14. One In Every Four
THE BATTLE of living things against cancer began so long ago that its origin is lost in time. But it must have begun in a natural environment, in which whatever life inhabited the earth was subjected, for good or ill, to influences that had their origin in sun and storm and the ancient nature of the earth. Some of the elements of this environment created hazards to which life had to adjust or perish. The ultraviolet radiation in sunlight could cause malignancy. So could radiations from certain rocks, or arsenic washed out of soil or rocks to contaminate food or water supplies.
The environment contained these hostile elements even before there was life; yet life arose, and over the millions of years it came to exist in infinite numbers and endless variety. Over the eons of unhurried time that is nature's, life reached an adjustment with destructive forces as selection weeded out the less adaptable and only the most resistant survived. These natural cancer-causing agents are still a factor in producing malignancy; however, they are few in number and they belong to that ancient array of forces to which life has been accustomed from the beginning.
With the advent of man the situation began to change, for man, alone of all forms of life, can create cancer-producing substances, which in medical terminology are called carcinogens. A few man-made carcinogens have been part of the environment for centuries. An example is soot, containing aromatic hydrocarbons. With the dawn of the industrial era the world became a place of continuous, ever-accelerating change. Instead of the natural environment there was rapidly substituted an artificial one composed of new chemical and physical agents, many of them possessing powerful capacities for inducing biologic change. Against these carcinogens which his own activities had created man had no protection, for even as his biological heritage has evolved slowly, so it adapts slowly to new conditions. As a result these powerful substances could easily penetrate the inadequate defenses of the body.
The history of cancer is long, but our recognition of the agents that produce it has been slow to mature. The first awareness that external or environmental agents could produce malignant change dawned in the mind of a London physician nearly two centuries ago. In 1775 Sir Percivall Pott declared that the scrotal cancer so common among chimney sweeps must be caused by the soot that accumulated on their bodies. He could not furnish the "proof" we would demand today, but modern research methods have now isolated the deadly chemical in soot and proved the correctness of his perception.
For a century or more after Pott's discovery there seems to have been little further realization that certain of the chemicals in the human environment could cause cancer by repeated skin contact, inhalation, or swallowing. True, it had been noticed that skin cancer was prevalent among workers exposed to arsenic fumes in copper smelters and tin foundries in Cornwall and Wales. And it was realized that workers in the cobalt mines in Saxony and in the uranium mines at Joachimsthal in Bohemia were subject to a disease of the lungs, later identified as cancer. But these were phenomena of the pre-industrial era, before the flowering of the industries whose products were to pervade the environment of almost every living thing.
The first recognition of malignancies traceable to the age of industry came during the last quarter of the 19th century. About the time that Pasteur was demonstrating the microbial origin of many infectious diseases, others were discovering the chemical origin of cancer -- skin cancers among workers in the new lignite industry in Saxony and in the Scottish shale industry, along with other cancers caused by occupational exposure to tar and pitch. By the end of the 19th century a half-dozen sources of industrial carcinogens were known; the 20th century was to create countless new cancer-causing chemicals and to bring the general population into intimate contact with them. In the less than two centuries intervening since the work of Pott, the environmental situation has been vastly changed. No longer are exposures to dangerous chemicals occupational alone; they have entered the environment of everyone -- even of children as yet unborn. It is hardly surprising, therefore, that we are now aware of an alarming increase in malignant disease.
The increase itself is no mere matter of subjective impressions. The monthly report of the Office of Vital Statistics for July 1959 states that malignant growths, including those of the lymphatic and blood-forming tissues, accounted for 15 per cent of the deaths in 1958 compared with only 4 per cent in 1900. Judging by the present incidence of the disease, the American Cancer Society estimates that 45,000,000 Americans now living will eventually develop cancer. This means that malignant disease will strike two out of three families.
The situation with respect to children is even more deeply disturbing. A quarter century ago, cancer in children was considered a medical rarity. Today, more American school children die of cancer than from any other disease. So serious has this situation become that Boston has established the first hospital in the United States devoted exclusively to the treatment of children with cancer. Twelve per cent of all deaths in children between the ages of one and fourteen are caused by cancer. Large numbers of malignant tumors are discovered clinically in children under the age of five, but it is an even grimmer fact that significant numbers of such growths are present at or before birth. Dr. W. C. Hueper of the National Cancer Institute, a foremost authority on environmental cancer, has suggested that congenital cancers and cancers in infants may be related to the action of cancer-producing agents to which the mother has been exposed during pregnancy and which penetrate the placenta to act on the rapidly developing fetal tissues. Experiments show that the younger the animal is when it is subjected to a cancer-producing agent the more certain is the production of cancer. Dr. Francis Ray of the University of Florida has warned that "we may be initiating cancer in the children of today by the addition of chemicals [to food] ... We will not know, perhaps for a generation or two, what the effects will be."
The problem that concerns us here is whether any of the chemicals we are using in our attempts to control nature play a direct or indirect role as causes of cancer. In terms of evidence gained from animal experiments we shall see that five or possibly six of the pesticides must definitely be rated as carcinogens. The list is greatly lengthened if we add those considered by some physicians to cause leukemia in human patients. Here the evidence is circumstantial, as it must be since we do not experiment on human beings, but it is nonetheless impressive. Still other pesticides will be added as we include those whose action on living tissues or cells may he considered an indirect cause of malignancy.
One of the earliest pesticides associated with cancer is arsenic, occurring in sodium arsenite as a weed killer, and in calcium arsenate and various other compounds as insecticides. The association between arsenic and cancer in man and animals is historic. A fascinating example of the consequences of exposure to arsenic is related by Dr. Hueper in his Occupational Tumors, a classic monograph on the subject. The city of Reichenstein in Silesia had been for almost a thousand years the site of mining for gold and silver ores, and for several hundred years for arsenic ores. Over the centuries arsenic wastes accumulated in the vicinity of the mine shafts and were picked up by streams coming down from the mountains. The underground water also became contaminated, and arsenic entered the drinking water. For centuries many of the inhabitants of this region suffered from what came to be known as "the Reichenstein disease" chronic arsenicism with accompanying disorders of the liver, skin, and gastrointestinal and nervous systems. Malignant tumors were a common accompaniment of the disease. Reichenstein's disease is now chiefly of historic interest, for new water supplies were provided a quarter of a century ago, from which arsenic was largely eliminated. In Cordoba Province in Argentina, however, chronic arsenic poisoning, accompanied by arsenical skin cancers, is endemic because of the contamination of drinking water derived from rock formations containing arsenic.
It would not be difficult to create conditions similar to those in Reichenstein and Cordoba by long continued use of arsenical insecticides. In the United States the arsenic-drenched soils of tobacco plantations, of many orchards in the Northwest, and of blueberry lands in the East may easily lead to pollution of water supplies.
An arsenic-contaminated environment affects not only man but animals as well. A report of great interest came from Germany in 1936. In the area about Freiberg, Saxony, smelters for silver and lead poured arsenic fumes into the air, to drift out over the surrounding countryside and settle down upon the vegetation. According to Dr. Hueper, horses, cows, goats, and pigs, which of course fed on this vegetation, showed loss of hair and thickening of the skin. Deer inhabiting nearby forests sometimes had abnormal pigment spots and precancerous warts. One had a definitely cancerous lesion. Both domestic and wild animals were affected by "arsenical enteritis, gastric ulcers, and cirrhosis of the liver." Sheep kept near the smelters developed cancers of the nasal sinus; at their death arsenic was found in the brain, liver, and tumors. In the area there was also "an extraordinary mortality among insects, especially bees. After rainfalls which washed the arsenical dust from the leaves and carried it along into the water of brooks and pools, a great many fish died."
An example of a carcinogen belonging to the group of new, organic pesticides is a chemical widely used against mites and ticks. Its history provides abundant proof that, despite the supposed safeguards provided by legislation, the public can be exposed to a known carcinogen for several years before the slowly moving legal processes can bring the situation under control. The story is interesting from another standpoint, proving that what the public is asked to accept as "safe" today may turn out tomorrow to be extremely dangerous.
When this chemical was introduced in 1955, the manufacturer applied for a tolerance which would sanction the presence of small residues on any crops that might be sprayed. As required by law, he had tested the chemical on laboratory animals and submitted the results with his application. However, scientists of the Food and Drug Administration interpreted the tests as showing a possible cancer-producing tendency and the Commissioner accordingly recommended a "zero tolerance," which is a way of saying that no residues could legally occur on food shipped across state lines. But the manufacturer had the legal right to appeal and the case was accordingly reviewed by a committee. The committee's decision was a compromise: a tolerance of 1 part per million was to be established and the product marketed for two years, during which time further laboratory tests were to determine whether the chemical was actually a carcinogen.
Although the committee did not say so, its decision meant that the public was to act as guinea pigs, testing the suspected carcinogen along with the laboratory dogs and rats. But laboratory animals give more prompt results, and after the two years it was evident that this miticide was indeed a carcinogen. Even at that point, in 1957, the Food and Drug Administration could not instantly rescind the tolerance which allowed residues of a known carcinogen to contaminate food consumed by the public. Another year was required for various legal procedures. Finally, in December 1958 the zero tolerance which the Commissioner had recommended in 1955 became effective.
These are by no means the only known carcinogens among pesticides. In laboratory tests on animal subjects, DDT has produced suspicious liver tumors. Scientists of the Food and Drug Administration who reported the discovery of these tumors were uncertain how to classify them, but felt there was some "justification for considering them low grade hepatic cell carcinomas." Dr. Hueper now gives DDT the definite rating of a "chemical carcinogen."
Two herbicides belonging to the carbamate group, IPC and CIPC, have been found to play a role in producing skin tumors in mice. Some of the tumors were malignant. These chemicals seem to initiate the malignant change, which may then be completed by other chemicals of types prevalent in the environment.
The weed-killer aminotriazole has caused thyroid cancer in test animals. This chemical was misused by a number of cranberry growers in 1959, producing residues on some of the marketed berries. In the controversy that followed seizure of contaminated cranberries by the Food and Drug Administration, the fact that the chemical actually is cancer producing was widely challenged, even by many medical men. The scientific facts released by the Food and Drug Administration clearly indicate the carcinogenic nature of aminotriazole in laboratory rats. When these animals were fed this chemical at the rate of 100 parts per million in the drinking water (or one teaspoonful of chemical in ten thousand teaspoonfuls of water) they began to develop thyroid tumors at the 68th week. After two years, such tumors were present in more than half the rats examined. They were diagnosed as various types of benign and malignant growths. The tumors also appeared at lower levels of feeding -- in fact, a level that produced no effect was not found. No one knows, of course, the level at which aminotriazole may be carcinogenic for man, but as a professor of medicine at Harvard University, Dr. David Rutstein, has pointed out, the level is just as likely to be to man's disfavor as to his advantage.
As yet insufficient time has elapsed to reveal the full effect of the new chlorinated hydrocarbon insecticides and of the modern herbicides. Most malignancies develop so slowly that they may require a considerable segment of the victim's life to reach the stage of showing clinical symptoms. In the early 1920's women who painted luminous figures on watch dials swallowed minute amounts of radium by touching the brushes to their lips; in some of these women bone cancers developed after a lapse of 15 or more years. A period of 15 to 30 years or even more has been demonstrated for some cancers caused by occupational exposures to chemical carcinogens.
In contrast to these industrial exposures to various carcinogens the first exposures to DDT date from about 1942 for military personnel and from about 1945 for civilians, and it was not until the early fifties that a wide variety of pesticidal chemicals came into use. The full maturing of whatever seeds of malignancy have been sown by these chemicals is yet to come.
There is, however, one presently known exception to the fact that a long period of latency is common to most malignancies. This exception is leukemia. Survivors of Hiroshima began to develop leukemia only three years after the atomic bombing, and there is now reason to believe the latent period may be considerably shorter. Other types of cancer may in time be found to have a relatively short latent period, also, but at present leukemia seems to be the exception to the general rule of extremely slow development.
Within the period covered by the rise of modern pesticides, the incidence of leukemia has been steadily rising. Figures available from the National Office of Vital Statistics clearly establish a disturbing rise in malignant diseases of the blood-forming tissues. In the year 1960, leukemia alone claimed 12,290 victims. Deaths from all types of malignancies of blood and lymph totaled 25,400, increasing sharply from the 16,690 figure of 1950. In terms of deaths per 100,000 of population, the increase is from 11.1 in 1950 to 14.1 in 1960. The increase is by no means confined to the United States; in all countries the recorded deaths from leukemia at all ages are rising at a rate of 4 to 5 per cent a year. What does it mean? To what lethal agent or agents, new to our environment, are people now exposed with increasing frequency?
Such world-famous institutions as the Mayo Clinic admit hundreds of victims of these diseases of the blood-forming organs. Dr. Malcolm Hargraves and his associates in the Hematology Department at the Mayo Clinic report that almost without exception these patients have had a history of exposure to various toxic chemicals, including sprays which contain DDT, chlordane, benzene, lindane, and petroleum distillates.
Environmental diseases related to the use of various toxic substances have been increasing, "particularly during the past ten years," Dr. Hargraves believes. From extensive clinical experience he believes that "the vast majority of patients suffering from the blood dyscrasias and lymphoid diseases have a significant history of exposure to the various hydrocarbons which in turn includes most of the pesticides of today. A careful medical history will almost invariably establish such a relationship." This specialist now has a large number of detailed case histories based on every patient he has seen with leukemias, aplastic anemias, Hodgkin's disease, and other disorders of the blood and blood-forming tissues. "They had all been exposed to these environmental agents, with a fair amount of exposure," he reports.
What do these case histories show? One concerned a housewife who abhorred spiders. In mid-August she had gone into her basement with an aerosol spray containing DDT and petroleum distillate. She sprayed the entire basement thoroughly, under the stairs, in the fruit cupboards and in all the protected areas around ceiling and rafters. As she finished the spraying she began to feel quite ill, with nausea and extreme anxiety and nervousness. Within the next few days she felt better, however, and apparently not suspecting the cause of her difficulty, she repeated the entire procedure in September, running through two more cycles of spraying, falling ill, recovering temporarily, spraying again. After the third use of the aerosol new symptoms developed: fever, pains in the joints and general malaise, acute phlebitis in one leg. When examined by Dr. Hargraves she was found to be suffering from acute leukemia. She died within the following month.
Another of Dr. Hargraves' patients was a professional man who had his office in an old building infested by roaches. Becoming embarrassed by the presence of these insects, he took control measures in his own hands. He spent most of one Sunday spraying the basement and all secluded areas. The spray was a 25 per cent DDT concentrate suspended in a solvent containing methylated naphthalenes. Within a short time he began to bruise and bleed. He entered the clinic bleeding from a number of hemorrhages. Studies of his blood revealed a severe depression of the bone marrow called aplastic anemia. During the next five and one half months he received 59 transfusions in addition to other therapy. There was partial recovery but about nine years later a fatal leukemia developed.
Where pesticides are involved, the chemicals that figure most prominently in the case histories are DDT, lindane, benzene hexachloride, the nitrophenols, the common moth crystal paradichlorobenzene, chlordane, and, of course, the solvents in which they are carried. As this physician emphasizes, pure exposure to a single chemical is the exception, rather than the rule. The commercial product usually contains combinations of several chemicals, suspended in a petroleum distillate plus some dispersing agent. The aromatic cyclic and unsaturated hydrocarbons of the vehicle may themselves be a major factor in the damage done the blood-forming organs. From the practical rather than the medical standpoint this distinction is of little importance, however, because these petroleum solvents are an inseparable part of most common spraying practices.
The medical literature of this and other countries contains many significant cases that support Dr. Hargraves' belief in a cause-and-effect relation between these chemicals and leukemia and other blood disorders. They concern such everyday people as farmers caught in the "fallout" of their own spray rigs or of planes, a college student who sprayed his study for ants and remained in the room to study, a woman who had installed a portable lindane vaporizer in her home, a worker in a cotton field that had been sprayed with chlordane and toxaphene. They carry, half concealed within their medical terminology, stories of such human tragedies as that of two young cousins in Czechoslovakia, boys who lived in the same town and had always worked and played together. Their last and most fateful employment was at a farm cooperative where it was their job to unload sacks of an insecticide (benzene hexachloride). Eight months later one of the boys was stricken with acute leukemia. In nine days he was dead. At about this time his cousin began to tire easily and to run a temperature. Within about three months his symptoms became more severe and he, too, was hospitalized. Again the diagnosis was acute leukemia, and again the disease ran its inevitably fatal course.
And then there is the case of a Swedish farmer, strangely reminiscent of that of the Japanese fisherman Kuboyama of the tuna vessel the Lucky Dragon. Like Kuboyama, the farmer had been a healthy man, gleaning his living from the land as Kuboyama had taken his from the sea. For each man a poison drifting out of the sky carried a death sentence. For one, it was radiation-poisoned ash; for the other, chemical dust. The farmer had treated about 60 acres of land with a dust containing DDT and benzene hexachloride. As he worked puffs of wind brought little clouds of dust swirling about him. "In the evening he felt unusually tired, and during the subsequent days he had a general feeling of weakness, with backache and aching legs as well as chills, and was obliged to take to his bed," says a report from the Medical Clinic at Lund. "His condition became worse, however, and on May 19 [a week after the spraying] he applied for admission to the local hospital." He had a high fever and his blood count was abnormal. He was transferred to the Medical Clinic, where, after an illness of two and one half months, he died. A post-mortem examination revealed a complete wasting away of the bone marrow.
How a normal and necessary process such as cell division can become altered so that it is alien and destructive is a problem that has engaged the attention of countless scientists and untold sums of money. What happens in a cell to change its orderly multiplication into the wild and uncontrolled proliferation of cancer?
When answers are found they will almost certainly be multiple. Just as cancer itself is a disease that wears many guises, appearing in various forms that differ in their origin, in the course of their development, and in the factors that influence their growth or regression, so there must be a corresponding variety of causes. Yet underlying them all, perhaps, only a few basic kinds of injuries to the cell are responsible. Here and there, in research widely scattered and sometimes not undertaken as a cancer study at all, we see glimmerings of the first light that may one day illuminate this problem.
Again we find that only by looking at some of the smallest units of life, the cell and its chromosomes, can we find that wider vision needed to penetrate such mysteries. Here, in this microcosm, we must look for those factors that somehow shift the marvelously functioning mechanisms of the cell out of their normal patterns.
One of the most impressive theories of the origin of cancer cells was developed by a German biochemist, Professor Otto Warburg of the Max Planck Institute of Cell Physiology. Warburg has devoted a lifetime of study to the complex processes of oxidation within the cell. Out of this broad background of understanding came a fascinating and lucid explanation of the way a normal cell can become malignant.
Warburg believes that either radiation or a chemical carcinogen acts by destroying the respiration of normal cells, thus depriving them of energy. This action may result from minute doses often repeated. The effect, once achieved, is irreversible. The cells not killed outright by the impact of such a respiratory poison struggle to compensate for the loss of energy. They can no longer carry on that extraordinary and efficient cycle by which vast amounts of ATP are produced, but are thrown back on a primitive and far less efficient method, that of fermentation. The struggle to survive by fermentation continues for a long period of time. It continues through ensuing cell divisions, so that all the descendant cells have this abnormal method of respiration. Once a cell has lost its normal respiration it cannot regain it -- not in a year, not in a decade or in many decades. But little by little, in this grueling struggle to restore lost energy, those cells that survive begin to compensate by increased fermentation. It is a Darwinian struggle, in which only the most fit or adaptable survive. At last they reach the point where fermentation is able to produce as much energy as respiration. At this point, cancer cells may be said to have been created from normal body cells.
Warburg's theory explains many otherwise puzzling things. The long latent period of most cancers is the time required for the infinite number of cell divisions during which fermentation is gradually increasing after the initial damage to respiration. The time required for fermentation to become dominant varies in different species because of different fermentation rates: a short time in the rat, in which cancers appear quickly, a long time (decades even) in man, in whom the development of malignancy is a deliberate process.
The Warburg theory also explains why repeated small doses of a carcinogen are more dangerous under some circumstances than a single large dose. The latter may kill the cells outright, whereas the small doses allow some to survive, though in a damaged condition. These survivors may then develop into cancer cells. This is why there is no "safe" dose of a carcinogen.
In Warburg's theory we also find explanation of an otherwise incomprehensible fact -- that one and the same agent can be useful in treating cancer and can also cause it. This, as everyone knows, is true of radiation, which kills cancer cells bur may also cause cancer. It is also true of many of the chemicals now used against cancer. Why? Both types of agents damage respiration. Cancer cells already have a defective respiration, so with additional damage they die. The normal cells, suffering respiratory damage for the first time, are not killed but are set on the path that may eventually lead to malignancy.
Warburg's ideas received confirmation in 1953 when other workers were able to turn normal cells into cancer cells merely by depriving them of oxygen intermittently over long periods. Then in 1961 other confirmation came, this time from living animals rather than tissue cultures. Radioactive tracer substances were injected into cancerous mice. Then by careful measurements of their respiration, it was found that the fermentation rate was markedly above normal just as Warburg had foreseen.
Measured by the standards established by Warburg, most pesticides meet the criterion of the perfect carcinogen too well for comfort. As we have seen in the preceding chapter, many of the chlorinated hydrocarbons, the phenols, and some herbicides interfere with oxidation and energy production within the cell. By these means they may be creating sleeping cancer cells, cells in which an irreversible malignancy will slumber long and undetected until finally -- its cause long forgotten and even unsuspected -- it flares into the open as recognizable cancer.
Another path to cancer may be by way of the chromosomes. Many of the most distinguished research men in this field look with suspicion on any agent that damages the chromosomes, interferes with cell division, or causes mutations. In the view of these men any mutation is a potential cause of cancer. Although discussions of mutations usually refer to those in the germ cells, which may then make their effect felt in future generations, there may also be mutations in the body cells. According to the mutation theory of the origin of cancer, a cell, perhaps under the influence of radiation or of a chemical, develops a mutation that allows it to escape the controls the body normally asserts over cell division. It is therefore able to multiply in a wild and unregulated manner. The new cells resulting from these divisions have the same ability to escape control, and in time enough such cells have accumulated to constitute a cancer.
Other investigators point to the fact that the chromosomes in cancer tissue are unstable; they tend to be broken or damaged, the number may be erratic, there may even be double sets.
The first investigators to trace chromosome abnormalities all the way to actual malignancy were Albert Levan and John J. Biesele, working at the Sloan-Kettering Institute in New York. As to which came first, the malignancy or the disturbance of the chromosomes, these workers say without hesitation that "the chromosomal irregularities precede the malignancy." Perhaps, they speculate, after the initial chromosome damage and the resulting instability there is a long period of trial and error through many cell generations (the long latent period of malignancy) during which a collection of mutations is finally accumulated which allow the cells to escape from control and embark on the unregulated multiplication that is cancer.
Ojvind Winge, one of the early proponents of the theory of chromosome instability, felt that chromosome doublings were especially significant. Is it coincidence, then, that benzene hexachloride and its relative, lindane, are known through repeated observations to double the chromosomes in experimental plants -- and that these same chemicals have been implicated in many well-documented cases of fatal anemias? And what of the many other pesticides that interfere with cell division, break chromosomes, cause mutations?
It is easy to see why leukemia should be one of the most common diseases to result from exposure to radiation or to chemicals that imitate radiation. The principal targets of physical or chemical mutagenic agents are cells that are undergoing especially active division. This includes various tissues but most importantly those engaged in the production of blood. The bone marrow is the chief producer of red blood cells throughout life, sending some 10 million new cells per second into the bloodstream of man. White corpuscles are formed in the lymph glands and in some of the marrow cells at a variable, but still prodigious, rate.
Certain chemicals, again reminding us of radiation products like Strontium 90, have a peculiar affinity for the bone marrow. Benzene, a frequent constituent of insecticidal solvents, lodges in the marrow and remains deposited there for periods known to be as long as 20 months. Benzene itself has been recognized in medical literature for many years as a cause of leukemia.
The rapidly growing tissues of a child would also afford conditions most suitable for the development of malignant cells. Sir Macfarlane Burnet has pointed out that not only is leukemia increasing throughout the world but it has become most common in the three-to four-year age bracket, an age incidence shown by no other disease. According to this authority, "The peak between three and four years of age can hardly have any other interpretation than exposure of the young organism to a mutagenic stimulus around the time of birth."
Another mutagen known to produce cancer is urethane. When pregnant mice are treated with this chemical not only do they develop cancer of the lung but their young do, also. The only exposure of the infant mice to urethane was prenatal in these experiments, proving that the chemical must have passed through the placenta. In human populations exposed to urethane or related chemicals there is a possibility that tumors will develop in infants through prenatal exposure, as Dr. Hueper has warned.
Urethane as a carbamate is chemically related to the herbicides IPC and CIPC. Despite the warnings of cancer experts, carbamates are now widely used, not only as insecticides, weed killers, and fungicides, but also in a variety of products including plasticizers, medicines, clothing, and insulating materials.
The road to cancer may also be an indirect one. A substance that is not a carcinogen in the ordinary sense may disturb the normal functioning of some part of the body in such a way that malignancy results. Important examples are the cancers, especially of the reproductive system, that appear to be linked with disturbances of the balance of sex hormones; these disturbances, in turn, may in some cases be the result of something that affects the ability of the liver to preserve a proper level of these hormones. The chlorinated hydrocarbons are precisely the kind of agent that can bring about this kind of indirect carcinogenesis, because all of them are toxic in some degree to the liver.
The sex hormones are, of course, normally present in the body and perform a necessary growth-stimulating function in relation to the various organs of reproduction. But the body has a built-in protection against excessive accumulations, for the liver acts to keep a proper balance between male and female hormones (both are produced in the bodies of both sexes, although in different amounts) and to prevent an excess accumulation of either. It cannot do so, however, if it has been damaged by disease or chemicals, or if the supply of the B-complex vitamins has been reduced. Under these conditions the estrogens build up to abnormally high levels.
What are the effects? In animals, at least, there is abundant evidence from experiments. In one such, an investigator at the Rockefeller Institute for Medical Research found that rabbits with livers damaged by disease show a very high incidence of uterine tumors, thought to have developed because the liver was no longer able to inactivate the estrogens in the blood, so that they "subsequently rose to a carcinogenic level." Extensive experiments on mice, rats, guinea pigs, and monkeys show that prolonged administration of estrogens (not necessarily at high levels) has caused changes in the tissues of the reproductive organs, "varying from benign overgrowths to definite malignancy." Tumors of the kidneys have been induced in hamsters by administering estrogens.
Although medical opinion is divided on the question, much evidence exists to support the view that similar effects may occur in human tissues. Investigators at the Royal Victoria Hospital at McGill University found two thirds of 150 cases of uterine cancer studied by them gave evidence of abnormally high estrogen levels. In 90 percent of a later series of 20 cases there was similar high estrogen activity.
It is possible to have liver damage sufficient to interfere with estrogen elimination without detection of the damage by any tests now available to the medical profession. This can easily be caused by the chlorinated hydrocarbons, which, as we have seen, set up changes in liver cells at very low levels of intake. They also cause loss of the B vitamins. This, too, is extremely important, for other chains of evidence show the protective role of these vitamins against cancer. The late C. P. Rhoads, one-time director of the Sloan-Kettering Institute for Cancer Research, found that test animals exposed to a very potent chemical carcinogen developed no cancer if they had been fed yeast, a rich source of the natural B vitamins. A deficiency of these vitamins has been found to accompany mouth cancer and perhaps cancer of other sites in the digestive tract. This has been observed not only in the United States but in the far northern parts of Sweden and Finland, where the diet is ordinarily deficient in vitamins. Groups prone to primary liver cancer, as for example the Bantu tribes of Africa, are typically subject to malnutrition. Cancer of the male breast is also prevalent in parts of Africa, associated with liver disease and malnutrition. In postwar Greece enlargement of the male breast was a common accompaniment of periods of starvation.
In brief, the argument for the indirect role of pesticides in cancer is based on their proven ability to damage the liver and to reduce the supply of B vitamins, thus leading to an increase in the "endogenous" estrogens, or those produced by the body itself. Added to these are the wide variety of synthetic estrogens to which we are increasingly exposed -- those in cosmetics, drugs, foods, and occupational exposures. The combined effect is a matter that warrants the most serious concern.
Human exposures to cancer-producing chemicals (including pesticides) are uncontrolled and they are multiple. An individual may have many different exposures to the same chemical. Arsenic is an example. It exists in the environment of every individual in many different guises: as an air pollutant, a contaminant of water, a pesticide residue on food, in medicines, cosmetics, wood preservatives, or as a coloring agent in paints and inks. It is quite possible that no one of these exposures alone would be sufficient to precipitate malignancy -- yet any single supposedly "safe dose" may be enough to tip the scales that are already loaded with other "safe doses."
Or again the harm may be done by two or more different carcinogens acting together, so that there is a summation of their effects. The individual exposed to DDT, for example, is almost certain to be exposed to other liver-damaging hydrocarbons, which are so widely used as solvents, paint removers, degreasing agents, dry-cleaning fluids, and anesthetics. What then can be a "safe dose" of DDT?
The situation is made even more complicated by the fact that one chemical may act on another to alter its effect. Cancer may sometimes require the complementary action of two chemicals, one of which sensitizes the cell or tissue so that it may later, under the action of another or promoting agent, develop true malignancy. Thus, the herbicides IPC and CIPC may act as initiators in the production of skin tumors, sowing the seeds of malignancy that may be brought into actual being by something else -- perhaps a common detergent.
There may be interaction, too, between a physical and a chemical agent. Leukemia may occur as a two-step process, the malignant change being initiated by X-radiation, the promoting action being supplied by a chemical, as, for example, urethane. The growing exposure of the population to radiation from various sources, plus the many contacts with a host of chemicals suggest a grave new problem for the modern world.
The pollution of water supplies with radioactive materials poses another problem. Such materials, present as contaminants in water that also contains chemicals, may actually change the nature of the chemicals by the impact of ionizing radiation, rearranging their atoms in unpredictable ways to create new chemicals.
Water pollution experts throughout the United States are concerned by the fact that detergents are now a troublesome and practically universal contaminant of public water supplies. There is no practical way to remove them by treatment. Few detergents are known to be carcinogenic, but in an indirect way they may promote cancer by acting on the lining of the digestive tract, changing the tissues so that they more easily absorb dangerous chemicals, thereby aggravating their effect. But who can foresee and control this action? In the kaleidoscope of shifting conditions, what dose of a carcinogen can be "safe" except a zero dose?
We tolerate cancer-causing agents in our environment at our peril, as was clearly illustrated by a recent happening. In the spring of 1961 an epidemic of liver cancer appeared among rainbow trout in many federal, state, and private hatcheries. Trout in both eastern and western parts of the United States were affected; in some areas practically 100 percent of the trout over three years of age developed cancer. This discovery was made because of a pre-existing arrangement between the Environmental Cancer Section of the National Cancer Institute and the Fish and Wildlife Service for the reporting of all fish with tumors, so that early warning might be had of a cancer hazard to man from water contaminants.
Although studies are still under way to determine the exact cause of this epidemic over so wide an area, the best evidence is said to point to some agent present in the prepared hatchery feeds. These contain an incredible variety of chemical additives and medicinal agents in addition to the basic foodstuffs.
The story of the trout is important for many reasons, but chiefly as an example of what can happen when a potent carcinogen is introduced into the environment of any species. Dr. Hueper has described this epidemic as a serious warning that greatly increased attention must be given to controlling the number and variety of environmental carcinogens. "If such preventive measures are not taken," says Dr. Hueper, "the stage will be set at a progressive rate for the future occurrence of a similar disaster to the human population."
The discovery that we are, as one investigator phrased it, living in a "sea of carcinogens" is of course dismaying and may easily lead to reactions of despair and defeatism. "Isn't it a hopeless situation?" is the common reaction. "Isn't it impossible even to attempt to eliminate these cancer-producing agents from our world? Wouldn't it be better not to waste time trying, but instead to put all our efforts into research to find a cure for cancer?"
When this question is put to Dr. Hueper, whose years of distinguished work in cancer make his opinion one to respect, his reply is given with the thoughtfulness of one who has pondered it long, and has a lifetime of research and experience behind his judgment. Dr. Hueper believes that our situation with regard to cancer today is very similar to that which faced mankind with regard to infectious diseases in the closing years of the 19th century. The causative relation between pathogenic organisms and many diseases had been established through the brilliant work of Pasteur and Koch. Medical men and even the general public were becoming aware that the human environment was inhabited by an enormous number of microorganisms capable of causing disease, just as today carcinogens pervade our surroundings. Most infectious diseases have now been brought under a reasonable degree of control and some have been practically eliminated. This brilliant medical achievement came about by an attack that was twofold -- that stressed prevention as well as cure. Despite the prominence that "magic bullets" and "wonder drugs" hold in the layman's mind, most of the really decisive battles in the war against infectious disease consisted of measures to eliminate disease organisms from the environment. An example from history concerns the great outbreak of cholera in London more than one hundred years ago. A London physician, John Snow, mapped the occurrence of cases and found they originated in one area, all of whose inhabitants drew their water from one pump located on Broad Street. In a swift and decisive practice of preventive medicine, Dr. Snow removed the handle from the pump. The epidemic was thereby brought under control -- not by a magic pill that killed the (then unknown) organism of cholera, but by eliminating the organism from the environment. Even therapeutic measures have the important result not only of curing the patient but of reducing the foci of infection. The present comparative rarity of tuberculosis results in large measure from the fact that the average person now seldom comes into contact with the tubercle bacillus.
Today we find our world filled with cancer-producing agents. An attack on cancer that is concentrated wholly or even largely on therapeutic measures (even assuming a "cure" could be found) in Dr. Hueper's opinion will fail because it leaves untouched the great reservoirs of carcinogenic agents which would continue to claim new victims faster than the as yet elusive "cure" could allay the disease.
Why have we been slow to adopt this common-sense approach to the cancer problem? Probably "the goal of curing the victims of cancer is more exciting, more tangible, more glamorous and rewarding than prevention," says Dr. Hueper. Yet to prevent cancer from ever being formed is "definitely more humane" and can be "much more effective than cancer cures." Dr. Hueper has little patience with the wishful thinking that promises "a magic pill that we shall take each morning before breakfast" as protection against cancer. Part of the public trust in such an eventual outcome results from the misconception that cancer is a single, though mysterious disease, with a single cause and, hopefully, a single cure. This of course is far from the known truth. Just as environmental cancers are induced by a wide variety of chemical and physical agents, so the malignant condition itself is manifested in many different and biologically distinct ways.
The long promised "breakthrough," when or if it comes, cannot be expected to be a panacea for all types of malignancy. Although the search must be continued for therapeutic measures to relieve and to cure those who have already become victims of cancer, it is a disservice to humanity to hold out the hope that the solution will come suddenly, in a single master stroke. It will come slowly, one step at a time. Meanwhile as we pour our millions into research and invest all our hopes in vast programs to find cures for established cases of cancer, we are neglecting the golden opportunity to prevent, even while we seek to cure.
The task is by no means a hopeless one. In one important respect the outlook is more encouraging than the situation regarding infectious disease at the turn of the century. The world was then full of disease germs, as today it is full of carcinogens. But man did not put the germs into the environment and his role in spreading them was involuntary. In contrast, man has put the vast majority of carcinogens into the environment, and he can, if he wishes, eliminate many of them. The chemical agents of cancer have become entrenched in our world in two ways: first, and ironically, through man's search for a better and easier way of life; second, because the manufacture and sale of such chemicals has become an accepted part of our economy and our way of life.
It would be unrealistic to suppose that all chemical carcinogens can or will be eliminated from the modern world. But a very large proportion are by no means necessities of life. By their elimination the total load of carcinogens would be enormously lightened, and the threat that one in every four will develop cancer would at least be greatly mitigated. The most determined effort should be made to eliminate those carcinogens that now contaminate our food, our water supplies, and our atmosphere, because these provide the most dangerous type of contact -- minute exposures, repeated over and over throughout the years.
Among the most eminent men in cancer research are many others who share Dr. Hueper's belief that malignant diseases can be reduced significantly by determined efforts to identify the environmental causes and to eliminate them or reduce their impact. For those in whom cancer is already a hidden or a visible presence, efforts to find cures must of course continue. But for those not yet touched by the disease and certainly for the generations as yet unborn, prevention is the imperative need.