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 be 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 Córdoba 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 Córdoba 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 1920s 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 bloodforming 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
microcos m, 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 but 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, 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
overgrowth 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 per cent 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, onetime 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 per cent of the trout over three
years of age developed cancer. This discovery was made because of a preexisting 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 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.
