Carcinogenicity of Alkylating Agents

Abstract

T O A CHEMIST interested in carcinogenesis, one of its fascinating aspects is the great variety of chemicals that after being administered to a test animal can lead to cancer. Some very simple molecules, that is, carbon tetrachloride or diazomethane, are carcinogenic in certain species of animals while in others only complex structures are cancer producing. Moreover, the production of ca,rcinogens that may be involved in the human environment is not wholly the province of man; a number of quite powerful carcinogens are produced by micro-organisms or plants. One such mycotoxin that has proved to be a potent carcinogen is aflatoxin (fig. 1), a metabolite elaborated by the fungus Aspergillus flavus. The discovery of aflatoxin resulted from an investigation of the cause of a mysterious disease that killed thousands of turkey poults in England in 1960, the fatality largely resulting from liver necrosis. The toxin was traced to moldy peanut meal included in the poultry feed. Further study led to the identification of the organism responsible, to the isolation and determination of the structure of aflatoxin (1, 2), and to the discovery that aflatoxin is a powerful hepatocarcinogen (3). Thus it has been estimated that hepatomas in rats are induced by a daily dose of 9,000 ,ug. per day of p-dimethylaminoazobenzene, a classic liver carcinogen, by 700 jug. per day of dimethylnitrosamine, but by only 10 jug. per day of aflatoxin B1. On a weight basis, therefore, the toxin is 900 times more effective than the standard azo dye. Hydrogenation of aflatoxin B1, the most abundant and most carcinogenic isomer, yields aflatoxin B2, which is much less toxic and carcinogenic and also a relatively minor mold product. Usually, contamination of peanuts or oil seeds by A. flavus occurs when the peanuts are stored in a moist place after harvesting. Expeditious and proper drying of the peanuts can prevent growth of the fungus and eliminate the production of toxin. Incidentally, the amount of aflatoxin formed varies, and a luxurious growth of A. flavus does not necessarily lead to a high yield of aflatoxin or vice versa. Is aflatoxin likely to be a carcinogen in man? It has been reported that certain African populations enjoy moldy corn or moldy peanuts. Whether contamination of these foods by aflatoxin may be a factor in the high incidence of liver cancer in parts of Africa remains to be determined definitely. Another naturally occurring compound that is carcinogenic is cyeasin (4), H13C-N (0) = NCH20C6H1105 (glucose), a glycoside isolated from the seeds of Cycas circinalis (cyeads), a species of palmlike plant found mostly in tropical or subtropical countries. The cyead nuts are also used in certain food products. The Dr. Weisburger is scientist director, Carcinogen Screening Section, Carcinogenesis Studies Branch, National Cancer Institute, Public Health Service, Bethesda, Md.