Chemical Carcinogenesis

The fate of these people seems singularly hard; in their early infancy, they are most frequently treated with great brutality, and almost starved with cold and hunger; they are thrust up narrow, and sometimes hot chimnies, where they are bruised, burned, and almost suffocated; and when they get to puberty, become particularly liable to a most noisome, painful, and fatal disease.
Percivall Pott's observations on cancer of the scrotum in chimney sweeps (1775)

The first reported "chemically induced" tumors were cancers of the scrotum in chimney sweeps in England. Why the favored site was the scrotum is a mystery. Presumably, boys in England, as here, were taught to wash their hands and face, and behind their ears. Fortunately, modern methods of cleaning chimneys, which do not involve using a small boy, were devised along with the use of cleaner fuels, so that chimney sweeps' cancer is a disease of the past.

Skin tumors were also well-known in workers in the tar industry. In 1915, two scientists, Katsusaburo Yamagiwa and Koichi Ichakawa, in Japan, were able to induce skin cancer in rabbits by repeated applications of tar. They were attempting to prove the "irritation hypothesis" of the cause of cancer. The irritation hypothesis of cancer grew out of the observation that cancers often arose at sites that were subject to repeated irritation. The hypothesis has not really been discarded, but has largely been supplanted by postulating the existence of viruses, specific chemicals, and other agents that might act at sites of irritation. No one has ever clarified the role of irritation in the production of cancer, so the hypothesis remains more or less in limbo. Everyone who has attempted to prove the irritation hypothesis has ended up finding something else. In the case of the induction of skin cancer in rabbits with tar, instead of proving the irritation hypothesis, Yamagiwa and Ichakawa opened up the whole new field of chemical carcinogenesis. It was soon discovered that there were specific chemicals that acted to cause cancer, apart from their ability to produce irritation. Irritation appears to play some role in the production of cancer, but we don't know what it is.

Following the discovery that cancer could be produced with coal tar, a good deal of work was done, largely in England, in an attempt to isolate the chemicals in the tar that were responsible for the skin cancers. A wide variety of compounds have since been isolated, and a good deal of very fine research has been devoted trying to understand how these chemicals act to produce tumors. There are now close to five hundred different chemical substances that have been shown to produce cancer. The implications with regard to our environment are obvious. Many of these compounds are the products of the incomplete combustion of hydrocarbons. Some of these anthracene-derived substances have been found in tobacco smoke, automobile exhaust, and in charcoal broiled meat.

Of particular interest are certain naphthylamine compounds which were found to produce cancer in the urinary bladder of workmen employed in the synthetic dye industry. These tumors often appear many many years after initial exposure to the carcinogen (cancer causer). It was very difficult to confirm the carcinogenic effect of these compounds on the bladder because most laboratory animals proved resistant (the exception to this was the dog, which reacts similarly to men).

Another interesting crystalline compound is urethane, which is rarely (but sometimes) injected as an anesthetic in man. It produced tumors of the lung in mice and, apparently, can also produce tumors of the liver and breast, and leukemia when it is administered soon after birth.

Unless something is done to change the trends, it appears that we will be continually exposed to more and more substances that have carcinogenic properties. Hopefully, we may be able to detect the activity of at least some of these before too much damage has been done.

The United States used to have a pretty high incidence of cancer of the stomach. This has plummeted to the point where this country is now at the bottom of the list with regard to mortality from cancer of the stomach. At the top of the list, in order, we find Japan, Finland, Austria; and joining the United States at the bottom of the list are Canada, Australia, and New Zealand. There has been some association of stomach cancer with populations that eat massive amounts of smoked fish and meats (it is important here to stress the word "massive"). With the price of smoked fish and meat being what it is, it isn't surprising that consumption has gone down in this country. These things have become luxury items rather than dietary staples. The fact that workers in the smoked fish and smoked meat industry, who ate a considerable amount of smoked food, have relatively high incidence of cancer of the intestines, is no reason to stop eating ham or smoked fish, or charcoal broiling your hamburgers. We are talking about people who live on it. One would not expect the occasional consumption of active carcinogenic (cancer causing) chemicals to he particularly harmful to an individual any more than the occasional smoking of a cigarette would be. One exception to this bromide is with nitrosamines and bladder cancer, where one exposure is enough to cause cancer. However, I would certainly think twice about trying to survive exclusively on a diet of smoked oysters or smoked sturgeon, particularly when it's combined with rare vintage wines. Whoever said it was easy to he rich?

The smoked food explanation may be valid for areas of the world such as Finland, but it hardly explains the high incidence of stomach cancer in Japan, where they do not smoke their food, but salt it to preserve it.

Much has been done with the interaction of carcinogenic chemicals with other substances (cocarcinogens). A mouse can have its skin painted with a powerful carcinogenic hydrocarbon and not develop skin tumors. Months later, the skin can be painted with an irritant such as croton oil (which will not ordinarily produce cancer) and skin cancers appear. Mice that have been fed urethane (which produced lung tumors, but not skin cancer) develop skin cancer when their skin is later painted with croton oil. There is a borderline between the chemical and the viral induction of cancer. This border was crossed when Francisco Duran-Reynals found that if you paint the skin of a mouse with methylcholanthrene (a powerful carcinogen) in doses that did not produce cancer, and subsequently innoculated the area with vaccinia (the virus used in vaccination against smallpox), that cancers were produced. Perhaps it is similar phenomena to what occurs when a carcinogen and some other chemical (co-carcinogen) is used; or perhaps it is something entirely different. There are many theoretical explanations, but none have been proved.

Sometimes a chemical can be relatively harmless, but is converted into a carcinogen. An example of this is the nut of a variety of palm tree (cycas) which is used as a food in some Pacific islands. When fed to rats, the substance (cycasin) produces cancer of the kidney, brain, liver, and other organs. If the same compound is given to rats that do not have intestinal bacteria (germ-free rats), no tumors are produced. The bacteria produce an enzyme which converts the cycasin into another substance called aglycone, and it is this substance that produced the cancer.

Advocates of the virus theory attempt to explain chemical carcinogenesis by saying that the chemical activates a virus. However, in terms of what we know about the behavior of viruses to date, there is no real indication that this explanation has any validity.

No one has figured out how chemical substances produce cancer. There has been much superb research done in an attempt to explain their action. Several carefully thought-out theories have been proposed, and some are still hanging fire.

Three years ago a new dimension was added to the production of cancer with chemicals. This new dimension is the product of cancer in the children of mothers treated with a chemical during pregnancy. About twenty-five years ago the treatment fad for high-risk pregnancies (these are women who started bleeding early in pregnancy and presented the possibility that they might lose their child) was the administration of massive doses of stilbestrol (a relatively long-acting synthetic female hormone). Some twenty years after these hormones were administered eight young women, between 15 and 22 years of age, were found to have developed cancer of the vagina (at one hospital). Cancer of the vagina is a relatively rare form of cancer, and is almost unheard of in women in that age group. This led to a complete study in which the mothers of these children were interviewed in an attempt to find out what they had in common. It turned out, with only one exception, that the mothers of these young women with cancer of the vagina had been given stilbestrol early in their pregnancy. The physicians who did this study pointed out that the risk to a girl whose mother was treated with high-dose stilbestrol during pregnancy is a small one. The oldest female offspring of women treated with stilbestrol could not be over 28 years of age at this writing.

Perhaps someone will locate all of the offspring of women who have been given this hormone in their pregnancy and will find out what is happening to them. These cancers, if caught in time, appear to be curable. Like irradiation of the thymus in infants, which causes leukemia and cancer of the thyroid, this iatrogenic (physician produced) cancer marches on. It has been said that the road to hell is paved with good intentions. It is a pity that the hell is undergone, not by those with the good intentions, but by their victims. The medical dark ages are not in the past; they are still with us.

(To young ladies whose motbers took stilbestrol early in pregnancy: There is little need to be frightened, because the probability of your developing cancer of the vagina is very small. Considering the large number of women who took stilbestrol early in pregnancy, the number of cases of cancer of the vagina represents an extremely small fraction. There are, however, a few precautions that are worth taking that will insure that, if you are one of the few who will develop cancer, the cancer will not be fatal. You should have an annual examination, including a Pap smear. Any vaginal bleeding occurring between menstrual periods should result in a very careful checkup. Any lumps in the wall of the vagina should be surgically removed. While there are not much data, the small bit of information that we have indicates that these cancers are curable by surgery.)

Every time that an article appears in a newspaper or magazine that talks about cancer-causing substances in food many people panic. The question arises, Should I eat broiled meat because it contains known chemical carcinogens? By the same token, Should I go out in the sun, because I know that sunlight causes skin cancer? Our world is full of cancer-causing substances, and there is no way that I know of to avoid all of them. The saving grace is that every chemical known to cause cancer has a dose effect; that is, the number of cancers increases with the dose of the substance. The same thing applies to ionizing radiation (see chapter "Radiation and Cancer.") The only way that I know of to protect oneself against carcinogens in food is to vary diet so that you are not subsisting entirely on charcoal-broiled steaks, or entirely on smoked meat or fish. The human body will tolerate small doses of almost anything. The risk of being killed in an automobile is considerably greater than the risk of dying of cancer of the intestine due to the ingestion of charcoal-broiled steaks.

There seems to be little that can be done about cancerophobia. Some of the victims of this disease would sooner commit suicide than run the risk of dying of cancer. By the time you take away all of the cancer-causing substances, there is little in life to make it worth living. There is, however, little point in taking unnecessary risks. By unnecessary risks I would include fanatical sun worshiping, living on diet soft drinks, subsisting on a diet of smoked fish and meat, eating charcoal-broiled steaks for breakfast, lunch, and dinner, subjecting ones self to unnecessary x-rays, and, the most dangerous hazard of all, inhaling large amounts of cigarette smoke. It is also a good idea to do everything that can be done to keep our environment as free of carcinogens as we can.

A word should be said about what the statisticians call "competing risk." I can explain what is meant by competing risk by an example: It comes from a friend of mine who developed a sure method of winning at roulette. In the game of roulette, the probability of a ball falling in a black or a red slot is 50:50. In other words, the probability of winning is approximately the same as the probability of loosing in any turn of the wheel, provided that you play black or red. This fellow had a foolproof system: He would play black or red and he would play a dollar each time. If he won, he would keep the dollar and play another dollar. Suppose, however, that he lost. He would then play two dollars, and if he won, the extra dollar would pay for his previous loss and the next dollar would be a win. If he lost again, he would double up again and continue with the same procedure. Obviously, he couldn't lose, with one possible exception: A string of continuous losses could break him. This is where the competing risk comes in: If he goes broke before he wins the amount of money he has set out to win, then he has essentially lost the game. The probability of his going broke before he broke the bank is extremely high, particularly if the amount of capital he started out with was smaller than the amount of capital that the bank started out with.

Another example is a woman, age 80, who is surgically treated for breast cancer. The probability of her dying of something else before cancer reoccurs is extremely high. The same thing is true of cancer and heart disease in a heavy smoker. The chances of his dying of heart disease are reduced by the chances of dying of lung cancer before he gets heart disease and, in turn, the chances of his dying of lung cancer are reduced because of the chances of his dying of heart disease first.

I put this paragraph on competing risks into this chapter instead of the one on statistics because I think that it is more applicable here. Assuming that a small amount of any carcinogen would increase your chances of dying of cancer of the stomach, you have to consider the probability of your dying of something long before the effect of the carcinogen gets you. Examples of some relative risks would be as follows: (1) The probability in a heavy smoker of his dying of lung cancer is greater than the probability of his dying in an automobile accident. In a nonsmoker, the probability of dying in an automobile accident is greater than the probability of dying of lung cancer. (2) In a motorcycle rider, the probability of dying accidentally is greater than the probability of dying of cancer (if you have treatable leukemia you can reduce your chances of dying of leukemia by riding a motorcycle). (3) For a student airplane pilot, the chances of his dying of cancer are less than his chances of dying accidentally. (4) The chances of someone living in Africa dying of cancer are less than the chances of someone living in the United States dying of cancer. (5) The chances of someone living in Africa dying of malaria are greater than the chances of someone living in the United States dying of malaria.

In other words, it is only if you intend to live forever that small doses of carcinogen are worth worrying about.

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