774 6. ARSENICALS 



the skin. The first to direct attention to this was Sir Jonathan Hutchinson 

 in 1887 when he described five cases of skin cancer, which he attributed to 

 the chronic ingestion of arsenite. By 1930 sufficient cases had been reported 

 so that the condition could be characterized definitely as an arsenical 

 multiple superficial epitheliomatosis, which is generally preceded by local 

 areas of hyperkeratosis. Fowler's solution* taken over a period of years 

 has generally been the etiological factor. There is a patchy melanosis and 

 there may be areas of dermatitis, multiple seborrheic warts, and abnor- 

 malities of the hair and nails; the hyperkeratosis occurs mainly on the palms 

 and soles, but may be found elsewhere. The cancers are usually epitheliomas 

 of the squamous cell type and malignant. It has been assumed that arsenic 

 retained in the skin acts as an irritant to induce neoplastic changes (Fran- 

 seen and Taylor, 1934), but actually it is not even certain whether arsenic 

 is the active agent or indirectly causes the accumulation of some carcino- 

 genic substances. It is true that the lungs of pulmonary carcinoma patients 

 contain more arsenic than normal lungs (7.14 and 4.13 //g/g AsgOg, respec- 

 tively) (Holland et at., 1960), and for many years attempts have been made 

 to correlate arsenic intake or tissue content with the incidence of cancer; 

 but even though such a correlation exists, it implies nothing relative to 

 mechanism. Experimental topical application of arsenite to the skin has 

 generally given negative results, although Leitch and Kennaway (1922) 

 reported that one skin cancer occurred in 100 mice painted with 0.71 milf 

 potassium arsenite solution for 4 months. Arsenite has been tested in a 

 variety of ways for carcinogenic activity with generally negative results 

 (Hartwell, 1951). Injected into bones for several years, arsenite produced 

 giant cell sarcoma in one case and some muscle tumors when administered 

 to fowls. Intraperitoneally, it caused peritoneal nodules and one tumor 

 of the diaphragm. Subcutaneously in the neck, it caused one sarcoma of 

 the ear. Other instances of tumor induction have been reported, but in all 

 cases the incidence is very low and there is some question as to the causative 

 role of arsenite. Since skin tumors are unquestionably related to arsenite 

 administration, it is not unlikely that other tumors may occasionally be 

 induced. It is improbable that an inhibition of keto acid oxidation would 

 be directly carcinogenic, although consequent metabolic disturbances could 

 conceivably predispose to cancer. The selective suppression of oxidative 

 processes might, according to certain hypotheses of carcinogenesis, bring 

 about a pattern of metabolism characteristic of tumor tissue, but whether 

 such will induce cancerous changes is not known. So little is known of the 

 effect on nucleic acid metabolism that no conclusions can be drawn as to 

 this. A good review of arsenical carcinogenesis is given by Neubauer (1947), 

 and F. Roth (1956, 1957, 1958) has not only reviewed the subject in an 



* The daily dose of Fowler's solution is probably around 0.1 ml and thus 100 nig 

 AsjOj, or perhaps twice this amount in some cases. 



