Agent or Process	Common Organ or Tissue Sites of Cancer
AMBIENT AND DIETARY EXPOSURE
Acetaldehyde (from alcoholic beverages)	Upper digestive tract
Aflatoxins	Liver
Areca nut	Oral cavity
Aristolochic acid (from plants)	Renal pelvis and ureter
Arsenic and arsenic compounds	Lung, skin
Erionite	Pleura, peritoneum
CULTURAL HABITS
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	Nasopharynx
Solar radiation	Skin
OCCUPATIONAL EXPOSURES
Aluminum production	Lung, urinary bladder
4-Aminobiphenyl	Urinary bladder
Asbestos	Lung, pleura, peritoneum, larynx, gastrointestinal tract
Auramine production	Urinary bladder
Benzene	Leukemia
Benzidine	Urinary bladder
Benzo[a]pyrene	Lung
Beryllium	Lung
Methyl ether	Lung
Boot and shoe manufacture and repair	Nasal sinus
Cadmium	Lung
Chromium (VI) compounds	Lung
Coal combustion (indoors)	Lung
Coal gasification	Lung, urinary bladder, scrotum
Coal-tar pitches	Skin, scrotum, lung
Coal tars	Skin, lung
Coke production	Skin, scrotum, lung, urinary bladder
Dioxin	Multiple sites
Ethylene oxide	Lymphatic, hematopoietic
Fission products	Multiple sites
Formaldehyde	Liver
Furniture and cabinet making	Nasal sinus
Hematite mining	Lung
Iron and steel founding	Lung
Ionizing radiation (all types)	Multiple sites
Isopropyl alcohol manufacture (strong acid process)	Nasal sinus
Leather dust	Nasal sinus
Magenta, manufacture of	Urinary bladder
Mineral oils (untreated and mildly treated)	Skin, scrotum
Mustard gas	Lung, larynx/pharynx
2-Naphthylamine	Urinary bladder
Nickel and nickel compounds	Lung, nasal sinus
Painting	Lung
Polychlorinated biphenyl (PCB-126)	Liver, bile duct, lymphoid tissue
2,3,4,7,8-Pentachlorodibenzofuran	Soft tissue sarcoma, non-Hodgkin lymphoma, cancer of the lung
Rubber industry	Urinary bladder, leukemia
Shale oils	Skin, scrotum
Silica, crystalline	Lung
Soots	Skin, scrotum, lung
Strong inorganic acid mists	Larynx
Talc containing asbestiform fibers	Lung
Toluidine	Urinary bladder
Underground mining with exposure to radon	Lung
Vinyl chloride	Liver, lung, gastrointestinal tract, brain
Wood dust	Nasal cavities, paranasal sinuses
THERAPEUTIC AGENTS
Analgesics mixtures containing phenacetin	Renal, urinary bladder
Azathioprine	Leukemia
N,N-Bis(2-chloroethyl)-2-naphthylamine	Urinary bladder
Busulphan	Lympho-hematopoietic tissue
1,4-Butanediol dimethanesulfonate	Leukemia
Chlorambucil	Leukemia
Chlornaphazine	Urinary bladder
Cyclosporin	Lymphoma
Cyclophosphamide	Urinary bladder, leukemia
Diethylstilbestrol	Breast, cervix
Estrogen replacement therapy	Endometrium, breast
Estrogen, nonsteroidal	Cervix/vagina, breast, endometrium, testes
Estrogens, steroidal	Endometrium, breast
Etoposide	Lymphohematopoietic tissue
Melphalan	Leukemia
8-Methoxypsoralen plus UV radiation	Skin
MOCA (Methylene bis[2-chloroaniline])	Urinary bladder
MOPP combination therapy	Leukemia
Oral contraceptives (combined)	Liver
Oral contraceptives (sequential)	Endometrium
Phenacetin	Renal pelvis, ureter
Semustine (methyl-CCNU)	Leukemia
Sulfur mustard	Lung
Tamoxifen	Endometrium
Thiotepa	Leukemia
Treosulfan	Leukemia
INFECTIOUS AGENTS
Clonorchis sinensis	Liver, bile duct
Epstein-Barr virus	Lymphoma
Helicobacter pylori	Stomach
Hepatitis B virus	Liver
Hepatitis C virus	Liver
Human immunodeficiency virus type 1	Kaposi sarcoma
Human papilloma viruses types 16, 18, others	Cervix
Human T-cell lymphotropic virus type I	Adult T-cell leukemia/lymphoma
Kaposi sarcoma herpesvirus	Kaposi sarcoma
Opisthorchis viverrini	Liver (cholangiocarcinoma)
Schistosoma haematobium	Urinary bladder

Data from the International Agency for Research on Cancer. IARC monographs on the evaluation of carcinogenic risk to humans, vols. 1–104. Lyon (France): IARC; 1970-2012. An updated listing of the overall evaluation of carcinogenicity to humans can be accessed at http://monographs.iarc.fr under the heading “classifications.” (Note: For examples of carcinogenic ionizing radiations, see Table 9-3.)

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.

Role of Environmental Agents in the Etiology of Human Cancers

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 epidemiological 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.

• Large differences in tumor incidence exist 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. Biological factors such as viruses (e.g., hepatitis B virus and human papilloma virus) and bacteria, elements of our “environment,” are also exceedingly important contributors to the human cancer burden. Biological factors are discussed in Chapter 11.

The English surgeon Percival Pott was among the first to document the association of an environmental agent with cancer.² 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 finding came about through the application of coal tar and fractions thereof to the skins of test animals, in which malignant skin tumors subsequently developed. 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 to 20 µg/kg).

Cutaneous occupational exposure to PAHs has been associated with increased risk of skin and scrotal cancers in chimney sweeps and in persons exposed to unrefined lubricating oils in the textile and machining industries.¹ Scrotal cancer among mule spinners in the Manchester (United Kingdom) 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, whereas 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 persons 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 also might 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.³ One major pathway results in 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 reactive metabolites that 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.

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). IARC 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. An elevated incidence of bladder cancer associated with benzidine manufacturing and production in the United States and Japan is complicated by probable co-exposure 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 persons showing the slow phenotype could be more susceptible to bladder cancer caused by aromatic amines. This finding is consistent with a meta-analysis indicating that NAT2 slow acetylation status is associated with an increased risk of bladder cancer in the general population.⁹

Benzene

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 petroleum products containing benzene and of lymphomas among workers in New York State who were 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).

Aflatoxins

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 µg/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 also has been demonstrated in a prospective epidemiological 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 (Box 9-1). 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.

Box 9-1 Health Effects and Control of Smoking

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 high-income countries. An estimated annual excess mortality of 400,000 is attributed to cigarette smoking in the United States. These deaths are the result of coronary heart disease, cancer, and various respiratory diseases.⁴⁰ 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 6 million deaths per year are attributed to tobacco use, with upward of 80% of these deaths in low- and middle-income countries. If current use trends continue unabated, estimates as high as 8 million deaths due to tobacco use annually could be expected by the year 2030, and a total of 1 billion this century.⁴¹

The addictive properties of tobacco smoking, due primarily to its nicotine content, cause both physiological and psychological 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, warning labels, and smoking prevention programs. Although the majority of ex-smokers have achieved abstinence without extensive personal assistance from organized cessation programs, other control measures (e.g., national health education programs, physician counseling, and 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 developing countries. These approaches will need to be applied more vigorously, especially in low- to middle-income countries, to stem the expansion of smoking worldwide. New challenges also are arising with the creation of new and emerging tobacco products such as dissolvable tobacco products, e-cigarettes, and hookah tobacco. The recent Family Smoking Prevention and Tobacco Control Act (2009) in the United States has given the U.S. Food and Drug Administration broad authority to regulate the manufacturing, distribution, and marketing of these and more traditional tobacco products to protect public health.

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

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