Abeloff's Clinical Oncology, 4th Edition

Part I – Science of Clinical Oncology

Section B – Genesis of Cancer

Chapter 9 – Environmental Factors

Paul T. Strickland,
Thomas W. Kensler


History of Identification of Human Carcinogens



The carcinogenic effects of many environmental and occupational agents were first described in humans.



Beginning in the 20th century with the advent of animal bioassay programs, evidence of carcinogenicity in experimental animals has preceded evidence from epidemiologic or case studies in humans.



The majority of human cancers probably result from the interaction of several or more carcinogenic influences (often unidentified) along with intrinsic factors (inherited genes, hormones, immune status).

Role of Environmental Agents in the Etiology of Human Cancer



Although the causes of most human cancers remain unidentified, cumulative data support the opinion that environmental agents are the principal causes of human cancers.



Cigarette smoking could be responsible for 25% of all cancers in the United States.



Chemical carcinogens include aromatic amines, benzene, aflatoxins, tobacco chemicals, and chemotherapeutic agents.



Radiation carcinogens include ultraviolet radiation, ionizing radiation, and radon.



A number of metal carcinogens have been identified, including arsenic, nickel, cadmium, and chromates. These have been associated largely with occupational exposures.



Fibers (asbestos, silica) and dusts are well established as etiologic agents in lung cancers.



Many components in the diet can influence the development of cancer through carcinogenic or anticarcinogenic mechanisms.

Exposure Biomarkers and Susceptibility Factors and Chemoprevention



The identification of molecular biologic markers of exposure, effect, and susceptibility (reflecting events before clinical disease) will help to further our understanding of human carcinogenesis.



The characterization of the human genome has permitted study of the roles of common polymorphisms in carcinogen metabolism or of DNA repair genes in susceptibility to cancer.



Primary and secondary approaches to the prevention of cancer will be greatly facilitated by the development of noninvasive biomarkers that identify high-risk individuals.



Tertiary prevention might also be enhanced by characterizing cancers with respect to etiology, genetic profile, or metabolic capacity.


The carcinogenic effects of a sizable number of environmental or industrial chemicals have first been described in humans. The influences of occupation and lifestyle in cancer occurrence were observed at least as early as the 16th century. Ramazzini in 1700 noted that nuns showed a higher frequency of breast cancer than was observed among other women. Also in that century, Paracelsus and Agricola described Bergkrankheiten in miners in the Schneeberg and Joachimstal regions of Europe. Bergkrankheiten was later recognized as lung cancer, probably caused by uranium and its decay product radon.[1]Subsequently, in 1761 Hill associated the use of tobacco snuff with cancer in the nasal passage, and in 1775 Pott noted the occurrence of soot-related scrotal cancer among chimney sweeps. In 1895 Rehn published evidence that occupational exposure to aromatic amines was associated with bladder cancer, whereas Unna in 1894 associated sunlight exposure with skin cancer. It was not until the early 20th century that animal models for chemical carcinogenesis were developed. For example, Yamagiwa and Ichikawa reported in 1915 on the production of skin tumors following topical application of crude coal tar to the ears of rabbits, and Sasaki and Yoshida reported in 1935 that feeding of azo dyes to rats led to the development of liver tumors. In the intervening decades, there has been substantial growth in our understanding of the roles of chemicals (both manufactured and naturally occurring), radiation, and viruses in the cancer process. Of particular importance has been the recognition that these extrinsic factors interact with intrinsic factors (e.g., inherited genes, hormones, immune status) to determine overall susceptibility and risk. A central role of diet in these interactions is featured by observations that diet can both enhance and inhibit tumor formation.

Contrary to experiences in earlier centuries, with the advent of animal bioassay programs, evidence of carcinogenicity in experimental animals has preceded evidence obtained from epidemiologic studies or case reports in many instances. Although the term carcinogen means “giving rise to carcinomas” (e.g., epithelial malignancies) in general, broader operational definitions are used for carcinogens in animal bioassays. A carcinogen may be defined as an agent whose administration to previously untreated animals leads to a statistically significant increased incidence of malignant neoplasms, compared with the incidence in appropriate untreated control animals, whether the control animals have a low or high spontaneous incidence of the neoplasms in question. Chemicals, radiation, and viruses are the primary agents identified. Synthetic and naturally occurring chemicals compose the largest group of known human carcinogens. More than 100 chemicals, chemical mixtures, biologic agents, physical agents, or industrial processes have been classified as human carcinogens ( Table 9-1 ) and more than 300 chemicals have been identified as animal carcinogens so far. These figures evolve from an environmental milieu of perhaps 107 chemicals, although the vast majority of these agents have not been evaluated for carcinogenicity.

Table 9-1   -- Agents and Processes Considered Carcinogenic in Humans by the International Agency for Cancer Research

Agent or Process

Common Organ or Tissue Sites of Cancer




Arsenic and arsenic compounds

Lung, skin


Pleura, peritoneum


Alcoholic beverages

Oral cavity, pharynx, larynx, esophagus, liver

Betel quid with tobacco

Oral cavity

Tobacco products, smokeless

Oral cavity

Tobacco smoke

Respiratory tract, urinary bladder, renal pelvis, pancreas

Salted fish, Chinese style


Solar radiation



Aluminum production

Lung, urinary bladder


Urinary bladder


Lung, pleura, peritoneum, larynx, gastrointestinal tract

Auramine O, manufacture of

Urinary bladder




Urinary bladder



Bis(chloromethyl)ether and chloromethyl methyl ether


Boot and shoe manufacture and repair

Nasal sinus



Chromium (VI) compounds


Coal gasification

Lung, urinary bladder, scrotum

Coal-tar pitches

Skin, scrotum, lung

Coal tars

Skin, lung

Coke production

Skin, scrotum, lung, urinary bladder


All cancers combined

Ethylene oxide

Lymphatic, hematopoietic



Furniture and cabinet making

Nasal sinus

Iron and steel founding


Isopropyl alcohol manufacture (strong acid process)

Nasal sinus

Magenta, manufacture of

Urinary bladder

Mineral oils (untreated and mildly treated)

Skin, scrotum

Mustard gas

Lung, larynx/pharynx


Urinary bladder

Nickel and nickel compounds

Lung, nasal sinus





Rubber industry

Urinary bladder, leukemia

Shale oils

Skin, scrotum

Silica, crystalline



Skin, scrotum, lung

Strong inorganic acid mists containing sulfuric acid


Talc containing asbestiform fibers


Underground mining with exposure to radon


Vinyl chloride

Liver, lung, gastrointestinal tract, brain

Wood dust

Nasal cavities, paranasal sinuses


Analgesics mixtures containing phenacetin

Renal, urinary bladder




Urinary bladder

1,4-Butanediol dimethanesulfonate







Urinary bladder, leukemia

Estrogen replacement therapy

Endometrium, breast

Estrogen, nonsteroidal

Cervix/vagina, breast, endometrium, testes

Estrogens, steroidal

Endometrium, breast



8-Methoxypsoralen plus UV radiation






Oral contraceptives (combined)


Oral contraceptives (sequential)









Epstein-Barr virus


Helicobacter pylori


Hepatitis B virus


Hepatitis C virus


Human immunodeficiency virus type 1

Kaposi's sarcoma

Human papilloma viruses types 16, 18, others


Human T-cell lymphotropic virus type I

Adult T-cell leukemia/lymphoma

Opisthorchis viverrini


Schistosoma haematobium

Urinary bladder

Data from International Agency for Research on Cancer: IARC monographs on the evaluation of carcinogenic risk to humans, Vol. 1–88, Lyon, IARC, 1970–2006. An updated listing of the overall evaluation of carcinogenicity to humans can be accessed on the Internet at http://monographs.iarc.fr under the heading “classifications”. (Note: for examples of carcinogenic ionizing radiations, seeTable 9-3 ).

methyl-CCNU, semustine; MOPP, mechlorethamine, vincristine, procarbazine, and prednisone (combination therapy).





Chemical carcinogens comprise a diverse array of chemical structures, including both organic and inorganic compounds. Relatively few carcinogens are direct acting, because the innate reactivity of such compounds also tends to make them unstable. Instead, most carcinogens require metabolic activation to reactive species, often in the target cells. Once formed, the reactive intermediates can interact with DNA to produce genetic lesions that can result in mutation of critical cellular genes, including oncogenes and tumor suppressor genes. Metabolic pathways can be influenced strongly by a variety of extrinsic and intrinsic factors and are important determinants of both interindividual and target organ susceptibilities to carcinogens. Carcinogenesis is a dynamic, multistage process through which a normal cell is converted into a malignant one. Although our understanding of the neoplastic process is incomplete, current knowledge provides considerable insight into the critical actions of carcinogens. The goal of this chapter is to highlight the roles of discrete chemical and physical agents in the etiology of human cancers. In turn, fuller understanding of the mechanistic basis for the actions of these carcinogenic agents will allow for more effective means to identify other carcinogens in our environment and to develop preventive strategies to interrupt, block, or reverse the neoplastic process.


The causes of most human cancers remain unidentified; however, considerable evidence suggests that “extraconstitutional” or environmental and lifestyle issues are important contributors. For example, cigarette smoking could be responsible for 25% of all cancers in the United States. The opinion that environmental agents are the principal causes of human cancers is derived largely from the following series of epidemiologic observations:



Although the overall incidence of all cancers is reasonably constant among countries, incidences of specific cancer types can vary up to several hundred fold.



There are large differences in tumor incidence within populations of a single country.



Migrant populations assume the cancer incidence of their new environment within one to two generations.



Cancer rates within a population can change rapidly.

Although the extent to which environmental agents contribute to human carcinogenesis remains to be defined precisely, a considerable number of epidemiologic studies indicate important roles for the various naturally occurring and manufactured chemicals, radiations, metals, and fibers found in our individual environments.


Polycyclic Aromatic Hydrocarbons

The English surgeon Percival Pott[2] was among the first to document the association of an environmental agent with cancer. During the late 18th century, he determined that the unusually high incidence of scrotal cancer among chimney sweeps was due to their occupational exposure to soot and tar. As a consequence, recommendations for bathing and use of protective clothing were promulgated by chimney sweepers’ guilds in parts of Europe, but not in England. Subsequent decreases in the incidence of scrotal cancer were observed in continental Europe, demonstrating the efficacy of simple prevention efforts. It was not until the present century that the active carcinogens in soot and coal tar were shown to be polycyclic aromatic hydrocarbons (PAHs).[3] This result was accomplished through the application of coal tar and fractions thereof to the skins of test animals that subsequently developed malignant skin tumors. Although many PAHs were identified in coal tar, most of the carcinogenic activity was attributed to the PAH benzo[a]pyrene.

Humans are exposed to PAHs from a variety of sources that include occupation, smoking, diet, and air.[4] PAHs are readily absorbed into the body through the skin, lungs, and gastrointestinal tract. Occupational and medicinal exposures constitute the highest levels of human PAH exposure (albeit in small groups within the population), whereas diet and smoking are the major sources of exposure to PAHs in the general population. Air concentrations of greater than 10 μg benzo[a]pyrene/m3 are characteristic of topside gas and coke work environments. Broiled, barbecued, or smoked meats and fish contain relatively high concentrations of benzo[a]pyrene (1–20 μg/kg).

Cutaneous occupational exposure to PAHs has been associated with increased risk of skin and scrotal cancers in chimney sweeps and in individuals exposed to unrefined lubricating oils in the textile and machining industries.[1] Scrotal cancer among mule spinners in the Manchester (UK) cotton industry was attributed to the saturation of the workers’ trousers with lubricating oil. A review of all admissions for scrotal cancer to the Royal Manchester Infirmary from 1902 to 1922 indicated that 49% had worked as mule spinners, while 16% had worked with tar or paraffin. As the textile industry declined in the middle 20th century, an increasing proportion of scrotal cancer was associated with cutting oils used in metal machining.

An excess of lung cancer has been demonstrated among individuals with substantial inhalation exposure to PAHs, including roofers and pavers, coke oven workers, certain steel and iron manufacturing workers, and aluminum production workers.[5] In addition, several studies suggest that workers highly exposed through inhalation might also be at increased risk of cancer at sites other than skin and lung. The strongest evidence for such an association is for bladder cancer, where a dose-response relationship has been demonstrated between PAH exposure and bladder cancer risk in aluminum workers after adjustment for smoking. Other sites with suggestive increases in risk include the pancreas and upper gastrointestinal tract.

Several biochemical pathways are involved in the metabolism of PAHs and of benzo[a]pyrene in particular ( Fig. 9-1 ).[3] The initial step in benzo[a]pyrene metabolism involves the epoxidation of an aromatic double bond by one of the cytochrome P-450 mono-oxygenases (CYP1A1). The epoxide-benzo[a]pyrene intermediates might form phenols or glutathione conjugates or be further oxidized by epoxide hydrolase to form dihydrodiol-benzo[a]pyrene. This latter metabolite can undergo a second oxidation step, resulting in the highly reactive 7,8-dihydrodiol-9,10-epoxide benzo[a]pyrene. Experimental studies demonstrate that cultured human lung or colon tissue metabolizes benzo[a]pyrene to the proximate carcinogen 7,8-dihydro-7,8-dihydroxybenzo[a]pyrene and that benzo[a]pyrene metabolites bind to DNA in cultured tissue. Oral administration of benzo[a]pyrene to rodents produces benzo[a]pyrene-DNA adducts in liver, stomach, colon, and intestine, and cancers of the esophagus, forestomach, intestine, lungs, and mammary gland.


Figure 9-1  Metabolic activation of benzo[a]pyrene and formation of DNA and protein adducts.



Aromatic Amines

The occurrence of bladder cancer among dye industry workers was reported in 1895 by the German physician Ludwig Rehn, who suggested a causal relationship. With the rapid expansion of the chemical industry during and after World War I, increased risk of bladder cancer was observed among workers employed in chemical manufacturing and textile dyeing.[6] An industry-wide study of workers exposed to dyes in England and Wales demonstrated increased risks of bladder cancer among men exposed to 1-naphthylamine (observed [O]/expected [E] = 8.6), benzidine (O/E = 13.9), 2-naphthylamine (O/E = 86.7), or mixed dyes (O/E = 54.7). The International Agency for Research on Cancer subsequently considered that the cancer hazard associated with exposure to 1-naphthylamine was due to the probable contamination of commercial-grade 1-naphthylamine with 4% to 10% 2-naphthylamine.[7] Additional studies in the dye industry identified auramine O and magenta as human bladder carcinogens. Increased risk of bladder cancer among rubber workers and in the electric cable industry has been attributed to the naphthylamine added to rubber as an antioxidant.

Excess risk of bladder cancer has been observed in the silk-dyeing industry, in which benzidine-based dyes are used extensively. Elevated incidence of bladder cancer associated with benzidine manufacturing and production in the United States and Japan is complicated by probable coexposure to 2-naphthylamine and o-toluidine. The production of these aromatic amines has declined in recent years; the result has been a considerable reduction in bladder cancer among workers in these industries.

Aromatic amines are metabolized and excreted through a process involving acetylation by N-acetyltransferase.[8] Genetic variation in one of the genes, NAT2, encoding this enzyme produces either rapid or slow metabolic phenotypes in humans. Analysis of the NAT2 phenotypes of patients with bladder cancer from the dye industry indicates that individuals showing the slow phenotype could be more susceptible to bladder cancer caused by aromatic amines. This is consistent with a recent meta-analysis indicating that NAT2 slow acetylation status is associated with an increased risk of bladder cancer in the general population.[9]


Exposure to benzene was suspected to be the cause of leukemia in a number of individual cases and case series reported worldwide between 1928 and 1976.[1] Case-control studies indicated increased risks of nonlymphocytic leukemia among workers in Sweden exposed to benzene-containing petroleum products and for lymphomas among workers in New York State exposed to benzene. Prospective studies conducted in the rubber industry provide the most convincing evidence for an association between benzene exposure and leukemia. Most of the excess leukemia in this industry is found among rubber workers exposed to solvents, including benzene. Excess mortality from leukemia has been observed among former employees of a rubber film production plant (O/E = 4.7) and a rubber coating plant (O/E = 3.7).


The hepatotoxic effect of aflatoxins was first recognized when aflatoxin-contaminated feed was inadvertently fed to poultry. Subsequent animal studies demonstrated the carcinogenic potential of the aflatoxins, particularly aflatoxin B1. The aflatoxins are produced by the fungal strains Aspergillus flavus and A. parasiticus. Grains and foodstuffs for human consumption such as corn, peanuts, and rice can become contaminated with aflatoxin during growth or storage. The considerable variation in levels of human exposure to aflatoxin worldwide is determined by climate and by the preventive measures used to protect susceptible foods from mold contamination and growth.[10]

Dietary aflatoxin is correlated with high liver cancer rates in sub-Saharan Africa and Asia. Case-control studies in the Philippines and Mozambique show an increased risk of liver cancer with estimated levels of aflatoxin consumption. The co-carcinogenic role of hepatitis B virus (HBV) infection and dietary aflatoxin in liver cancer has been the focus of several studies. The incidence of liver cancer in different regions of Swaziland correlated more closely with aflatoxin intake than with HBV infection. A prospective study conducted in Guangxi Province, China, compared the incidence of liver cancer in regions of high and low aflatoxin contamination and determined HBV infection status.[10] A strong interaction between aflatoxin exposure and HBV-positive status was observed for relative risk of liver cancer. Among HBV-positive individuals, the incidence of liver cancer was 649 per 100,000 in the high-aflatoxin region and 66 per 100,000 in the low-aflatoxin region, whereas among HBV-negative individuals, the incidence of liver cancer was 99 per 100,000 and <1 per 100,000 in high- or low-aflatoxin regions, respectively.

The new techniques of molecular dosimetry for human carcinogen exposure have been applied in populations exposed to aflatoxin. With individual exposures often in excess of 10 to 100 mg/day, the presence of aflatoxin metabolites and DNA adducts can be quantified in the urine after exposure. The association of urinary aflatoxin-DNA adducts with risk of liver cancer has also been demonstrated in a prospective epidemiologic study.[11]

Tobacco Chemicals

Tobacco use causes more cancer deaths worldwide than any other human activity. Cigarette smoking is associated with cancers of the lung, oral cavity, pharynx, larynx, esophagus, bladder, renal pelvis, and pancreas. The use of smokeless tobacco (chewing tobacco or snuff) leads to cancer of the oral cavity. Thus, although combustion enhances the carcinogenic properties of tobacco, it is not required for cancer induction.

Although the carcinogenic properties of tobacco tar were first demonstrated experimentally during the 1920s, evidence of a human cancer risk from the use of tobacco did not appear until 1939, when Muller and colleagues[12] reported an association between tobacco use and lung carcinoma in Germany. Subsequent epidemiologic studies conducted in the United States and the United Kingdom during the next decade confirmed this causal relationship. These findings met with considerable resistance in both the scientific community and the general public, however. Unlike occupational exposure to carcinogens, which was subject to regulation in many countries, tobacco exposure was a personal habit considered by many users to be more pleasurable than dangerous. Unfortunately, the addictive characteristics of nicotine, a major constituent of tobacco, made it more difficult for tobacco users to reduce their consumption. Societal acceptance of a causal association with lung cancer was advanced by the first reports from the Royal College of Physicians in the United Kingdom (1962) and from the Surgeon General in the United States (1964) regarding the risks of tobacco use. By contrast, the tobacco industry has steadfastly resisted attempts to educate the public to the health hazards of tobacco use and has continued to market cigarettes aggressively, particularly in developing countries. Explosive increases in the incidence of lung cancer, probably even outranking those already occurring in the United States, can be anticipated in these countries over the next few decades. Based on tobacco usage trends, it is estimated that more than one million new cases per year of lung cancer will occur in China in the 21st century.[12]

More than 3000 chemicals have been identified in cigarette smoke, of which at least 30 are known to be carcinogenic in animals ( Table 9-2 ). The gas phase of tobacco smoke contains several carcinogenic or tumor-promoting compounds, including dimethylnitrosamine, dialkylnitrosamines, vinyl chloride, acrolein, and benzene. The particulate phase contains carcinogenic and co-carcinogenic PAHs, methylated PAHs, heterocyclic hydrocarbons, chlorinated hydrocarbons, phenols, catechols, and metals. Organ-specific carcinogens in the particulate phase include N-nitrosamines (and precursors), which have been associated with esophageal and pancreatic cancers, and aromatic amines, which are associated with kidney and bladder cancers. An important finding from experimental studies is the strong interactive effect observed when certain mixtures of these compounds are assayed for carcinogenic potential.

Table 9-2   -- Tumorigenic Agents in Tobacco Smoke


Mainstream Smoke Compounds (per Cigarette)



20–70 ng


4–22 ng


6–21 ng


6–12 ng


20–40 ng


40–60 ng


4 ng


1.7–3.2 ng




4–20 ng


0.6 ng



1–2 μg


0.1 ng


3–10 ng


0.7 ng



0.1–180 ng


3–13 ng


0–25 ng


1.5–110 ng


0–36 ng


0.12–2.7 μg


0.08–0.77 μg


0.14–4.6 g



30–200 ng


1–22 ng


2–5 ng



70–100 μg


18–1400 ng


10–20 μg



12–48 μg


3.2–15 μg


0.73–1.21 μg


20–38 ng

Vinyl chloride

1–16 ng



24–43 ng


40–120 ng


0–600 ng


4–70 ng


41–62 ng


0.03–1.0 pCi

From Reducing the Health Consequences of Smoking: 25 Years of Progress. Washington, DC, U.S. Department of Health and Human Services, 1989.




Chemotherapeutic Agents

The systemic toxicity of sulfur mustard gas among soldiers exposed during World War I led to investigations of the mechanism of action of nitrogen mustard compounds. The cytotoxic effect observed in lymphatic tissues was subsequently replicated and studied in experimental animal models. This property of nitrogen mustards and other alkylating compounds prompted their use as antineoplastic drugs during the 1940s. Several other types of drugs were developed at that time for use in the treatment of cancer, including the antibiotic actinomycin A and the antimetabolite methotrexate. Later decades saw the introduction of a variety of alkylating agents (e.g., chlorambucil, cyclophosphamide, bis-chloroethylnitrosourea, busulfan, cisplatin), antimetabolites (5-fluorouracil, 6-mercaptopurine), antibiotics (adriamycin, bleomycin, daunomycin), and mitotic inhibitors (vincristine, vinblastine) as antineoplastics.

As early as 1948, the carcinogenic properties of the anticancer drug 4-aminostilbene and its metabolites were reported. This and subsequent findings led to the institution of carcinogenesis bioassays for new anticancer drugs under development by the National Cancer Institute. Preneoplastic dysplasias were frequently observed in the epithelial tissues of patients with cancer undergoing chemotherapy. The appearance of frank second malignancies among patients treated by chemotherapy was reported during the 1970s. In addition, renal transplant patients receiving anticancer drugs for immunosuppression showed excess risks of mesenchymal and epithelial cancers.

The successful treatment of Hodgkin's disease with multiagent chemotherapy is associated with the long-term complication of acute myeloid leukemia (AML) and non-Hodgkin's lymphoma. Increased risk of acute myeloid leukemia among patients treated for non-Hodgkin's lymphoma, ovarian cancer, multiple myeloma, or small-cell carcinoma of the lung has also been attributed to antineoplastic therapy. The risk of acute myeloid leukemia is most strongly associated with the alkylating antineoplastics—particularly cyclophosphamide, melphalan, busulfan, treosulfan, and semustine (methyl-CCNU)—or with combination chemotherapies that include alkylating agents.

A large case-control study conducted in collaboration with 11 population-based cancer registries and two large oncology hospitals in Europe and Canada identified 114 cases of leukemia among 99,113 ovarian cancer survivors.[13] Patients receiving chemotherapy alone had a relative risk for leukemia of 12 as compared with patients treated by surgery alone. By contrast, patients receiving radiation therapy alone (as compared with surgery alone) had no significant increase in the risk of leukemia. In order of decreasing leukemogenic potency, the drugs melphalan, thiotepa, chlorambucil, cyclophosphamide, and treosulfan were independently associated with significantly increased risk of leukemia. Combination treatment with adriamycin and cisplatinum also increased the risk of leukemia, indicating that one or both of these drugs is leukemogenic in humans.



Solar ultraviolet (UV) radiation is the major physical carcinogen in our environment and the primary cause of skin cancer in humans. More than 800,000 individuals will develop new basal cell carcinoma or squamous cell carcinoma of the skin each year in the United States, making nonmelanoma skin cancer the most common cancer.[7] The incidence of both nonmelanoma and melanoma skin cancer among light-skinned individuals is increasing at a rate of 3% to 5% per year in the United States. This increase has been attributed to changing lifestyle and leisure habits over the past five decades, resulting in an increase in the number of people receiving greater exposure to sunlight. Although basal cell carcinoma occurs more frequently than squamous cell carcinoma (the ratio of basal cell to squamous cell carcinoma is approximately 3:1), the incidence of squamous cell carcinoma seems to be increasing more rapidly than that of basal cell carcinoma. In addition, squamous cell carcinoma metastasizes more frequently and is responsible for more deaths than are caused by basal cell carcinoma.

The relationship between solar UV exposure and skin cancer in humans has been demonstrated from incidence data in human populations residing at different latitudes. The incidence of nonmelanoma skin cancer shows a generally increasing trend with decreasing latitude among individuals with similar skin types.[7] Nonmelanoma skin cancers and the premalignant skin neoplasm, actinic keratosis, are also associated with cumulative lifetime UV exposure estimated from outdoor activities. This is particularly apparent among those with outdoor occupations such as farmers and sailors. The anatomic distribution of these skin neoplasms, primarily on sun-exposed areas, including the face, ears, neck, and hands, is consistent with a solar etiology. The phenotypic characteristics of light skin complexion, ease of sunburning (skin type), and light hair color are known to enhance the risk of nonmelanoma skin cancer. Pigmentation of the skin, either constitutive or induced (as in tanning), clearly plays an important role in protecting skin from the carcinogenic effects of UV radiation. Individuals with moderately to heavily pigmented skin (Latin, Hispanic, Negroid) show much lower rates of skin cancer than do those with poorly or nonpigmented skin (Celtic, albino). The importance of pigmentation is also demonstrated by the finding that susceptibility to sunburn is a strong indicator of risk of both basal and squamous cell carcinoma.

Molecular evidence also supports an etiologic role of solar UV in human skin cancer. Increased levels of DNA photodamage are detected in the normal epidermis of individuals following exposure to solar UV radiation. In addition, analysis of mutational spectra in human nonmelanoma skin cancer DNA shows that mutations specific for UV radiation (dipyrimidine mutations) are frequently present.

Animal studies confirm the carcinogenic effects of UV radiation and indicate that the UV-β portion (280–320 nm) of the solar spectrum is primarily responsible for the carcinogenic properties of sunlight. This wave band encompasses the long-wavelength end of the absorbance spectrum of DNA and has been shown to cause mutations in mammalian cells. Stratospheric ozone efficiently absorbs UV-β wavelengths below 300 nm, thereby determining the short-wavelength end of the solar spectrum reaching the earth's surface. Concern over the destruction of stratospheric ozone due to environmental pollution with chlorofluorocarbons, resulting in increased intensity of UV-β radiation at the earth's surface, has encouraged the refinement of risk estimates for human skin cancer under conditions of reduced atmospheric ozone.


The discovery and manipulation of ionizing radiation in the early 20th century led to detrimental health effects among many researchers. Toxicity, radiation burns, and cancer were observed among handlers of radioactive materials. The deaths of Marie Curie and Thomas Edison's assistant from cancer have been attributed to severe radiation exposure. The use of radium in luminous paint during the 1930s led to a high incidence of osteosarcoma among dial painters who inadvertently ingested radium when shaping their brush tips with the tongue.[1] By the 1940s, an elevated incidence of leukemia was observed among radiologists. After World War II, excess leukemia was observed among atomic bomb survivors and among patients treated with x-rays.

Epidemiologic studies of populations exposed to high doses of radiation indicate increased risks for a variety of cancers, depending on the type of radiation and route of exposure ( Table 9-3 ). Among atomic bomb blast survivors, excess leukemias appeared within several years of exposure, whereas excess cancers of the breast, lung, esophagus, thyroid, colon, bladder, and ovary, as well as multiple myeloma appeared only 20 to 25 years later. In contrast, populations exposed to nuclear weapons fallout show only excess risk of thyroid cancer due to radioactive iodine. Heavy exposure to x-rays for diagnostic or therapeutic procedures has been associated with increased risk of the following types of cancers: leukemia after in utero exposure; breast cancer after repeated chest exposure; leukemia, lung, stomach, and esophagus after spinal exposure; and thyroid, skin, and neck after scalp or thymus exposure.[5]

Table 9-3   -- Examples of Radiation-Induced Cancers

Sources of Exposure

Exposure Circumstances

Cancer Types



Atomic bombing survivors in Hiroshima and Nagasaki

Leukemia, breast, lung, thyroid, stomach, colon, multiple myeloma, esophagus, ovary


Populations exposed through atmospheric testing, including Marshall Islanders, veterans in the Pacific, general population in Nevada, Utah




Children exposed in utero



Cerebral and limb angiography; of biliary passages


Fluoroscopic x-ray

Monitoring of lung infections in patients with tuberculosis




Postpartum mastitis



Ankylosing spondylitis

Leukemia, lung, stomach, esophagus


Treatment for cancer of the cervix

Leukemia, stomach, rectum, bladder, vagina, female genital, lung, buccal cavity, nasopharynx, esophagus


Treatment of benign head and neck conditions

Thyroid, skin, central nervous system


Ankylosing spondylitis, bone tuberculosis

Bone sarcoma



Early radiologists

Skin, leukemia


Uranium, hard-rock miners

Lung cancer

X-ray, γ-rays, neutrons

Nuclear industry

Multiple myeloma

Radium isotopes

Radium dial painters

Bone, head sarcoma

Adapted from Higginson J, Muir CS, Munoz N: Human Cancer: Epidemiology and Environmental Causes. Cambridge monographs on cancer reseach. Cambridge, Cambridge University Press, 1992.




The use of cobalt-60 x-ray treatment for cervical cancer is associated with leukemia and cancers of the stomach, rectum, bladder, vagina, buccal cavity, nasopharynx, and lung. Because most radiation exposure in ambient or occupational environments occurs as protracted low-dose exposure, an important public health concern is the cancer risk from low-level exposure. However, most risk estimates are extrapolated from high to low doses and from acute to chronic exposures and are therefore subject to several assumptions that profoundly influence the resulting low-level risk estimates. Populations with potential (or known) low-level radiation exposures include employees in the nuclear industry, individuals living near nuclear production or storage facilities, military personnel participating in atmospheric nuclear weapons tests or living near test sites, patients receiving diagnostic radiation, and residents of buildings with radon contamination. In addition, nuclear accidents such as the Chernobyl incident in the former Soviet Union produce both acute and chronic exposure to local and distant populations.


Radon gas is encountered in hard rock mining for iron, tin, fluorspar, and uranium.[7] The radioactive decay of radon and its products produces alpha particles. The earliest reports defining an association between lung cancer and mining described the high rate of lung cancers among uranium miners in the Schneeberg region of Czechoslovakia in the late 19th century. Many potential causes were proposed, including radon inhalation. Studies of lung cancer mortality among Colorado uranium miners demonstrated dose-related increases in lung cancer risk in miners with protracted exposure to radon.[1] In addition, small-cell undifferentiated carcinomas predominated in highly exposed miners, in contrast to the typical distribution of pulmonary cancer pathology in the general U.S. population. Elevated risk of lung cancer has also been reported for iron ore miners in England, France, and Sweden; however, the proportion of risk attributable to radon in these populations is more difficult to assess.

Analysis of lung cancer mortality and smoking in Colorado uranium miners suggests a greater than additive mortality rate for cumulative radon exposure and cumulative cigarette smoking.[7] In other words, the increased risk of lung cancer among miners as compared with nonminers is larger when comparing smokers than when comparing nonsmokers. Interestingly, among atomic bomb survivors, cigarette smoking and radiation exposure have only an additive effect for lung cancer risk. This anomaly has been attributed to the different exposure patterns experienced by atomic bomb survivors (acute) and uranium miners (protracted).



Medicinal use of inorganic arsenic was associated with skin cancers in the early 20th century. More recently, excess skin cancer has been observed in populations exposed to arsenic-contaminated drinking water, whereas excess lung cancer has been found in populations with occupational exposure to inorganic arsenic compounds.[1] An increased risk of lung cancer of 6- to 14-fold was reported for gold miners in Rhodesia, where the ore contains arsenic. Chronic arsenism was also prevalent among these miners. Several studies in Japan, Sweden, and the United States have documented excess lung cancers among workers involved in copper smelting. Inorganic arsenic is a byproduct of the smelting process and is also used as a hardener. Two large retrospective studies of copper smelters have shown that lung cancer mortality is related to estimated arsenic exposure.

Another source of occupational exposure is the manufacture and use of arsenical pesticides.[1] An early study of mortality among workers at a factory manufacturing arsenical sheep dip in Wales found an excess of skin and lung cancers, particularly among those directly involved in the chemical processes. Case-control studies in two U.S. plants manufacturing arsenical pesticides found arsenic dose-related increases in risk of lung cancer. Reports of skin and lung cancers among vineyard workers with exposure to arsenic fungicides and pesticides appeared during the late 1950s. An autopsy series of 82 vineyard workers exposed in Germany found 61 deaths from cancer, including 44 respiratory tract cancers; many skin cancers and Bowen's disease were also reported.


The nickel refining industry was established in South Wales around 1900. During the subsequent 40 years, evidence accumulated for increased rates of nasal cancer, and later, lung cancer among workers in nickel refineries.[7] Several prospective studies in England and Wales found elevated risks of nasal cancer (O/E = 12) and lung cancer (O/E = 16), particularly among process workers in the refinery. The highest cancer risk was associated with the calcination of impure nickel copper sulfate. Further studies indicated that the cancer risk began to decline when environmental controls were introduced in the industry during the 1930s. Evidence of excess cancer risk associated with nickel exposure as late as the 1950s was reported in a refinery in Norway, however. Excess nasal, laryngeal, and lung cancers were observed; smoking and nickel exposure seemed to contribute to lung cancer risk in an additive manner.


Elevated risk of prostate and lung cancer among workers exposed to cadmium has been reported. Cadmium exposure has a stronger association with lung cancer than with prostate cancer.[7] Several small historical prospective studies of cadmium smelters and battery workers show increased risks of prostate cancer (O/E = 1.2 to 3.5) and lung cancer (O/E = 1.35); however, a larger study of 7000 workers exposed to cadmium for at least 1 year showed no increased risk of prostate cancer. A major nonoccupational source of cadmium exposure is from cigarette smoke, which contains 1 to 2 μg cadmium per pack of cigarettes.


Several reports of lung cancer in chromate industry workers appeared in Germany during the 1930s. Subsequent epidemiologic investigations examined this association in workers involved in chromate production, chromate pigment manufacture, and chrome plating.[7] Excess lung cancer was found among workers in three chromate production plants in England (threefold excess) and in a production plant in Baltimore (twofold excess). Exposure to lead and zinc chromate pigments, but not to lead pigment alone, was related to excess lung cancer in a British study. Confirmatory results have been reported for workers exposed to lead and zinc chromates in the Netherlands, West Germany, and Norway. Experimental investigations indicate that the hexavalent salts of chromium are highly carcinogenic, whereas trivalent chromium is not carcinogenic.

Fibers and Dusts


The appearance of lung cancer in asbestosis patients was first reported in the 1930s. Over the next 50 years, many different study complications were recognized and overcome in the process of determining the lung cancer risk associated with the naturally occurring silicate fiber, asbestos.[5] A major problem was exposure assessment, in that many workers were mobile, having variable levels of exposure in a variety of industries or worksites. Furthermore, measurement techniques for asbestos fibers were also variable, making the use of historical measurements suspect. Some studies did not report asbestos type; that is, chrysotile, amosite, anthophyllite, or crocidolite. The long latency period between first exposure and lung cancer also complicates risk estimates. Misdiagnosis of the cancer pathologies specific to asbestos (mesothelioma) is a potential problem, especially in studies that depend on death certificates.

More than 30 epidemiologic studies have been mounted to examine lung cancer risk in workers with potential exposure to asbestos during mining, milling, manufacturing, insulating, and shipbuilding.[1] In general, these studies demonstrate enhanced risk of lung cancer, and possibly enhanced risk of laryngeal cancer. The association between asbestos exposure and mesothelioma of the lung, a relatively rare cancer, was reported in the early 1960s. This finding was confirmed among insulation workers, asbestos manufacturing workers, and other occupationally exposed populations.

Cases of pleural malignancies in Denmark and Germany in the 1930s were reported to be concentrated in seaport towns rather than in other urban areas. Later studies of the geographic distribution of mesothelioma deaths in England and Wales demonstrated a correlation between mesothelioma and areas of high asbestos use related to shipbuilding, gas mask manufacture, or asbestos manufacturing. Further studies led to the conclusion that risk of mesothelioma was not limited to the workers but extended to members of their household and to residents living in the vicinity of asbestos-related industries.

Evidence of a synergistic effect of asbestos and smoking for lung cancer risk was found among insulation workers in New York.[7] The age-standardized mortality ratio for lung cancer was 5.2 for nonsmoking asbestos-exposed workers (compared with nonexposed nonsmokers), 10.8 for nonexposed smokers, and 53.2 for asbestos-exposed smokers. Thus, the risk of lung cancer from both smoking and exposure to asbestos is much greater than the sum of the risks associated with either exposure. A similar result was reported for female workers at a British asbestos factory, but the results for male workers at the same factory could not distinguish between additive or multiplicative effects.


Exposure to silica dusts occurs in several occupational groups, including foundry workers, pottery workers, miners, and quarry workers. Examination of occupational mortality statistics in high-exposure segments of these industries consistently show an increased risk for lung cancer among silica-exposed workers.[1] Two studies using silicosis registries have shown an association between silicosis and lung cancer. Excess mortality from lung cancer (O/E = 2.8) was found among 3600 men recorded in the Swedish silicosis registry from 1931 to 1969. An excess of lung cancer deaths (O/E = 2.0) was also found among 1910 miners registered with silicosis in Ontario, Canada, from 1940 to 1975. Pottery workers in the United States showed a significant excess of lung cancer among men whose work entailed making ceramic plumbing fixtures.

Wood Dust

The cancer risk associated with wood dust has been investigated in furniture workers, carpenters, woodworkers, lumberjacks, sawmill workers, and paper or pulp mill workers.[7] Excess nasal adenocarcinoma is found consistently among furniture workers in several countries, primarily with exposure in the 1920s and 1930s. The highest risk is seen among those with exposure to hardwood dusts, and after a latent period of 30 years. Small increases in risk of larynx cancer, lung cancer, and Hodgkin's disease have also been reported among persons with these occupations.


Most of the known human carcinogens discussed in the foregoing sections have been identified from occupational and iatrogenic exposures; however, with the exception of tobacco, such agents are rather minor contributors to the current overall cancer burden. Exposures to many of these agents have been typically at high doses in small, well-defined cohorts. Most human cancers probably result from interactions of several or more carcinogenic influences, none of which singly is readily detectable. The carcinogenic process is subject to influence by many modifying variables, which in the aggregate probably represent the largest determinant of human cancer. These variables can be constitutive, including age, gender, immunologic status, and genetic composition. Extraconstitutional variables are also very important, particularly diet and lifestyle habits such as smoking and alcohol consumption. Many epidemiologic studies indicate that general increases in consumption of fiber-rich cereals, fruits, and vegetables and decreased consumption of fat-rich foods and excessive alcohol will serve as prudent approaches to reducing overall cancer risk.

Many components in the diet can contribute to carcinogenesis. Two major influences are fat and calorie consumption. Fat consumption is most strongly associated with the hormone-dependent cancers (breast, ovary, and endometrium in females and prostate in males) and the gastrointestinal cancers (gallbladder, colon, and rectum in both sexes). It is not known whether these relationships are causal and, if so, whether they relate to the type of fat (saturated, unsaturated, polyunsaturated) or to the overall caloric content of the diet. Dietary fat intervention studies such as the Women's Health Trial might provide direct information on the effects of reducing dietary fat consumption on the incidences of cancer and other diseases. Decreased fat consumption could exert protective effects through both direct and indirect means. Fats can promote tumor development directly and are also a major source of calories ( Box 9-1 ). Animals fed high-fat diets consistently demonstrated enhanced tumorigenic outcomes. Conversely, it has been recognized for decades that caloric restriction has a very powerful, general inhibitory effect on carcinogenesis in many induced and spontaneous laboratory animal tumor models. The behavioral changes required to effect comparable population-wide reductions in fat and/or calorie consumption, however, pose formidable challenges.

Box 9-1 


The risk of colon cancer is strongly associated with consumption of red meat and animal fat. This association has been observed in several international correlative studies and case-control studies. Prospective studies of colon cancer risk demonstrate an association with consumption of red meat and animal fat (but not with vegetable fat), independent of total energy intake.[26] The increased risk associated with animal fat is due primarily to meat intake as opposed to dairy product intake. Other studies have addressed cooking practices, finding that consumption of fried foods and barbecued, broiled, or smoked meats is associated with increased risk of colorectal cancer.

Despite these observations, and despite rapid advances in the molecular genetics of susceptibility and predisposition, the specific chemical etiologies of colon and other diet-associated cancers remain unclear. Several hypotheses have been proposed to explain the strong association of colon cancer risk with red meat and animal fat. Diets high in fat increase the incidence of chemically induced colon cancers in rats and also increase the excretion of primary bile acids, which are converted to secondary bile acids by bacterial metabolism. Some secondary bile acids (e.g., deoxycholic and lithocholic acid) are colon tumor promoters in animal models. Thus, it has been hypothesized that increased animal fat in the human diet leads to promotion of colon tumors by secondary bile acids. An alternative (or complementary) hypothesis is that carcinogens in cooked meats contribute to colon carcinogenesis. The cooking of meat produces at least two major classes of carcinogens—polycyclic aromatic hydrocarbons (PAHs) and heterocyclic aromatic amines—which induce genotoxic damage or cancer in the gastrointestinal tracts of animals receiving these compounds orally.[27] Because cooked meats are a major source of animal fat in Western diets; it has been suggested that cooking-induced carcinogens in meat, rather than animal fat, play a causative role in colon cancer. Estimates of average daily ingestion of PAHs and heterocyclic amines from diet are comparable (0.1–10 μg/day).

Recent studies have explored the role of cooking-induced carcinogens as risk factors for colorectal carcinogenesis by administering food frequency questionnaires with detailed sections on cooking methods and doneness levels. This information is then linked to PAH and heterocyclic amine databases of food items cooked or prepared under a variety of conditions. One such study reported increasing risk for colorectal adenoma with quintile of daily intake of benzo[a]pyrene.[28]

In addition to PAHs, highly mutagenic heterocyclic amine compounds are formed during the broiling or frying of meat and fish as a result of pyrolysis of amino acids and proteins. More than a dozen heterocyclic amines have been identified; the most common forms are quinolines, quinoxalines, pyridines, and carbolines.[27] These compounds are highly mutagenic in bacteria and carcinogenic in animals, causing colon cancer, mammary cancer, liver cancer, prostate cancer, and lymphoma. PhIP (2-amino-1-methyl-6-phenylimidazo(4,5-β)pyridine) is one of the most common heterocyclic amines formed in broiled and fried meats, occurring at levels comparable to or greater than those of benzo[a]pyrene. Male rats fed PhIP develop colon adenocarcinomas, whereas female rats develop mammary adenocarcinomas. A recent study assessing heterocyclic amine intake in colon cancer cases and controls found an increased risk for colon cancer among those who had the highest quintile of heterocyclic amine intake.[29] The precise role of heterocyclic amine compounds and PAHs in the etiology of human colon cancer, however, requires further confirmation.

Many minor dietary components act as carcinogens or anticarcinogens.[14] Dozens of natural mutagens and carcinogens derived from plant, fungal, and bacterial sources have been described, which present a significant carcinogenic challenge to humans. These natural carcinogens, however, are opposed by an equally expansive array of food-derived anticarcinogens. These anticarcinogens consist of both nutrient (e.g., vitamins, minerals) and non-nutrient components, many of which function as antioxidants. In addition to scavenging oxidants, many of the non-nutrient anticarcinogens in plants alter the balance between the metabolic activation and inactivation of chemical carcinogens. Inverse epidemiologic associations between risk of cancer at several sites and ingestion of fruits and vegetables have been observed.[15] These associations might be linked to β-carotene, other carotenoids, folate, fiber, vitamin C, and other antioxidants, and to other components of the fruits and vegetables. Although a protective role of specific nutrients has been difficult to establish in many instances, inverse relationships between intake of foods rich in vitamin C and oral, esophageal, and gastric cancer incidence and between β-carotene intake and lung cancer incidence have been described. A fuller understanding of the role of dietary factors in human carcinogenesis is destined to have a significant impact on disease incidence.


Assessing Human Exposure: Role for Intermediate Biomarkers

Increased understanding of the mechanistic basis of carcinogenesis provides opportunities for the identification of molecular biologic markers reflecting events occurring between exposure and clinical disease. These molecular biologic markers can be classified into three major categories:



Markers of exposure reflecting either an internal or a biologically effective dose of carcinogen



Markers of effect indicating a biologic response to an exposure



Markers of susceptibility that characterize the inherent susceptibility of an individual to a carcinogenic agent[16]

It is anticipated that the use of biologic markers will help define the roles of environmental agents (particularly in complex mixtures) in the etiology of human cancer.

The interaction of a carcinogen with macromolecules was demonstrated by Miller and Miller in 1947, when they showed that azo dye bound to the liver protein of treated rats. Later studies indicated the importance of carcinogen modification of DNA (either directly or after metabolic activation) in the cancer process. The measurement of carcinogen metabolites, carcinogen-DNA adducts, or carcinogen-protein adducts in human tissues or fluids provide the basis for molecular dosimetry research and the rapidly expanding field of “molecular” cancer epidemiology. The potential advantage of this approach is that more accurate assessments of individual or group dose may be achieved than through estimates of carcinogen exposure in the environment or workplace.

Carcinogen-DNA and carcinogen-protein adducts have been detected in tissues from a variety of human populations with known or suspected carcinogen exposure. [16] [17] PAH-DNA adducts are elevated in white blood cells from individuals occupationally exposed to airborne PAHs, including coke oven workers, foundry workers, and aluminum plant workers. Increased levels of PAH-DNA adducts have also been reported in lung tissue from heavy smokers. DNA isolated from exfoliated bladder epithelial cells of cigarette smokers has been shown to contain 4-aminobiphenyl adducts. Alkylation damage has been detected in DNA from esophageal tissue of persons living in regions with documented dietary exposure to nitrosamines. Aflatoxin adducts are found in hepatic DNA following dietary exposure to this mycotoxin. Cisplatin-DNA intrastrand adducts have been measured in white blood cells of patients undergoing cancer chemotherapy.

Carcinogen-DNA adducts excreted in urine provide a noninvasive means for quantifying DNA damage. Urinary concentration of aflatoxin-guanine adducts is strongly correlated with dietary aflatoxin intake. In addition to their use as indicators of previous carcinogen exposure, DNA adducts have the potential for use as direct indicators of future cancer risk. The first prospective test of this application appeared in 1992, when detectable levels of aflatoxin-guanine adducts, as well as several other aflatoxin metabolites, in urine were shown to be predictive of liver cancer development.[11] Furthermore, an interactive effect for liver cancer risk was seen between urinary aflatoxin biomarkers and HBV infection history.

Carcinogen-protein adducts have also proved useful as biomarkers of human exposure. Alkylation damage in hemoglobin has been used as an exposure index in risk assessment analyses of individuals occupationally exposed to ethylene oxide. 4-aminobiphenyl adducts in hemoglobin are highly specific (and sensitive) markers of exposure to cigarette smoke.[16] The level of 4-aminobiphenyl hemoglobin adducts is related to the number of cigarettes smoked, the type of tobacco, and the metabolic phenotype of the smoker. The levels of these adducts drop markedly after smoking cessation.

Unreacted carcinogen metabolites excreted in urine are also used to monitor human exposure to and uptake of carcinogens and related compounds. Concentrations of hydroxylated PAHs (e.g., 1-hydroxypyrene) in urine are elevated in smokers, in patients after topical treatment with coal tar, in road pavers, in coke oven workers, in aluminum plant workers, and in individuals ingesting PAHs from food.[18] In occupational settings, the concentration of urinary 1-hydroxypyrene is highly correlated with estimated or measured concentrations of airborne PAHs. This noninvasive approach to exposure assessment has potential application as a routine biomonitoring tool. In all these studies, significant differences in adduct or metabolite levels are often observed between individuals with similar carcinogen exposure. These differences have been attributed to several factors, including individual biologic variability, exposure misclassification, and confounding variables such as diet, physical activity, smoking, or personal environment. An understanding of the true basis for these differences will be useful in elucidating the determinants of individual susceptibility to cancer. By identifying specific modulators that enhance or inhibit carcinogen metabolism and the formation of adducts, it will be possible to examine their effects on human cancer risk.

Metabolic Polymorphisms and Human Susceptibility

Another major area of research in molecular cancer epidemiology is the study of individual metabolic phenotypes and their roles in determining biomarker levels and human susceptibility to carcinogens.[19] Certain cytochrome P-450 metabolic enzymes are known to be involved in the activation of specific human carcinogens, and some have been linked to increased cancer risk. For example, inducible CYP1A1 activity is higher in cultured lymphocytes from lung cancer cases than in controls. Genetic polymorphisms in the CYP1A1 structural gene have also been associated with lung cancer risk in Asian populations.

Hepatic arylamine N-acetyltransferase correlates with individual differences in susceptibility to human bladder cancer.[19] A series of genetic polymorphisms of this enzyme exist in humans, resulting in slow- and rapid-acetylator phenotypes. The rapid-acetylator phenotype seems to protect aromatic amine-exposed individuals from bladder cancer These results are attributed to the competition of N-acetylation of arylamines against the formation of reactive arylamine metabolites that reach the bladder.

A recent meta-analysis of 22 case-control studies in the general population examined the effect of slow acetylation on risk of bladder cancer.[9] Overall, the slow-acetylation phenotype/genotype was found to increase risk of bladder cancer by about 40% as compared with rapid acetylators (odds ratio of 1.4, with 95% confidence interval of 1.2–1.6). This is the clearest example of a common metabolically modified cancer risk in the general population. The carcinogenic exposure in this case is, presumably, due to aryl amine compounds from various sources, including cigarette smoke.

DNA Repair and Human Susceptibility

An important mechanism that protects the genome from mutagenic effects of carcinogens is the repair of cellular DNA. The importance of this protection is perhaps best illustrated by the unusually severe effects of sunlight on individuals who are deficient in DNA repair.[20] The rare inherited disorder xeroderma pigmentosum (XP) is characterized by various levels of DNA-repair deficiencies. Individuals with XP show an unusually high incidence of multiple skin cancers and rarely live beyond early adulthood in the absence of protective measures against sunlight. The median age of onset for nonmelanoma skin cancers among XP patients is approximately 8 years of age, as compared with about 60 years of age in the general population. In addition, the prevalence of melanoma of the skin is unusually high among XP patients.

Several other inherited diseases show altered cellular response to DNA damage.[21] Ataxia telangiectasia, Bloom syndrome, and Fanconi's anemia are autosomal recessive genetic disorders characterized by chromosomal instability, with patients developing malignancies more frequently and at younger age than occurs in the general population. Approximately 10% of individuals with ataxia telangiectasia develop malignancies, primarily of the lymphoreticular system, before the age of 20. Heterozygous relatives of individuals with ataxia telangiectasia and those with Fanconi's anemia are also at moderately increased risk of cancer as compared with unrelated persons.

Although these diseases clearly represent unusual cases, some forms of these diseases (e.g., complementation group XP-E) show only moderate deficiencies in DNA repair—approximately 60% to 90% of normal—yet remain unusually susceptible to cancer. This finding suggests that small reductions in DNA repair efficiency can lead to considerable increases in cancer susceptibility. Interestingly, significant variability in DNA repair proficiency has been demonstrated among disease-free “normal” individuals. This variability in the general population could contribute to differences in susceptibility not only to skin cancer but also to cancers of other organs.


An aging population and a decline in mortality from cardiovascular disease could soon herald the emergence of cancer as the major cause of death in the United States. Moreover, the curative treatment of many established (and especially disseminated) malignancies remains an enigmatic problem for which progress is measured in small steps. Clearly, the optimal way for dealing with virtually all diseases, including cancer, is prevention. As a consequence, the challenge to public health professionals is to devise and implement preventive measures against cancer.

As presented in Figure 9-2 , the prevention of cancer can take several forms. Primary prevention targets healthy individuals and can be achieved by avoiding exposure to risk factors. Another approach is to stimulate the defense mechanisms of the host to interfere with the carcinogenic process. Secondary prevention measures use early detection and intervention before pathologic conditions are clinically apparent. The success of these strategies will be greatly facilitated by the development of noninvasive biomarkers that identify high-risk individuals. Finally, tertiary prevention is aimed at minimizing the effect of existing disease and consequent disability by avoiding development of new cancers and complications or relapses after therapy for initial malignancies.


Figure 9-2  Strategies for prevention of multistage carcinogenesis.



Identifying Human Carcinogens

The major current strategy for cancer prevention is the avoidance of exposure to environmental, industrial, and social hazards ( Box 9-2 ). Identification of human carcinogens takes two forms. In several instances (e.g., soot and coal tars, aromatic amines, vinyl chloride, and benzene), carcinogenic compounds were discovered after they were suspected of being involved in the development of cancers in humans. However, currently most carcinogenic substances are identified in the course of long-term toxicologic studies in animals. The value of this approach is buttressed by the fact that for those chemicals identified as being causally associated with human cancer, and for which there has been adequate experimental evaluation, all have been shown to cause cancer in laboratory animals.[22] However, animal bioassays for carcinogenicity are very costly (several million dollars per compound) and time consuming (5 years). Therefore, much attention is being directed toward the development and validation of short-term tests for carcinogens. Many assays for genotoxicity using mutagenesis, chromosome damage, or DNA repair as endpoints are used to screen chemicals for carcinogenic potential. Short-term assays for modifying factors such as co-carcinogens, tumor promoters, and anticarcinogens are being developed as well. A major difficulty in the use of animal bioassays is estimation of risk to humans. The assumptions contained in interspecies comparisons and high- to low-dose extrapolations render a straightforward assessment difficult. Bioassays are typically conducted with high doses of carcinogens to provide adequate tumor yields and statistical strength; however, there are strong concerns on mechanistic grounds as to the relevance of these types of exposures to chronic low-dose exposures in human populations. Protective host defense systems could be overwhelmed in these aberrant exposure settings. Another controversial issue in dose-response relationships is whether no-effect or threshold levels exist for chemical carcinogens. Based on considerations of metabolism, the barriers to electrophiles reaching critical targets in DNA, multiple alleles for transforming and/or suppressor genes, DNA repair, and other factors, it seems likely that for every carcinogen there must be a threshold. It could be very low for powerful carcinogens and correspondingly higher for weak carcinogens. Faced with the inability in practice to define human thresholds, however, prudent policy dictates avoidance of carcinogens wherever possible. The current regulatory posture in the United States assumes that all animal carcinogens are potential human carcinogens.

Box 9-2 


A series of reports from the U.S. Surgeon General since 1964 have argued that cigarette smoking is the most significant source of preventable morbidity and premature mortality in developed countries. An estimated annual excess mortality of 350,000 is attributed to cigarette smoking in the United States. These deaths are the result of coronary heart disease, cancer, and various respiratory diseases.[30] Cancers associated with smoking or smokeless tobacco use include those of the lung, oral cavity, esophagus, pharynx, larynx, and bladder. Weaker associations have been reported for cancers of the pancreas, kidney, stomach, nasopharynx, and cervix.[12] The overall increase in risk of disease among smokers compared with nonsmokers is about tenfold for lung cancer, sixfold for chronic obstructive pulmonary disease, and twofold for myocardial infarction. The combined effect of smoking-related diseases on the average life expectancy of smokers is a reduction of 5 to 8 years.

On a worldwide basis the data are equally disturbing. An estimated 4 to 5 million deaths per year are attributed to tobacco use—the majority of these in developed countries. If current usage trends continue unabated, estimates as high as 10 million deaths due to tobacco use annually could be expected by the year 2030.[30] Most of these deaths (approximately 7 million) are expected to occur in developing countries, where tobacco use is increasing rapidly. Whereas percentage of world tobacco consumption in developing countries was 49% in 1974 through 1976, this figure increased to 61% in 1984 through 1986 and to 70% in the year 2000. Per capita consumption of cigarettes is increasing most rapidly in developing Asian countries. Although the majority of tobacco is produced in developing countries, the declining market in developed countries has refocused the efforts of producers in these countries toward developing countries for continued growth.

The addictive properties of tobacco smoking, due primarily to nicotine, cause both physiologic and psychologic dependence. Withdrawal symptoms can be severe and include irritability, aggressiveness, hostility, depression, difficulty concentrating, and a craving for tobacco. These pharmacologic factors are reinforced by social factors such as peer pressure, emulation of family role models, and cultural influences. Because most smokers begin smoking, and often form lifelong smoking habits, in their teenage years, preventive educational measures should be focused on this age group.

Smoking control measures use various strategies: cessation programs, clinical or community interventions, governmental or private-sector regulations, taxation of tobacco products, and smoking prevention programs. Although the majority of ex-smokers have achieved abstinence without extensive personal assistance from organized cessation programs, other control measures (national health education programs, physician counseling, indoor smoking regulations) and family pressure are important influences contributing to smoking cessation. Smoking prevention programs, particularly in schools, and government taxation have been somewhat effective in reducing the initiation of smoking among children and adolescents in developed countries. These approaches will need to be applied in developing countries to stem the expansion of smoking worldwide.

Cancer Chemoprevention

The use of chemical or dietary interventions to alter the susceptibility of humans to the actions of carcinogens and to retard, block, or reverse carcinogenesis can be applied to all levels of prevention and has been termed chemoprevention.[23] There are many indications that these strategies are extremely effective in laboratory animals. Moreover, chemoprevention against cancer also works in humans.[24]Recent investigations have established significant site- and agent-specific effects in the prevention of invasive skin, upper aerodigestive tract, and breast cancers in high-risk groups.

It was first observed in the early part of the 20th century that carcinogenesis could be modified by discrete chemical agents. These initial experiments demonstrated that the formation of skin tumors in rodents could be blocked by local application of chemopreventive agents. The protective agents used in these early studies, however, were typically carcinogens or toxins themselves. Consequently, their application to humans did not appear to be practical. Thus, the field of cancer chemoprevention did not receive significant attention until the early 1970s, when Wattenberg demonstrated that dietary antioxidants could protect against tumor formation.[25] The experimental observations that seemingly innocuous preservatives found in the Western diet could dramatically protect against diverse carcinogens at distal sites sparked the development of chemoprevention as a viable strategy for the reduction of human cancers. Thus far, more than 20 classes of discrete chemicals have been shown to be effective inhibitors of experimental carcinogenesis.[25]

The expectation that effective chemoprotection against cancer can be achieved is supported by the view that cancer is unlikely to be the exception to the history of other major (infectious and noninfectious)diseases of humans, in which the mortality began to decline as a result of protective and preventive measures far in advance of specific treatments. Cancer chemoprevention could be especially valuable in populations at high risk of certain neoplasms, particularly as improved molecular techniques allow for the identification of these high-risk individuals. Preventive strategies can involve both prescriptive interventions with specific nutrients, non-nutrients, and drugs in selected populations at high risk of cancer, and lifestyle changes that include altered nutrition and social habits. These latter approaches might ultimately play an even greater role in the overall reduction of cancer in the general population.


The carcinogenic effects of many environmental and occupational agents were first described in humans. These observations were replicated in animal models beginning in the early 20th century. Whereas carcinogenic agents come in many forms, including naturally occurring and manufactured chemicals, radiations, metals, fibers, and viruses, tobacco use is probably the single most important cause of cancer. Nonetheless, the majority of human cancers probably result from interactions of several or more carcinogenic influences, none of which singly is readily detectable. Elucidation of the carcinogenic process has led to the recognition that both extrinsic and intrinsic factors interact to determine overall susceptibility and risk.

The identification of molecular biologic markers of exposure, effect, and susceptibility, reflecting events occurring before clinical disease, will help to further our understanding of human carcinogenesis. It is anticipated that the use of biologic markers will help define the roles of environmental agents (particularly in complex mixtures) in the etiology of human cancers. With the recent characterization of the human genome, much attention has focused on the role of common polymorphisms in carcinogen metabolism or of DNA repair genes and susceptibility to cancer. By identifying specific factors that enhance or inhibit carcinogen metabolism and biomarker formation, it will be possible to examine their effects on human cancer risk.

Primary and secondary approaches to the prevention of cancer will be greatly facilitated by the development of noninvasive biomarkers that identify high-risk individuals. Tertiary prevention might also be enhanced by characterizing cancers with respect to etiology, genetic profile, or metabolic capacity. The use of chemical or dietary interventions to alter the susceptibility of humans to the actions of carcinogens and to retard, block, or reverse carcinogenesis can be applied to all levels of prevention and has been termed chemoprevention. Preventive strategies can involve both prescriptive interventions with specific nutrients, non-nutrients and drugs in selected populations at high risk of cancer, and lifestyle changes that include altered nutrition and social habits.

The major current strategy for cancer prevention is the avoidance of exposure to environmental, industrial, and social hazards that increase the risk of cancer. Currently, most carcinogenic substances are identified in the course of long-term toxicologic studies in animals. Much attention is also directed toward the development and validation of short-term tests for carcinogens, such as mutagenicity, chromosome damage, or DNA repair.


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