728 6. ARSENICALS 



(see accompanying tabulation) (Eagle et al., 1944 c). There seems to be 

 a rough parallel between the local inflammatory activity and the systemic 

 toxicity. It is difficult to understand the low potencies of some of these 



Phenylarsenoxide Eifective concentration (milf) 



J9-NHCONH2 11.1 



P-SO2NH2 10.0 



P-CONH2 5.7 



w-CONH^ 4.7 



3-NH2-4-OH 2.1 



P-NHCOCH3 1 . 1 



p-OK 0.18 



Unsubstituted 0.12 



39-NH2 0.11 



substances, unless it is a matter of lack of penetration into the cells. After 

 World War I it was believed that vesicants such as lewisite are irritant 

 because of the HCl released in the tissues by hydrolysis. During World 

 War II the group at Oxford under Peters emphasized the reactivity of such 

 arsenicals with SH enzymes, especially pyruvate oxidase, and it was indeed 

 shown that lewisite inhibits pyruvate oxidation in the skin (Thompson, 

 1946), although there was little justification for concluding that a selective 

 inhibition of pyruvate oxidase occurs, inasmuch as only succinate oxidation 

 was examined in addition. At the present time it is generally accepted that 

 vesication, at least that caused by arsenicals, is due to a biochemical lesion 

 at the pyruvate oxidase level (Peters et al., 1946; Peters, 1955). However, 

 tempting as the picture is, there is no direct evidence for it. When lewisite 

 is applied to the skin and erythema results, it is not known if the action 

 is primarily on the vessels or on the skin cells. Vasodilatation could be sec- 

 ondary and result from products released from damaged cells. Vesication 

 is the result of accelerated escape of plasma through capillary beds and 

 can result from various types of cellular damage. Certainly it appears that 

 the keto acid oxidases are among the enzyme systems most sensitive to 

 the arsenicals, but this is only circumstantial evidence that here is the site 

 of the biochemical lesion in the production of vesication. Histological stud- 

 ies of the effects of lewisite on the skin by Cameron et al. (1946) indicate 

 damage to the skin cells. The blister in human skin shows a roof of epidermis, 

 but the epidermal cells are badly injured, having lost their structure and 

 exhibiting degenerate nuclei. The dermal cells also are damaged, as are 

 the endotheilal cells of the blood vessels, which are often necrotic. Since 

 these results were obtained by using pure lewisite droplets, little can be 

 concluded relative to the specificity of action at lower concentrations, but 



