The veil of secrecy behind which many of the scientific investigations in relation to the prosecution of the war have necessarily and properly been .conducted is gradually being lifted. Among the large number of startling items of information thus disclosed, few claim greater medical interest, particularly in respect to novelty and far-reaching significance, than do the war gases. The effects of chlorin attracted attention because this gas was the first to be employed, in the spring of 1915, in that hideous inhumanity known as gas warfare. The interest in chlorin and some of its later substitutes has been eclipsed by the consideration of the so-called mustard gas, dichlorethylsulphid, which had assumed a role of primary importance by the time the armistice was signed.
The distinctly local effects of mustard gas have been repeatedly described.. They consist mainly of conjunctivitis and superficial necrosis of the cornea; hyperemia, edema, and later necrosis of the skin, leading to a skin lesion of great chronicity; and congestion. and necrosis of the epithelial lining of the trachea and bronchi.
These localized effects, severe though they may be, have not always seemed to suffice to account for the symptoms that sometimes attend intoxication with mustard gas. Such phenomena as vonuting and diarrhea, hyperexcitability and convulsions, and. irregularities of the heart, observed in animals exposed to the deadly vapors, suggest the presence of systemic effects that are due to absorption of the poison into the blood stream and its distribution throughout the organism. This point of view is substantiated by the investigatons of E. K. Marshall (1) and his colleagues in the Pharmacologic Research Section of the Medical Division of the Chemical Warfare Service, US. Army. Dichlorethylsulphid appears to be excreted in the urine, in part at least, as dihydroxyethylsulphid; a compound devoid of chlorin and shown to be comparatively nontoxic. The lesions of the intestine suggest that excretion of the substance may also take place there.
An outstanding fact about mustard gas is its progressive hydrolysis in aqueous solution, whereby it breaks down readily to yield hydrochloric acid and residual compounds of low toxicity. Marshall and his associates have therefore attempted to correlate the toxicity of dichlorethylsulphid with the liberated hydrochloric acid. They picture the sequence of events as follows: Dichlorethylsulphid is very slightly soluble in water and very freely soluble in organic solvents, or has a high lipoid solubility or partition coefficient. It would, therefore, be expected to penetrate cells very readily. Its rapid powers of penetration are practically proved by its effects on the skin. Having penetrated within the living cell, it would undoubtedly hydrolyze. The liberation of free hydrochloric acid within the cell would produce serious effects and might account for the actions of dichlorethylsulphid.
Observations made on lower forms of animals likewise
favor
this hypothesis. Even though the undecomposed "mustard gas" is
only slightly soluble in water, its peculiar lipoid-soluble properties
enable
it to penetrate into cells and presumably collect in relatively high
concentration
in the cell lipoids and fats of the protoplasm. In this situation,
Clowes,
Lillie and Chambers (2) remark, the substance serves as a reservoir of
toxic
material which continually enters solution in the aqueous phases of the
protoplasm and is continually being decomposed there. Since, by its
hydrolytic
decomposition, it yields acid, the dissolved "mustard" acts
destructively
on the protoplasm as soon as the available buffer compounds (which
normally
prevent protoplasmic hyperacidity) are exhausted. The destructive
action
is thus due primarily to the hydrochloric acid freed by hydrolysis..
The
theory of the intracellular liberation of. hydrochloric acid as the
mechanism
of action is consistent with the known facts of the pathology of
mustard
gas., Its skin 1esion resembles hydrochloric acid burns. Many of the
war
gases can readily yield an. acid by hydrolysis. The toxicity of
dimethylsulphate
may thus be due to an intracellular liberation of sulphuric acid. The
ideal
mode of treatment, would seem to lie in the use of a basic substance
having
solubilities and penetrating power like that of mustard gas, but
yielding
a base on hydrolysis so as to neutralize the acid formed by the
war gas. Fortunately there is no longer need for haste in the search
for
a perfect antidote of this sort.
1. Lynch, Vernon; Smith, H. W., and Marshall, E. K., Jr.: On Dichlorethyl sulphide (Mustard Gas), I, The Systemic Effects and Mechanism of Action, J. Pharmacol. & Exper. Therap. 12:265 (Dec.)
2. Lillie, R. S.; Clowes. G. H. A.. and Chambers, R.: Preliminary Report of Experiments on the Action of Dichloroethylsulfide (Mustard gas) on the Cells of Marine Organisms, Science 49: 382 (April 18) 1919