In 1775, a prominent English surgeon, Percivall Pott, broke a leg and spent his time of recovery writing a book on his observations. He devoted a few pages to the subject of cancer of the scrotum in chimney sweeps, which he attributed to long exposure and intimate contact with soot. This was the first clear description of an occupational cancer. During the industrial revolution of the 19th century, several additional examples of occupational cancers were identified.
The father of cellular pathology, Rudolph Virchow of Germany taught that chronic irritation was a cause of cancer, and this was considered to be the common denominator of these industrial cancers. Better hygienic measures, stimulated by appropriate legislation, led to the reduction of the industrial problems. Attempts to reproduce cancers in animals with some of the suspected materials were unsuccessful, as the medical literature of the early part of this century attests. In 1915, however, two patient Japanese investigators, Katsusaburo Yamagiwa and Koichi Itchikawa continued to paint the ears of rabbits with tar for many months, and were rewarded by the conclusive development of skin cancers at the site of application of the tar. By 1933, British scientists under the leadership of Ernest Kennaway isolated a pure chemical, 3,4-benzpyrene, from tar, and showed that it produced cancers at the site of application in mice. This polycyclic hydrocarbon, beautifully fluorescent under ultraviolet light, was one of a large series of chemical compounds that readily produced cancers of the skin or of the subcutaneous tissues in laboratory rodents.
Particular excitement was aroused when a powerful member of this class of compounds was made in the laboratory from desoxycholic acid, a component of bile, and it was suspected that cancers could be due to the synthesis by the body of carcinogens from cholesterol and other steroid chemicals. There are many such chemicals in the body, including sex hormones and hormones of the adrenal gland. These optimisms soon foundered because such chemicals could not be found and because many other, unrelated chemicals were added to the list of carcinogens, or cancer producing chemicals. It should be emphasized that this line of investigations is far from complete, and a return of interest can be safely predicted.
Japanese workers also introduced a series of azo dyes that on feeding to rats gave rise to liver cancers. The prolific chemists expanded the list of cancer producing chemicals to several hundred, including many of unrelated structure in so far as chemical configuration was concerned. The search for a simple relationship between chemical structure and cancer producing activity was replaced by more sophisticated investigations of the mode of action of the chemicals.
It was shown that the ubiquitous hydrocarbons could be identified in a wide variety of tars, oils, soots, and products of incomplete combustion of vegetable material such as the smoke of trash and tobacco, burnt coffee beans, and the deposits on smoke preserved meat and fish. With the aid of radioactive isotope labels in the structure of the chemicals, it was shown that they were eliminated primarily through the gastrointestinal tract. The azo dyes were eliminated from the body primarily in the urine, after metabolic changes in the liver. The compounds had the property of binding tightly with tissue proteins.
The female sex hormones, including artificial compounds with estrogenic activity such as diethylstilbestrol, produce a wide variety of cancers in rodents, at sites distant to application but in tissues that respond physiologically to these hormones. The list includes cancers of the breast, the testis, and the uterus, and an increase in the occurrence of leukemia. The reactions occur in certain inbred strains of mice and not in others, indicating the importance of the genetic background of the animal.
With crude mixtures of materials such as tars, which contain many irritating chemicals, an inflammatory reaction at the site of application is almost inevitable. With pure chemicals in small doses, however, cancers may arise without evidence of preceding inflammatory changes. Also, many irritating chemicals that destroy tissues do not possess the property of evoking cancers, thus separating the response of carcinogenesis from that of inflammation.
It was noted that tars with very small amounts of cancer producing chemicals were more effective in producing cancers than the pure chemicals themselves. This indicated the presence of other compounds in the mixture that accelerated or stimulated the reaction, and these compounds were called cocarcinogens. I. Berenblum of Israel extended this concept in a series of ingenious experiments. Mice painted just once with a powerful carcinogenic hydrocarbon did not develop cancers, but if the same skin site were painted months later with croton oil, a material usually without carcinogenic activity, cancers promptly appear. The interpretation of this finding is that the hydrocarbon produced the essential change of cells to cancer, but that the biologic completion of the process required further steps which could be evoked by different chemicals.
Another complication was introduced by studies with urethane, a simple carbamate that was found to produce lung tumors in mice. Urethane does not produce skin cancers in mice even after prolonged application to the skin or after ingestion. But if mice that are fed urethane have their skin painted with croton oil, cancers of the skin are produced. Thus, urethane is an “incomplete” carcinogen for the skin, requiring the addition of a cocarcinogen to complete its reaction.
Important contributions to the understanding of carcinogenic action have been made by two husband-wife teams of investigators, the Millers of Wisconsin, and the Weisburgers of Bethesda, working with cancer-info-producing chemicals of the azo-dye and of the fluorene type. One of the latter, 2-acetylaminofluorene, was suggested for use as an insecticide, but studies on its chronic toxicity in rats showed that it produced a wide variety of cancers. This stopped its economic development, but led to its use as a tool in cancer research.
Studies with isotopically labeled acetylaminofluorene showed that the rat converts the chemical into a hydroxylated metabolite in the liver, and that this metabolite rather than the parent compound was the active carcinogen. Guinea pigs given the compound over protracted periods failed to develop tumors, and metabolic studies showed that this species did not hydroxylate the chemical. In rats, single doses of acetylaminofluorene are ineffective in evoking cancers; the compound has to be given over a period of several weeks in order to produce carcinogenic reaction. This was elucidated by finding that the necessary enzymes in the liver for the hydroxylation of the compound are not present until the animal is exposed for some time to the compound. In effect, an enzyme had to be mobilized by the animal to meet the toxic challenge of the chemical, but this defense reaction had the harmful effect of producing metabolites that are carcinogenic.
The metabolic participation of the host in carcinogenic reaction was also demonstrated for the polycyclic hydrocarbons. When mice are given small doses of carbon tetrachloride before being injected with a carcinogenic hydrocarbon, many more tumors of the lung are produced than with the same dose of hydrocarbon alone. Carbon tetrachloride injures the liver, which is involved in the detoxification and the elimination of these compounds from the body, and in effect the animals were not able to protect themselves against the hydrocarbon.
Carcinogens, therefore, include many types of compounds that act in different, complex ways. Some produce cancers at the site of contact, perhaps by direct, specific injury to the cells. Others produce cancers at distant sites. Some require metabolic conversion for activity, others are incomplete in their action and are potentiated by still other chemicals. Still other groups of chemicals are not carcinogenic, or very weakly so, but either stimulate or complete reactions initiated by ineffective dose levels of carcinogens.
The discovery of carcinogens such as 3,4-benzpyrene led chemists to synthesize many related chemicals in order to study the relationship of chemical structure to biologic activity. Minor chemical changes in the molecule may convert an active carcinogen into a chemical that is completely devoid of this activity. It has been shown with several combinations that the simultaneous injection of a carcinogen and a closely related inactive chemical relative prevents or retards the action of the carcinogen. These may be called anticarcinogens. The interpretation of the finding is that the inactive chemical competes for the same unknown attachment groups within the cell that are required for the carcinogenic change. This line of investigations eventually may uncover chemicals that will prevent the development of cancer in individuals who are unavoidably exposed to certain cancer producing hazards, not unlike an antidote.
The availability of a wide variety of pure chemicals that produce cancer, and their analogues, has been a great boon to the cancer research workers. Under natural conditions, however, few people are exposed to pure chemicals. Such exposure is usually to mixtures and crude products, such as tar and smoke. Recently, increasing interest has been focused upon cancer producing materials in food, introduced as food additives for purposes such as food preservation, or occurring naturally.
The alkaloids of Senecio jacobaea, a plant used by African natives in diet, and chili peppers, lead to the development of liver cancers in rats. These and similar sources of cancer producing materials from plants, in association with deficient vitamin and protein intake, may play a role in the occurrence of liver cancers in Africa.
Some strains of a common mold, Aspergillus flavus, which grows on wet peanuts and corn, makes a lactone-type of compound called aflatoxin. The compound is very destructive to the livers of fowl, especially ducklings and turkeys. When fed to rats, it produces cancers of the liver. The chemical appears to be one of the more active carcinogens for the liver, producing its effects at doses of a few micrograms. Molds and bacteria growing on food products used by man may represent another source of environmental carcinogens.
Carcinogenic materials may also be the result of changes in food brought about by methods by which such food is prepared or preserved. An example of this occurred in the finding of many liver tumors in rainbow trout that were raised on food pellets of fish meal and cottonseed meal as the main constituents. The cancer producing agents have been traced to the lipid fraction, and it is suspected that this represents the production of carcinogens from the natural food sources converted by heat and other treatment during the manufacturing process.
The occurrence of cancer producing chemicals in food may be more quickly identified by the application of a novel experimental procedure recently reported from the laboratories of Charles Huggins of Chicago. Rats are fed a known cancer producing chemical of the polycyclic hydrocarbon type. At the same time, the animals are injected under the skin with presumably inert materials, such as talc. Sarcomas, a connective tissue cancer, arise at the site of the injections in rats fed the carcinogenic hydrocarbon, but not in rats that receive identical injections and are maintained on carcinogen free diet. An interpretation of the finding is that the carcinogen localizes at the site of the nonspecific injury. A similar phenomenon is seen in rabbits that are injected, into a vein, with a cancer producing Shope virus, and the opposite ear is wounded. Cancers will arise at the site of the wound, due to the localization of virus at the site. These observations may explain reports of occasional induction of cancers in animals with a variety of materials such as sugars, which often cannot be verified in other laboratories. They may also be related to reports of cancers occurring in animals maintained on diets deficient in specific vitamins. It is possible that such findings may indicate that the animals were ingesting unsuspected carcinogens during the experiment, that were exteriorized by the experimental procedure.
Interest in chemicals that produce cancer started with observations on man, and the laboratory investigations lead us back to man. In human populations, long-term exposure to pure chemicals is a relatively rare event; usually such chemicals are a part of complex mixtures, and usually the people are exposed to other complex environmental factors as well. Studies of occupational groups, or of groups exposed to unusual environmental situations because of habit or habitation, have established an impressive list of carcinogenic hazards for man.
Among the effects of industrial exposures that have been demonstrated to increase the risk to cancer are the following: bladder cancer among aniline dye workers that handle betanaphthylamine and some related chemicals; bone cancer among workers who ingest or inhale radium; lung cancer among workers who inhale chromates, radioactive ores, asbestos, and iron; cancer of the nasal sinuses and of the lung in nickel mine workers; skin cancer among workers handling distillation and fractionation products of coal, oil shale, lignite and petroleum.
Industrial settings are important sources of potentially useful information of immediate applicability to man. Unfortunately, such information is not easy to acquire because long term careful observations on groups that have considerable occupational turnover are required, and because neither management nor the employee unions are too anxious to participate in such epidemiologic studies in view of possible medicolegal complications.
Hazards to which certain occupations are exposed have more general implications to the general population of the area. Industrial wastes are discharged into the air and into the waters of the community, and represent potentially important sources of additional carcinogenic hazard.
Among the environmental, occupational cancers that are unknown in the United States is the chronic epidemic of bladder cancer in Egypt, among the peasants that toil in the waters of the Nile infested with a fluke, Schistosoma haematobium. The parasite enters the body through the skin, and eventually encysts itself in the bladder wall, producing chronic changes that may eventually terminate in cancer. Our knowledge of this important cancer producing situation is really limited to clinical descriptions, and experimental studies are badly needed. Does the parasite secrete some chemical substances, or carry a virus, to explain its relationship to. cancer? Or is this an instance of specific cocarcinogenic irritation that allows the localization in the bladder of unidentified carcinogens in the diet of the people?