This section is from the book "Research In Physiopathology As Basis Of Guided Chemotherapy With Special Application To Cancer", by Emanuel Revici. Also available from amazon: Research In Physiopathology
In studying sulfur mustard, we were first interested in its effects upon body lipids and, through them, upon the lipidic system of organisms. In inducing sulfur mustard's characteristic skin lesions, an interesting relationship was observed. Pure sulfur mustard was applied to mechanically epilated skin of rats. If a sufficient amountó2 to 3 dropsówas used and spread on one square cm., the animal died. However, the time of death varied. If the lesion showed a massive necrosis, followed by deep ulceration, similar to a burn of the third degree, the animal died in about three weeks. However, if the lesion was only erythematous, similar to a burn of the first degree, the animal died in only 3 to 4 days. It seemed as if the lesion itself intervened secondarily in the pathogenesis of changes leading to death. Sick but still living cells appear to have an activity which is highly detrimental. The abnormal cells apparently produce substances which are responsible for rapid death of the animal. In widely necrotic tissues, these abnormal but still living cells are limited in number; in an erythematous lesion, they form the lesion itself. This correlation of toxicity with local lesion was confirmed by the fact that excision of the lesion itself, if performed in time, prevented death in some animals. The administration of ferrous sulfate to rats having sulfur mustard applied to their skin was seen to induce the erythematous form of the lesions, with death in 3-4 days.
The similarity between the influence exerted by mustard burns and caloric burns with a sufficiently extensive first degree burn producing more rapid death than a third degree burn, was of interest.
Analysis of the body of an animal killed by a mustard burn reveals abnormal amounts of unsaturated fatty acids and reduced amounts of sterols. In some cases, where death occurred after more than three weeks, body sterols were found to be almost completely lacking. In these cases, almost no insaponifiable fraction could be found. The lesion itself, especially an erythematous and edematous one, was very rich in unsaturated fatty acids. Histological study of these skin lesions revealed changes similar to those obtained through the intradermic injection of concentrated solutions of body acid lipidic fractions. The study of these lesions further revealed that the lesions themselves were separated from the organism by a barrier of adipous cells, the result of an exaggeration in number of the cells of the subdermic fatty layer.
We studied these important changes from several points of view. We could show that an exaggeration of the adipous layer underneath the skin occurs when lipoids with negative character, such as polyunsaturated fatty acids, thiolipoids, etc. act upon the skin. Thus, this subcutaneous adipous formation appears to be a defense weapon, designed to keep such lipoids from passing into the organism. The defense appears to be unequal for males and females, as shown in the following study.
In collaboration with the late Prof. R. Leroux of the Faculty of Medicine in Paris, we studied histological changes in the ears of rats after local application to the skin of a small amount of pure sulfur mustard. Normally there are no adipous cells in the pavillion itself except at its base. Twenty minutes after the application of sulfur mustard on the skin of the ear, 2 or 3 layers of adipous cells were seen in the connective tissue between skin and cartilage. (Chapter 6, Note 22)
Curiously enough, the rapid appearance of adipous cells 20 minutes after application occurred in females and not in males. The spaying of females or castration of males did not change this response even after a lapse of months. The administration of male sex hormones to female ratsó spayed or notóor of female sex hormones to malesócastrated or not óalso produced no change. It was only by the administration to males, over a period of days, of a sufficiently large amount of the insaponifiable fraction obtained from the bodies of rats that this rapid response was induced. The administration to females of the acid lipid fraction obtained from rat bodies was seen to prevent the rapid adipous response. This difference in response between males and females, can be related to the differences in the amounts of members of the two groups of lipids ordinarily found in males and females, as mentioned above.
We studied sulfur mustard from the point of view of pharmacological activity. Doses of 100 mcgr./100 gr. of body weight (of a 0.1% solution of sulfur mustard in oil) were nontoxic in rats and mice. Except for an intensive local reaction at the injection site, no important immediate changes were obtained in humans when 1 to 3 cc. of the 0.2% solution was injected intramuscularly. The influence upon painóa decrease in the intensity of acid pattern and an increase for the alkaline patternówas only temporary. The influence on tumor evolution was not sufficient to warrant clinical use of this agent, especially in view of the persistent and intensive systemic changes toward an offbalance of the type D which appeared after a few days. Through its anti A action, which is the most intensive of all agents tested, sulfur mustard remains one of the most interesting substances for experimental studies, especially for the effects exerted upon the anti fatty acids.