (64).
Water alone produces more severe blister and scabbing (63).
Vapor tests (Cassel).- Collargol, 10 percent (93) did not furnish protection, giving the same results as on the bare skin.
Liquid alcoholic dichlorethylsulphide.- Alkresta (purified fuller's earth) in 50 percent glycerin (16) furnishes a fair protection, while 50 percent glycerin alone increases vesication (15).

FIG. 228.- Efficiency of dry powders. Dichlorethylsulphide vapor was applied. Note the normal lesion in the bare skin (26); the slight protection afforded by zinc stearate (30); and the complete protection from kaolin, fuller's earth, and charcoal (indicated by the absence of lesions in a straight line drawn from 26 to 30). The photograph was taken 3 days after the application. (The numbers in parenthesis refer to experiments.)

SOAPS

Plain soap.-"Soft soap" furnishes considerable protection, chiefly, it is presumed, by acting as a solvent. It acted as well as linseed oil or zinc oleate in the vapor test (65). It may also be incorporated with the ointments; for instance, 5 percent with petrolatum (91), and 3 percent in the linseed kaolin mixture (119). The addition of the soap modifies ointments so that they can be applied more smoothly and also facilitates their removal by washing. These advantages, however, are not very great, and it is conceivable that the alkalinity of the soaps might injure some skins.
Metallic soaps.- Certain reports by other workers indicated that metallic soaps and resinates would be especially effective. This was not confirmed. Those tried had only at limited success, and this was attributable mainly to their mechanical action as absorbents and fillers.

PLASTER

Lead plaster (54).- Protected well in the vapor test, but this was explained by the dense consistence of the film.

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OINTMENTS

Zinc oleate (the old U. S. P. preparation).- Protected partially in the vapor test, being about equal to linseed oil (53) and very little better than kaolin- petrolatum ointment (50). On another subject (97) it protected completely, but so did ointment of zinc oxide or boric acid.
Zinc stearate in the dry form (30, 107).- Protects very little, even against vapor; much less than dry kaolin (28), talcum (108), or zinc oxide.
Zinc stearate petrolatum ointment.- Furnished protection against vapor (95), but so did similar ointments of zinc oxide (96) and boric acid (99).
Silver abietate (resinate), dry.- This furnished only a relatively slight protection against vapor (107), being inferior to talcum (108).
Silver abietate-petrolatum ointment.- This protects against the vapor (101), but so did a similar boric acid ointment (99).

POWDERED AND COLLOIDAL METALS AND METALLIC OXIDES

These were tried in the hope that they might act as catalysts, accelerating the hydrolysis of the dichlorethylsulphide. The results show that this does not occur under the conditions of their use on the skin. They furnish some protection, but no more than any indifferent powders. The following were tried:
In dry powderform.- Powdered zinc (79): Protection against vapor much less than dry kaolin (73). Manganese dioxide (103) and zinc oxide (105): Protect against vapor, but so did talcum (108).
As water pastes.- Zinc dust paste (71): Protects very little better than fuller's earth paste (68), both being about the same as on the bare skin (62). Collargol, 10 percent (93): Does not protect
As petrolatum ointments.-Zinc dust ointment: Protects somewhat better than petrolatum; but probably not better than any indifferent powder, such as hexamethylanamin (20). Manganese dioxide ointment (98), zinc oxide oint- ment (96), and collargol ointment (94): Protect against vapor, but so did boric ointment (99).

CHLORINE PREPARATIONS

The caustic action of dichlorethylsulphide is destroyed by further chlorination. Chlorinated lime and the chloramines are effective under working conditions. Their efficiency is limited; and their practical application is further confined by their irritant action on the skin, the instability of some of the preparations, and the cost of the chloramines.

Their efficiency is illustrated by Figure 227 and by the following experiments:
In the vapor tests.- Complete protection was secured by: Dichloramine-T, dry (76), or in water paste (69), or as 10 percent dusting powder (78) and 10 percent in chlorcosane. Calx chlorinata, in the same forms (75, 70, 77). The efficiency of dichloramine-T and calx chlorinate was equal to that of dry charcoal, and superior to all others. Chloramine-T paste, Squibb (52), gave almost complete protection.
Against concentrated liquid G34.-Dichloramine-T, 10 percent in chlorcosane gave only partial protection (121), but was somewhat more efficient than linseed kaolin pastes (118, 119). This is shown in the Figure 227.