People all over the world are exposed to cancer-causing chemicals present in air, water, food, consumer products, and even in soils and dusts. In their places of work some people come into contact with additional cancer-causing agents, generally at higher exposure levels than those experienced by the general population. Some people deliberately expose themselves, and incidentally expose others, to the large number of known and suspected carcinogens present in tobacco smoke. People are also exposed to various physical agents – ultraviolet radiation from the sun and sunlamps and other forms of natural and artificially produced radiation – that increase cancer risks.
We are all being assaulted by chemical and physical carcinogens. Add to this the substantial viral and genetic contributions. No wonder the chances of developing some form of cancer over our lifetime is about one in three (for women) and one in two (for men).
But we are moving too quickly. Before we can begin to contemplate the contribution of all these environmental carcinogens to the total cancer problem we need to acquire a better understanding of what is meant by the terms “carcinogen” or “cancer-causing chemical” and of how certain substances get to carry these labels.
We shall begin with a little history, and then move to a discussion of cancer statistics and the causes of cancer, and then provide some background on cancer biology and the mechanisms of tumor develop- ment. Some of the general characteristics of chemical carcinogens will also be covered. The methods for identifying chemical carcinogens are the subject of Chapter6. How their risks are estimated is left to later chapters.
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Cancer and chemical carcinogens – historical perspective The large group of diseases we refer to as cancers1 have in common cells that have lost the capacity to control their own growth. This disease can arise in any organ or tissue of the body. The unregulated growth of body cells results in the production of masses that compress, invade, and destroy contiguous normal tissues. Cancer cells then break off or leave the original mass and are carried by the blood or lymph to distant sites of the body. There they set up secondary colonies, or metastases, further invading and destroying other organs.
It is certain that these diseases are not totally a product of the indus- trial age or the era of modern chemical technology. Lack of solid statistical information forces us to avoid the question of how much human cancer there would now be if the industrial revolution and its chemical and physical products had never appeared on earth, but if the average age at death had nevertheless increased exactly as it has over the past two centuries. This is, of course, an unlikely histori- cal scenario, in that products of the industrial revolution have con- tributed substantially to the fact that more people are living to old age. Particularly important have been medicines that prevent death in early childhood, antibiotics that cure infections, agricultural technol- ogy, and many forms of medical technology and public sanitation. We also bring up the issue of average age at death because most cancers are diseases of old age. If many people die early from other diseases, then the numbers of people alive to contract cancer are fewer. To be mean- ingful, statistics on cancer rates must contain an adjustment for differ- ences in the distribution of ages in the populations under investigation, whether comparisons are being made for the same population at dif- ferent points in time, or for different populations at the same point in time.
Human cancers were much discussed by Galen and most medical commentators ever since, and dozens of hypotheses regarding the ori- gins (etiologies) of these diseases are recorded in the medical liter- ature. A seminal event relevant to our present concerns about the environment occurred in 1775. A British surgeon, Percival Pott, pub- lished his observations on high rates of cancer of the scrotum among London chimney sweeps. Pott attributed the cancers to the soot with
1 Early Greek medicine recognized cancers, and tumors were described by Galen, the Greek physician to Roman Emperors (second century AD), as “crab-like” in form.Karinos, the Greek word for crab, is the origin of the English word cancer. The Latin word for crab iscancer.
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which these workers came into contact. The surgeon reached conclu- sions about the causal relationship between soot and scrotal cancer on several grounds, not least of which was the fact that the occurrence of these cancers could be reduced if certain hygienic practices were followed to reduce direct contact with soot. Pott’s observations can be said to be the first to reliably establish a cause–effect relation between an environmental agent and cancer, and also to recognize the impor- tance of good industrial hygiene measures to protect workers from hazardous agents.
For the 16 centuries prior to Pott’s observations the medical view of cancer was the one proffered by Galen in about 200 AD. The Greek physician drew upon then-current views of the composition of the human body and postulated that cancers were caused by certain imbalances within the body. The four body “humors” (the biological counterparts of the famous basic elements of nature – Earth, Air, Fire, and Water) were blood, phlegm, yellow bile, and black bile. Diseases resulted from imbalances in these humors, and excessive amounts of black bile (melancholia) gave rise to cancer. That melancholy states contributed to cancer dominated medical thinking until well into the nineteenth century, and it is of course still fashionable in some circles. Pott’s observations prompted other investigations into external sources of the problem, and a series of similar observations throughout the nineteenth century, involving other sources of “soots and tars,” arsenicals used in medicine, and occupational cancers in the developing chemical industry, gradually undermined the Galenian theory.
Pott knew nothing about the chemical composition of soot; in fact, his paper does not say much about causal agents or the possible impor- tance of the findings. We now know that soots are mostly composed of inorganic carbon (a biologically rather inert material2which is also the major ingredient of graphite and, in crystalline form, of diamond), but they also contain small amounts of many different chemicals that are grouped under the general heading of polycyclic aromatic hydrocar- bons (PAHs). The PAHs occur as degradation products whenever any organic materials – fuels, foods, tobacco, for example – are burned or heated to high temperature. These chemicals are also present in unburned petroleum and products such as coal tars. Occupational skin cancers associated with materials related to soots were reported
2 Carbon is chemically rather inert, but fine particles of carbon are among the categories of Particulate Matter discussed in theprevious chapter.
139 by several investigators in England and Scotland during the last quar- ter of the nineteenth century. Ross and Cropper, two British scientists, proposed in 1912 that coal-tar related cancers were induced by chem- icals, the same chemicals also found in soots and combustion products of various sorts.
Although they did not know it at the time, two Japanese scientists, Katsusaburo Yamagiwa and Koichi Ichikawa, provided in 1915 indi- rect but nevertheless significant experimental confirmation of Pott’s observations on soots, when they were able to produce skin tumors on the ears of rabbits to which they had applied coal tar (not soot) for many months. The work of the Japanese investigators is also impor- tant because it represented the first laboratory production of tumors with an environmental chemical (or chemical mixture).3 Of particu- lar interest was their observation that the tumors (which they called
“folliculoepitheliomata”) appeared only after many months of contin- uous application of the cancer-causing agent. That studies of chronic duration are necessary to detect most carcinogens has been amply confirmed since the pioneering work of Ichikawa and Yamagiwa.
Yamagiwa was justifiably proud of his achievement and wrote a haiku, perhaps the only one “celebrating” this dreaded disease.
Cancer was produced!
proudly I walk a few steps.
In the 1920s the British scientist, Ernest L. Kennaway (1881–1958), suspecting that the carcinogenically active components of coal tar were to be found among the PAHs, tested one member of the class called dibenz[a,h]anthracene on the skin of shaved mice and found it to be carcinogenic. This work, reported in theBritish Medical Journal in 1930 (Kennaway and Heiger), was the first in which a single chemical compound was shown to be capable of producing tumors. A team of chemists at the London Free Cancer Hospital processed about two tons of coal tar pitch and isolated small amounts of a pair of isomeric PAHs, benzo(a)pyrene and benzo(e)pyrene. The former proved to be
3 Certain animal cancers had already been shown to be produced by viruses by Ellerman and Bang (1908) and Rous (1911).
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carcinogenic, the latter not. The chemical structures of these two PAHs and Kennaway and Heiger’s PAH are as shown, in a shorthand form:
Dibenz[a,h]anthracene Benzo[e]pyrene
C C C
C C C
C C C
C C
C C
C C C C
C C C H
H
H
H H H H H H H
H
H
Benzo[a]pyrene (long form)
Benzo[a]pyrene (abbreviated form) These chemical structures are simply abbreviated forms of those intro- duced in Chapter1. Polycyclic aromatic hydrocarbons are composed of carbon and hydrogen atoms only. The form of the abbreviation is illustrated with benzo(a)pyrene, which is shown in both abbreviated (on the right) and “long” forms (on the left). In the “long” form all carbon and hydrogen atoms are explicitly shown, with each carbon atom carrying the required four bonds. Note that the carbon atoms are arranged in rings of six each – they are “cycles” of carbon atoms, all of which contain six electrons (represented by the circle which was intro- duced earlier in connection with the discussion of benzene). Because PAHs contain several of these rings of carbon fused together, they are called “polycyclic.”
Many PAHs are present in smoke and other products of combus- tion, and in pitches and tars. Some are carcinogens, others are not;
carcinogenicity depends strongly upon details of chemical structure, specifically the ways in which the carbon rings are attached to each
141 other. The PAHs are an important class of environmental pollutants, because of their widespread occurrence.
Innovations in chemical synthesis of dyes gave rise to one of the first major chemical industries. Following up on the work of the German physician Ludwig Rehn, who reported large “clusters” of bladder cancer cases among dye workers in the 1890s, occupational physicians began during the 1930s to study systematically the per- sisting high rate of this disease among dye workers. A decade or more of research by epidemiologists, occupational physicians, and chemists led to the identification of a number of substances calledaro- matic aminesandamino-azocompounds as the culprits. The work of people such as Wilhelm Hueper on bladder cancers in the dye indus- try provided a major impetus to research and testing to identify other chemical carcinogens to which workers and the general public might become exposed. In 1937, Hueper and his associates at the National Cancer Institute (NCI) reported the experimental production of blad- der tumors in dogs, from administration of the aromatic amine called 2-naphthylamine (see structure).
NH2
2-Naphthylamine
Hueper and several colleagues at the NCI were instrumental in draw- ing public attention to the issue of carcinogens in the workplace and the general environment during the two decades following the work on bladder cancer. Hueper’s work and opinions were favor- ably cited many times by Rachel Carson inSilent Spring. Ms. Carson wrote:
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.
Carson’s chapter entitled “One in Every Four” (referring to what was at the time the lifetime risk of cancer development in the US pop- ulation), relies heavily on Hueper’s work; she quotes him with great respect, and it is clear that most of her views on the subject are derived from him. It would be a mistake to conclude that Hueper alone was responsible for moving into full public view what science understood
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at mid-century about environmental carcinogens. Scientists through- out the world began sounding alarms, though generally far quieter ones, concerning the growing body of evidence that industrial products and by-products, and even some natural chemicals, could be significant contributors to human cancers. Rachel Carson’s book, following by two years the great cranberry scare mentioned in the Preface, height- ened public interest and moved Congress to enact by the early 1970s several major environmental laws that required regulatory controls to be placed on many of the products that had been incriminated by the work of Hueper and others. All of these laws called for stringent controls on exposure to carcinogens.
On October 24, 1969, the Department of Health, Education, and Welfare (precursor to Health and Human Services) established an expert committee to advise the Department on carcinogens. The “Ad Hoc Committee on the Evaluation of Low Levels of Environmental Chemical Carcinogens” issued its report to the Surgeon General of the Public Health Service in April, 1970. The committee worked under the direction of Umberto Saffiotti, a physician trained in occupational medicine at the University of Bologna, who had become Associate Scientific Director for Carcinogenesis at the NCI. The committee’s report and recommendations summarized thinking, at least that of scientists within the NIH and their immediate advisors, on the sci- entific evidence that had accumulated since Pott’s findings in the late eighteenth century. The committee’s twelve recommendations, it can be readily observed, also reflect much of what can be found in the writings of Wilhelm Hueper, although they also derive from a number of more limited expert panel reports commissioned by various arms of the federal government since the early 1960s. The recommenda- tions restate, with great emphasis, the special dangers of low level carcinogen exposure. One recommendation states that “the principle of zero tolerance . . . should be retained. . . .” The committee called for the use of animal tests to identify carcinogens, emphasized the need for testing at high doses, and also made some policy recommenda- tions regarding the need for more comprehensive legislation to control carcinogens. Perhaps the following passage from the report is the defining one:
The effects of carcinogens on tissues appear irreversible. Exposure to small doses of a carcinogen over a period of time results in a summation or poten- tiation of effects. The fundamental characteristic which distinguishes the car- cinogenic effect from other toxic effects is that the tissues affected do not seem
143 to return to their normal condition. This summation of effects in time and the long interval (latent period) which passes after tumor induction before the tumor becomes clinically manifest demonstrate that cancer can develop in man and in animals long after the causative agent has been in contact and disappeared.
It is, therefore, important to realize that the incidence of cancer in man today reflects exposure of 15 or more years ago; similarly, any increase of carcinogenic contaminants in man’s environment today will reveal its carcino- genic effect some 15 or more years from now. For this reason it is urgent that every effort be made to detect and control sources of carcinogenic contamina- tion of the environment well before damaging effects become evident in man.
Similar concepts may apply to the need for evaluation of other chronic toxic- ity hazards. Environmental cancer remains one of the major disease problems of modern man.
Cancer statistics
In the United States cancer caused 22.8% of all deaths in 2002, second to heart disease (28.5%) and slightly more than the next five causes (cerebrovascular disease, chronic respiratory disease, accidents, dia- betes, and influenza and pneumonia) combined. Perhaps more signif- icantly, death rates from cancer remained unchanged from 193.9 per 100 000 in 1950 to 193.4 per 100 000 in 2002, while death rates from heart disease declined from 586.8/100 000 to 240.1/100 000 during the same period. Death rates reflect both how much disease occurs and how well it is detected and treated. The relatively large decline in death rates from heart disease reflects large advances in prevention and treatment, which have, it is seen, not been nearly so successful in the case of cancer. Death rates vary by race, gender, and ethnic- ity. They are highest for African-American men, and lowest for white women.
Table5.1provides 2005 statistics from the American Cancer Society on new cases, not deaths, for the cancers that occur most frequently.
Cancer incidence rates vary by race and gender in about the same way that death rates vary.
The incidence rates for various cancers can be derived from the data in Table 5.1 and other information, and expressed as lifetime probabilities, or risks. Thus, for example, these statistics tell us that, if incidence rates remain as they are now, then a male born today has a 50% risk of developing cancer over his lifetime, and a female has a
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Table 5.1 2005 Estimated New Cancer Casesa (US)
Percent of Percent of
Men total cases Women total cases
710 040 total cases 662 870 total cases
Prostate 33% Breast 32%
Lung and bronchus 13% Lung and bronchus 12%
Colon and rectum 10% Colon and rectum 11%
Urinary bladder 7% Uterine corpus 6%
Melanoma of skin 5% Non-Hodgkin lymphoma
4%
Non-Hodgkin lymphoma
4% Melanoma of skin 4%
Kidney 3% Ovary 3%
Leukemia 3% Thyroid 3%
Oral cavity 3% Urinary bladder 2%
Pancreas 2% Pancreas 2%
All other sites 17% All other sites 21%
Source: American Cancer Society, 2005
a Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.
33% risk. Lifetime risks for men are largest for cancers of the prostate (1 in 6), lung and bronchus (1 in 13), colon and rectum (1 in 17) and urinary bladder (1 in 28). For women breast cancer leads the way (lifetime risk 1 in 7), followed by cancer of the lung and bronchus (1 in 18), colon and rectum (1 in 18), and uterus (1 in 38). These are the risks of developing cancers and say nothing about the chances of surviving them. Incidence rates such as these are critical to an understanding of how successful we are at preventing cancer. Death rates tell us more about the success of medical intervention.
Causes of human cancer
With some exceptions, cancer experts generally cannot determine with high confidence the specific cause of cancer in an individual. At best they can understand the factors that contribute to the cancer rates observed in large populations. Differences in the rates of certain types of cancers in different regions of a country, different countries of the
145 world, and in the same population studied at different times, provide some indication of the relative importance of various factors. Epi- demiologists also learn a great deal from studies of specific exposure situations. Several trends emerge from these types of investigation:
(1) Somewhere between 70% and 90% of human cancers appear to be of environmental origin. Here “environmental” is used very broadly, and refers to anything not genetic. It refers not only to industrial chemicals and pollutants, but includes factors such as diet, sexual habits, smoking behavior, and natural and manmade radiation.
(2) Most cancers are not caused by individual carcinogenic factors, but by several factors. This view is consistent with our understanding that the gradual transformation of a normal cell to a malignant one occurs in steps, and that different agents may be involved at different steps (see the section on Mechanisms).
(3) In many cases a single factor may be so important that it is considered
“the cause.” Cigarette smoking, for example, is an important cause of lung cancer because in the absence of this habit about 85% of lung cancers would be avoided.
(4) It has become customary among cancer epidemiologists to talk about cer- tain “lifestyle” factors as important contributors to cancer risk. Lifestyle factors (smoking, dietary patterns, alcohol consumption) are assumed to be largely under the control of individuals. These are distinguishable from factors that are less directly in the control of individuals (occupa- tion, medicines, consumer products), and those over which individuals have little or no control (food additives, pesticides, environmental pollu- tants). Just how much control individuals have over the various “lifestyle factors” is of course much debated.
In 1981, two eminent British cancer experts, Sir Richard Doll and Richard Peto published a paper in theJournal of the National Can- cer Institute entitled “The causes of cancer: Quantitative estimates of avoidable risks of cancer in the United States today.” The authors drew upon a vast body of literature of the type mentioned above, and attempted to allocate the deaths caused by cancers among various responsible factors. The authors concluded that a certain percentage of human cancer deaths could be avoided if exposure to the respon- sible factors could be eliminated or controlled in some way, although the appropriate degree and nature of control for some of the “lifestyle”
factors, especially diet, is still highly uncertain. The Doll and Peto esti- mates are presented in Table5.2. The factors are listed in a somewhat different order from how they were listed by the original authors, because of our interest in clearly separating “lifestyle factors” (the first