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Environmental Carcinogenesis
Introduction to Cancer and the Environment
Environment, Genetics, and Cancer
Overall human cancer risk is determined by complex interactions between host genetics and environmental exposures. On exposure to a cancer-causing agent, a cascade of events is set into motion that converts normal cells into cancer cells. This process is referred to as carcinogenesis, and cancer-causing agents are referred to as carcinogens. Hundreds of confirmed and suspected environmental carcinogens have been identified. Environmental factors are generally believed to account for a significant portion of cancer mortality worldwide. In the context of the current chapter, we refer to the environment as any substance or agent that is normally present outside of the human body and that interacts with the human body to increase cancer risk. Genetically controlled host factors also contribute to cancer risk, primarily through modulation of responses to environmental agents. Understanding the causes of cancer and the underlying mechanisms that lead to cancer development provides a rational basis for developing prevention strategies. In this chapter, we discuss the major known environmental causes of cancer and, where applicable, underlying mechanisms. In addition, where known, significant gene-environment interactions are highlighted.
History of Chemicals and Cancer
The environmental contribution to chronic diseases such as cancer has been recognized for centuries. In 1775, Dr. Percival Pott observed that chimney sweeps experienced an increased incidence of scrotal cancer, which was attributed to frequent and heavy exposure to soot. A century later, an excess of skin cancers was reported in coal tar workers in Germany and related to their occupational exposure. In the early 20th century, these observations were experimentally validated by Yamagiwa and Ichikawa, who demonstrated that multiple topical applications of coal tar to rabbit ears induced skin carcinomas. These studies were the first to demonstrate that a complex mixture was capable of inducing cancer. Sir Ernest Kennaway and others furthered these studies in the 1920s and 1930s. The group fractionated coal tar with the goal of isolating the principal carcinogenic agent. Fractions were screened for a characteristic blue-violet fluorescence spectrum, which was highly correlated with carcinogenic potency. Ultimately, benzo[ a ]pyrene (B[ a ]P), which is composed entirely of carbon and hydrogen ( Figure 7-1 ), was identified, synthesized, and shown to be a potent carcinogen in animal models. Collectively, these important early studies indelibly transformed the study of environmental carcinogenesis. In isolating a compound from coal tar that could induce cancer in animals, an occupational carcinogen exposure was linked to cancer incidence, and the utility of animal models of carcinogenicity in the interpretation of human epidemiologic associations was established.
Kennaway’s studies in the early 20th century immediately preceded major progress in understanding the biochemical nature of genetic material and cellular replication. Beginning shortly after the discovery of benzo[ a ]pyrene, Avery and colleagues pursued experiments to reveal the identity of the transforming material of pathogenic Streptococcus pneumoniae . Results of their analyses showed that nucleic acids carried genetic information, although their findings were not widely accepted until the 1950s when Hershey and Chase published data demonstrating that DNA is the genetic material of viruses. Shortly thereafter, work with mutagenic mustard gas suggested that DNA was the target of carcinogens, and data published in the early 1960s revealed that mutagens covalently modify DNA. Further, the carcinogenic potency of a series of hydrocarbons was positively correlated with the extent of their reaction with DNA. These and other studies provided compelling evidence for DNA as a target of carcinogens and gene mutation as a major mechanism whereby agents induce cancer. With this foundational knowledge, the list of known carcinogens has grown rapidly, along with a greater understanding of the mechanisms of cancer development associated with these agents.
Causes of Cancer
Epidemiology and Causal Criteria
The landmark findings of Kennaway, Avery, Hershey, Chase, and others in the early part of the 1900s guided a period of rapid advancement in the laboratory concerning the molecular basis of cancer. In contrast, the discovery of specific human carcinogens has been largely guided by epidemiologic studies of cancer incidence. The study of worldwide cancer incidence patterns, including analysis of cancer risk among migrant populations, has confirmed the critical role of environment in determining cancer risk. Studies of exposure cohorts and observational studies of cancer incidence have been especially crucial in the identification of the biologic, physical, and chemical agents capable of causing cancer. Similarly, epidemiologic studies have revealed numerous lifestyle choices and socioeconomic factors associated with increased risk of cancer.
Cancer risk is known to vary extensively worldwide. For instance, liver cancer risk varies 20- to 40-fold internationally; the incidence is highest in eastern Asia and lowest in northern Europe and Central America. Prostate cancer rates are high in the United States, Canada, and Scandinavia, especially in comparison with the rates in China and other Asian countries. Similarly, breast cancer risk has historically been higher in the United States and European countries than in Asia, Africa, and South America. These observations suggest that (1) genetic differences among ethnic groups alter cancer risk and/or (2) differences in environmental exposures among geographic locations affect the risk of developing cancer.
Capitalizing on known ethnic variation in cancer rates, analysis of cancer risk in migrant populations has been undertaken and has yielded important information concerning the relative contribution of environment versus genetics in cancer etiology. In these studies, the rate of cancer in migrant cohorts is compared with the rate of cancer among people of the same ethnicity living in the country of origin and to the cancer rate of people in the destination population. For example, breast cancer incidence among Asian immigrants to the United States has been compared with that of women still living in their country or region of origin. The breast cancer risk of Asian American women born in the East has been shown to rise with increasing number of years lived in the West. Ultimately, the risk of breast cancer among Asian American women approaches that of U.S.-born White women and is significantly higher than that of Asian women still living in the country of origin. Numerous studies of this kind demonstrate that even while in the first generation following relocation, immigrant populations assume a pattern of cancer risk in common with native populations rather than with populations in their country of origin. These studies imply that environmental factors play a significant role in determining cancer risk. Similarly, studies of cancer risk in twins have suggested the importance of environmental factors in determining overall cancer risk.
Recent population-based evidence further underscores the overall importance of environmental factors in determining cancer risk. Cancers that were once associated with affluence and/or the Western lifestyle are on the rise in less developed countries. Rates of colon, breast, and lung cancers in developing countries have increased as their economies have transitioned. Multiple factors likely contribute to this trend, including non-genetically controlled influences such as tobacco use, diet, and physical activity.
In addition to population-based evidence, case-control and cohort studies have been used to identify specific environmental agents and factors that are now considered to be human carcinogens. To assess the likelihood that a particular environmental exposure is causally linked to cancer, epidemiologic data are interpreted in the context of mechanistic data and other considerations. The strength of evidence for a causal role in cancer development is evaluated using criteria developed as a modification of Bradford-Hill’s criteria (1965) for assessment of evidence of causation :
- 1.
Strength of Association: Large-magnitude effects on cancer risk are less likely than small-magnitude effects to be due to chance.
- 2.
Temporal Relationship: To be causal, the environmental exposure must have happened in advance of the appearance of cancer.
- 3.
Biologic Plausibility: Relationships that can be supported by laboratory evidence or a plausible mechanistic hypothesis are more likely to be causal relationships.
- 4.
Dose-Response Relationship: Studies that demonstrate a gradient in disease outcome whenever a gradient in exposure has occurred provide stronger support for a causal relationship than those studies that do not demonstrate a positive correlation between dose and response.
- 5.
Consistency: The most probable causal relationships are consistently demonstrated in multiple studies of the exposure-disease relationship.
Using these criteria, numerous cancer-causing agents and/or risk factors have been identified for further characterization.
Known Cancer Risk Factors
In a landmark paper published in 1981, Doll and Peto summarized available epidemiologic data to estimate the percentage of U.S. cancer deaths attributable to a variety of environmental and lifestyle influences. Their analyses suggested that as many as 60% of all cancer deaths could be attributed to two environmental factors: diet and tobacco use. More than 30 years later, these estimates appear to remain valid; diet and tobacco use continue to be primary determinants of cancer mortality. Additional factors cited by multiple investigators and regulatory agencies as contributing to cancer risk include occupation, radiation, alcohol, pollution, infections, medications, and reproductive and socioeconomic factors.
Smoking
Tobacco use remains the single most important and avoidable factor in determining cancer risk. Smoking is estimated to contribute to at least 30% of all cancer deaths. Lung, bladder, esophageal, pancreatic, uterine, oral, and nasal cavity cancers, among others, have all been associated with tobacco use. Approximately 90% of all lung cancer deaths can be attributed to smoking. Lung cancer risk is greatest for persons who begin smoking at an early age and continue smoking for many years, and the risk of tobacco smoke–induced lung cancer is directly proportional to the dose inhaled. Tobacco smoke is a complex mixture of chemicals, 55 of which are known or suspected human carcinogens ( Table 7-1 ). On absorption in the lungs, these agents may act locally or at distal sites to (1) induce DNA damage and (2) alter cellular growth and proliferation. A synergistic effect has been noted in the case of combined tobacco use and heavy alcohol use. Despite antitobacco sentiment, approximately one fifth of U.S. citizens are still smokers, and smoking rates in countries such as China remain high; therefore, smoking-induced cancers are likely to continue to be prevalent worldwide.
Table 7-1
Carcinogens in Tobacco Smoke
Adapted from Hecht SS. Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst 1999;91:1194.
| Carcinogen Class | No. of Compounds | Example Compound |
|---|---|---|
| Polycyclic aromatic hydrocarbons | 10 | Benzo[ a ]pyrene 5-Methylchrysene Dibenz[ a , h ]anthracene |
| Aza-arenes | 3 | Dibenz[ a , h ]acridine |
| N -nitrosamines | 7 | 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) N -Nitrosodiethylamine |
| Aromatic amines | 3 | 4-Aminobiphenyl |
| Heterocyclic amines | 8 | 2-Amino-3-methylimidazo[ 4 , 5 - f ]quinoline |
| Aldehydes | 2 | Formaldehyde |
| Miscellaneous organic compounds | 15 | 1,3-Butadiene Ethyl carbamate |
| Inorganic compounds | 7 | Nickel Chromium Cadmium Arsenic |
| Total | 55 |
Diet
The effects of diet on cancer risk have been attributed both to dietary chemical constituents and to overall energy consumption. As many as 14% to 30% of cancer deaths have been attributed to overweight and obesity. Overweight and obesity, as defined by the ratio of weight to height known as body mass index (BMI), are prevalent at epidemic proportions in the United States and other developed countries. Overweight and obesity have been associated with elevated risk of cancers of the colon, breast, endometrium, kidney, liver, pancreas, gallbladder, ovary, cervix, rectum, and esophagus as well as risk of non-Hodgkin’s lymphoma and multiple myeloma. In addition, animal studies have consistently demonstrated that restricting calorie intake can significantly reduce cancer risk, whereas inducing obesity can significantly elevate cancer risk. Despite these findings, a complete understanding of the mechanistic basis for the effect of dietary energy balance status on cancer formation is not conclusively known. Elevated steroid hormone production in adipose tissue has been proposed as the basis for obesity-induced endometrial and breast cancers; adipose-derived leptin, adiponectin, and proinflammatory molecules may affect cancer development more broadly. Recent studies have suggested that alterations in circulating insulin-like growth factor 1 (IGF-1) levels may account for some of the effects of altered dietary energy balance status on cancer risk.
In addition to excess calorie intake, certain dietary constituents may affect cancer risk. In the United States, cancer risk due to food additives is presumed to be quite low because the U.S. Food and Drug Administration (FDA) strictly regulates food additive use. In 1958, an amendment to the Food, Drugs, and Cosmetic Act of 1958, referred to as the Delaney Clause, was approved and stated that “the Secretary (of the FDA) shall not approve for use in food any chemical additive found to induce cancer in man, or, after tests, found to induce cancer in animals.” Presumably, therefore, cancer risk due to food additive consumption is quite low. Nonetheless, inadvertent food contaminants such as the plasticizer bisphenol A remain a source of concern. Bisphenol A is a weak endocrine-disrupting agent that has been associated with a variety of health effects including increased cancer risk. Fungal toxins such as aflatoxins are food contaminants resulting from mold growth on foodstuffs. Several of these toxins have been shown to be extremely potent mutagens and in some cases potent carcinogens (e.g., aflatoxin B 1 [AFB 1 ]). Red meat consumption has been associated with elevated colorectal cancer risk, possibly due in part to the carcinogenic nitrosamine and heterocyclic amine content of preserved or heat-treated meats.
Although examples of carcinogenic dietary constituents can be identified, a possibly greater dietary determinant of cancer risk is consumption of anticarcinogenic fruits and vegetables. Consumption of fruits and vegetables has consistently been linked to reduced cancer risk for a variety of cancer types. Fruits and vegetables contain numerous antioxidant compounds, which may guard against oxidative DNA damage or other forms of carcinogenic assault. In fact, tea phenols such as epigallocatechin-3-gallate (EGCG), the turmeric component curcumin, grape-derived resveratrol, and lycopene from tomatoes are all proposed cancer preventive agents. On the other hand, excess consumption of herbal health supplements is an emerging dietary concern due to their widespread use in the absence of proper validation or safety assessment. As an example, renal failure was noted in women who consumed weight-reducing Chinese herbal pills. The pills were inadvertently substituted with a nephrotoxic herb, Aristolochia fangchi , containing aristolochic acids. Aristolochic acids are mutagenic and carcinogenic, and a high rate of urothelial carcinoma was noted in the population of women who consumed these pills.
Occupation
Many carcinogens have been identified at the cost of human exposure and cancer incidence that occurred as a result of industrialization. Human epidemiologic studies highlight the potency of chemical and physical carcinogens and how lack of understanding leads to lack of preparation and protection. In the 1800s, high incidence of bladder cancer among workers in the aniline dye industry was recognized. Later, evidence was reported demonstrating that 2-napthylamine and benzidine were two carcinogenic agents responsible for this unusual cancer incidence. Also during the early 1900s, nearly 5000 workers were hired to apply luminous radium-containing paint to watch and instrument dials. Because of their occupational radiation exposure and a lack of precautionary practices, a large excess of bone cancers was noted among this cohort. Thousands of workers were exposed to vinyl chloride before its ability to induce angiosarcoma of the liver was recognized. Since the 1970s, strict workplace regulations and protective measures in the United States have largely prevented such dramatic incidents. The Occupational Safety and Health Administration (OSHA) was signed into existence in 1970 by the U.S. government with the goal of ensuring worker safety and health by improving the workplace environment. OSHA sets the legal limit for worker exposure to hazardous compounds in the United States. These limits are referred to as permissible exposure limits (PELs). PELs have been issued for approximately 500 chemicals, a portion of which are known or suspected carcinogens. Also created in 1970, the Environmental Protection Agency (EPA) is charged with protecting human health and the environment. In addition to other roles, the EPA regulates the release of industrial pollution, including carcinogens. Before these institutions were in place, employment in a wide variety of settings was linked to elevated risk of numerous cancers ( Table 7-2 ).
Table 7-2
Environmental Carcinogens Associated with Occupation
| Occupation | Carcinogen Exposure | Associated Cancer Type |
|---|---|---|
| Iron and steel founding | PAH, chromium, nickel, formaldehyde | Lung |
| Copper mining and smelting | Arsenic | Skin, bronchus, liver |
| Underground mining | Radon (ionizing radiation ) | Lung |
| Aluminum production | PAH | Lung |
| Coke production | PAH | Lung, kidney |
| Painting | Chromium, solvents | Lung |
| Furniture and cabinet making | Wood dust | Nasal sinus |
| Boot and shoe manufacture | Leather dust, benzene | Nasal sinus, leukemia |
| Rubber industry | Aromatic amines, solvents | Bladder, leukemia |
| Nickel refining | Nickel | Nasal sinus, bronchus |
| Vinyl chloride manufacture | Vinyl chloride | Liver |
| Dye and textile production | Benzidine-based dyes | Bladder |
PAH, Polycyclic aromatic hydrocarbons.
Despite regulatory measures, occupational exposure to carcinogens continues. In the U.S. President’s Cancer Panel Report of 2008-2009, members highlighted 14 types of environmental contaminants from industrial, manufacturing, and agricultural sources (polyhalogenated biphenyls, asbestos, chromium, perchloroethylene/trichloroethylene, particulate matter, mercury, formaldehyde, endocrine-disrupting chemicals, atrazine, DDT, nitrogen fertilizers, phosphate fertilizers, and veterinary pharmaceuticals) due to their cancer-causing potential and high probability of human exposure. The group estimated that millions of workers continue to be exposed to high levels of these and other agents each year. The families of exposed workers also experience higher than average exposure due to home contamination and may be at elevated cancer risk. As examples, chromium used in leather tanning, manufacture of dyes and pigments, wood preservation, and chrome plating is an established risk factor for lung cancer. Perchloroethylene, heavily used in dry-cleaning businesses, is classified as a probable carcinogen by the International Agency for Research on Cancer (IARC), and formaldehyde (a group 1 human carcinogen) is a synthetic starting material in manufacturing and a widely used disinfectant and preservative.
Causes of Cancer by Organ Site
Although an extensive list of known human carcinogens has been collected, the cause of many common cancers is still unknown. As shown in Table 7-3 , gastric, liver, and cervical cancers are each clearly linked with biologic carcinogens: Helicobacter pylori , hepatitis B virus (HBV), and human papillomavirus (HPV), respectively. The vast majority of lung cancer cases can be linked to tobacco use, and mesothelioma incidence is strongly correlated with exposure to asbestos. In contrast, the causes of most brain, pancreas, and prostate cancers remain largely unknown. For many other cancer types such as bone cancers, relatively rare exposures have been causally linked to incidence, yet the associated attributable risk is quite low. The remainder of cases continues to be largely unexplained. In general, linking particular cancers to specific exposure events can be problematic, and further work is necessary to uncover the primary causes of a significant number of cancers. Limiting factors include the inability to accurately estimate exposure dose and duration and a lack of understanding of combinatorial effects in multi-exposure events and finally lack of adequate biomarkers of exposure.
Table 7-3
Exposures Associated with Human Cancers, as Identified by the IARC (Partial Listing)
Adapted from Cogliano et al. Preventable exposures associated with human cancers. J Natl Cancer Inst 2011;103:1835.
| Cancer Site | Carcinogenic Agents with Sufficient Evidence in Humans | Agents with Limited Evidence in Humans |
|---|---|---|
| Oral cavity | Alcohol, betel quid, HPV, tobacco smoking, smokeless tobacco | Solar radiation |
| Stomach | Helicobacter pylori , rubber production industry, tobacco smoking, x-rays, gamma radiation | Asbestos, Epstein-Barr virus, lead, nitrate, nitrite, pickled vegetables, salted fish |
| Colon and rectum | Alcohol, tobacco smoking, radiation | Asbestos, Schistosoma japonicum |
| Liver and bile duct | Aflatoxins, alcohol, Clonorchis sinensis , estrogen-progestin contraceptives, HBV, HCV, Opisthorchis viverrini, plutonium, thorium-232, vinyl chloride | Androgenic steroids, arsenic, betel quid, HIV, polychlorinated biphenyls, Schistosoma japonicum , trichloroethylene, x-rays, gamma radiation |
| Pancreas | Tobacco smoking, smokeless tobacco | Alcohol, thorium-232, x-rays, gamma radiation, radioiodines |
| Lung | Tobacco smoking, aluminum production, arsenic, asbestos, beryllium, bis (chloromethyl) ether, chloromethyl methyl ether, cadmium, chromium, coal combustion and coal tar pitch, coke production, hematite mining, iron and steel founding, MOPP, nickel, painting, plutonium, radon, rubber production, silica dust, soot, sulfur mustard, x-rays, gamma radiation | Acid mists, manufacture of glass, indoor emissions from household combustion, carbon electrode manufacture, chlorinated toluenes and benzoyl chloride, cobalt metal with tungsten carbide, creosotes, engine exhaust, insecticides, dioxin, printing processes, welding fumes |
| Skin—melanoma | Solar radiation, UV-emitting tanning devices | |
| Other skin cancers | Arsenic, azathiopurine, coal tar pitch, coal tar distillation, cyclosporine, methoxsalen plus UVA, mineral oils, shale oils, solar radiation, soot, x-rays, gamma radiation | Creosotes, HIV, HPV, nitrogen mustard, petroleum refining, UV-emitting tanning devices |
| Mesothelioma | Asbestos, erionite, painting | |
| Breast | Alcohol, diethylstilbestrol, estrogen-progesterone contraceptive and menopausal therapy, x-rays, gamma radiation | Estrogen menopausal therapy, ethylene oxide, shift work resulting in circadian disruption, tobacco smoking |
| Uterine cervix | Diethylstilbestrol (exposure in utero), estrogen-progestogen contraception, HIV, HPV, tobacco smoking | Tetrachloroethylene |
| Ovary | Asbestos, estrogen menopausal therapy, tobacco smoking | Talc-based body powder, x-rays, gamma radiation |
| Prostate | Androgenic steroids, arsenic, cadmium, rubber production industry, thorium-232, x-rays, gamma radiation, diethylstilbestrol (exposure in utero) | |
| Kidney | Tobacco smoking, x-rays, gamma radiation | Arsenic, cadmium, printing processes |
| Urinary Bladder | Aluminum production, 4-aminobiphenyl, arsenic, auramine production, benzidine, chlornaphazine, cyclophosphamide, magenta production, 2-naphthylamine, painting, rubber production, Schistosoma haematobium, tobacco smoking, toluidine, x-rays, gamma radiation | Coal tar pitch, coffee, dry cleaning, engine exhaust, printing processes, occupational exposures in hair dressing and barbering, soot, textile manufacturing |
| Brain | X radiation, gamma radiation | |
| Leukemia and/or lymphoma | Azathiopurine, benzene, busulfan, 1,3-butadiene, chlorambucil, cyclophosphamide, cyclosporine, Epstein-Barr virus, etoposide with cisplatin and bleomycin, fission products, formaldehyde, Helicobacter pylori , HCV, HIV, human T-cell lymphotropic virus type 1, Kaposi’s sarcoma herpesvirus, melphalan, MOPP, phosphorus-32, rubber production, semustine, thiotepa, thorium-232, tobacco smoking, treosulfan, X radiation, gamma radiation | Bischloroethyl nitrosourea, chloramphenicol, ethylene oxide, etoposide, HBV, magnetic fields, mitoxantrone, nitrogen mustard, painting, petroleum refining, polychlorophenols, radioiodines, radon-222, styrene, teniposide, tetrachloroethylene, trichloroethylene, dioxin, tobacco smoking (childhood leukemia in smokers’ children) |
HBV, Hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HPV, human papillomavirus; IARC, International Agency for Research on Cancer; MOPP, mustargen-oncovin-procarbazine-prednisone chemotherapy; UVA, ultraviolet A light.
Classes and Types of Carcinogens
Carcinogen Evaluation and Classification
The U.S. National Toxicology Program (NTP), the World Health Organization’s International Agency for Research on Cancer (IARC), the U.S. EPA, and other agencies characterize and report the carcinogenicity of environmental agents and other factors (including drugs). Each entity independently evaluates the available evidence to rate the cancer-causing potential of a chemical, chemical mixture, occupational exposure, physical agent, biologic agent, or lifestyle factor. The most frequently referenced database is the IARC Monographs on the Evaluation of Carcinogenic Risks to Humans . IARC defines carcinogens as agents “capable of increasing the incidence of malignant neoplasms, reducing their latency, or increasing their severity or multiplicity.” Agents are selected for evaluation on the basis of two factors: (1) evidence of potential carcinogenicity and (2) known exposure of humans. During the scientific review and evaluation of potential carcinogens, a working group is formed and charged with summarizing available data concerning anticipated exposure levels, human epidemiologic data, and studies of cancer-producing capacity in animals. Although the goal of the IARC Monographs has been to identify carcinogens regardless of an explanatory mechanism, information on mechanisms can also be used as supporting data. All agents evaluated by IARC are classified into one of five categories as shown in Table 7-4 . As of the most recent report, 108 agents, groups of agents, or exposure scenarios are listed as “Carcinogenic to Humans” (a partial listing is shown in Table 7-5 ). An additional 64 are listed as “Probably Carcinogenic to Humans.” These agents are extremely diverse in structure, potency, and mechanism.
Table 7-4
IARC Classification of Suspected Carcinogenic Agents
| Group 1: Carcinogenic to humans: Sufficient evidence of carcinogenicity in humans exists or sufficient evidence of carcinogenicity in animals is supported by strong evidence of a relevant mechanism of carcinogenicity in humans. |
| Group 2A: Probably carcinogenic to humans: Limited evidence of carcinogenicity in humans exists but sufficient evidence of carcinogenicity in animals has been demonstrated. Alternatively, inadequate evidence in humans with sufficient evidence in animals may be supported by strong evidence that a similar mechanism of carcinogenicity would occur in humans. |
| Group 2B: Possibly carcinogenic to humans: Limited evidence of carcinogenicity in humans exists but inadequate evidence in experimental animals. Alternatively, this classification can be used for agents for which there are inadequate data in humans but sufficient evidence in animals or strong mechanistic data. |
| Group 3: Unclassifiable as to carcinogenicity in humans: Inadequate evidence in humans and animals exists. Alternatively, sufficient evidence of carcinogenicity may exist in animals but strong mechanistic data predict a lack of carcinogenicity in humans. |
| Group 4: Probably not carcinogenic to humans: Evidence suggesting a lack of carcinogenicity in humans and animals exists. |
IARC, International Agency for Research on Cancer.
Table 7-5
Selected IARC Known Human Carcinogens
| 4-Aminobiphenyl | Hepatitis B virus |
| Arsenic | Hepatitis C virus |
| Asbestos | Human immunodeficiency virus type 1 |
| Azathioprine | Human papillomavirus |
| Benzene | Human T-cell lymphotropic virus |
| Benzidine | Melphalan |
| Benzo[ a ]pyrene | 8-Methoxypsoralen |
| Beryllium | Mustard gas |
| N , N -Bis(2-chloroethyl)-2-naphthylamine | 2-Naphthylamine |
| Bis(chloromethyl)ether | Nickel compounds |
| Chloromethyl methyl ether | N ′-Nitrosonornicotine (NNN) |
| 1,4-Butanediol dimethanesulfonate | Phosphorus-32 |
| Cadmium | Plutonium-239 |
| Chlorambucil | Radioiodines |
| 1-(2-Chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea | Radium-224 |
| Chromium[VI] | Radium-226 |
| Cyclosporine | Radium-228 |
| Cyclophosphamide | Radon-222 |
| Diethylstilbestrol | Silica |
| Epstein-Barr virus | Solar radiation |
| Erionite | Talc-containing asbestiform fibers |
| Estrogen-progestogen menopausal therapy | Tamoxifen |
| Estrogen-progestogen oral contraceptives | 2,3,7,8-Tetrachlorodibenzo- para -dioxin |
| Estrogen therapy | Thiotepa |
| Ethylene oxide | Treosulfan |
| Etoposide | Vinyl chloride |
| Formaldehyde | X- and gamma (γ)-radiation |
| Gallium arsenide | Aflatoxins |
| Helicobacter pylori | Soots Tobacco Wood dust |
IARC, International Agency for Research on Cancer.
Types of Carcinogens
Carcinogens can be grouped into one of three categories according to their composition: (1) physical carcinogens, (2) biologic carcinogens, and (3) chemical carcinogens. The term physical carcinogen encompasses multiple types of radiation (e.g., ultraviolet [UV] and ionizing radiation). Biologic carcinogens refer to viral and bacterial infections that have been associated with cancer development (e.g., human papillomavirus [HPV] and hepatitis B virus [HBV]). Most carcinogens can be categorized as chemical carcinogens. As examples, heavy metals, organic combustion products (e.g., B[ a ]P), hormones, and fibers (e.g., asbestos) are considered to be chemical carcinogens. Note that in the discussion that follows, only selected carcinogens that are known to be carcinogenic in humans are described (see Table 7-5 ). For a more comprehensive listing of carcinogenic agents, including those listed in other IARC categories, refer to the WHO IARC monograph database ( http://monographs.iarc.fr/ENG/Monographs/PDFs/index.php ) and additional references.
Physical Carcinogens
Examples of physical carcinogens include UV and ionizing radiation. Radiation refers to flow of energy-bearing particles; ionizing radiation refers to radiation that is of sufficiently high energy to remove an electron from an atom or molecule with which it collides. Exposure to ionizing radiation of various forms has been shown to cause multiple types of cancers. In addition, solar radiation is of sufficient energy to elicit photochemical damage to the skin, ultimately leading to cancer formation.
The incidence of skin cancers such as melanoma, basal-cell carcinoma, and squamous-cell carcinoma has risen dramatically in recent years. The risk of developing skin cancer is highest in equatorial regions and correlates with the number of blistering sunburns encountered during childhood. Correlative studies such as these, in addition to mechanistic studies at the cellular and organismal levels, indicate that most skin cancers arise because of exposure to solar radiation. In particular, UV radiation in the 100- to 400-nm range appears to be causative. The health effects of UV radiation vary according to wavelength. Consequently, UV radiation is examined in three regions of wavelength: UVA, 315 to 400 nm; UVB, 280 to 315 nm; UVC, 100 to 280 nm. In contrast to UVC radiation, UVB and UVA can bypass the earth’s atmosphere, including stratospheric ozone; therefore, UVA and UVB are believed to contribute to a much higher attributable risk of cutaneous carcinogenesis than UVC. Moderate UVB exposure results in an erythema response, and UVB is well absorbed by cellular molecules such as DNA, melanin, amino acids, carotene, and urocanic acids. UVB is more potent in inducing skin tumors in hairless mice than UVA. However, exposure to UV light of any wavelength results in DNA damage and mutation in in vitro models, and UVA also induces tumors in hairless mice. For this reason, excess exposure to any wavelength of UV light is considered unsafe, and tanning beds have been placed on the IARC’s list of human carcinogens.
For UV radiation to produce an adverse reaction in skin, photon energy must be absorbed by the target biomolecules such as DNA. Although melanin produced by resident melanocytes is a critical UV radiation absorption filter, unfiltered photons may generate oxidative stress and/or damage DNA. UV irradiation of DNA results in the formation of pyrimidine dimers and other photodamage such as DNA strand breaks and pyrimidine-pyrimidone photoproducts. When these lesions are not repaired, DNA mutations can result. The hallmark UVB radiation-induced mutations are C→T or CC→TT transitions. Target genes for solar radiation–induced mutations include but are not limited to TP53 (squamous-cell carcinomas [SCCs], basal-cell carcinomas [BCCs], melanoma), CDKN2A (melanoma), BRAF (melanoma), NEDD9 (melanoma), and PTCH (BCCs, possibly SCCs). UV irradiation of skin keratinocytes also alters numerous cell signaling pathways such as growth arrest and DNA damage-response (i.e., p53, GADD45, mismatch repair genes), apoptotic (i.e., bcl-2, fas), and mitogenic (i.e., ras, ERK) signaling pathways.
In addition to solar radiation, ionizing radiation in the form of x-rays, nuclear fallout, and therapeutic irradiation as well as energy deposition from radon gas also contribute to the incidence of human cancers. Epidemiologic studies of radiation workers and atom bomb survivors of Hiroshima and Nagasaki as well as the use of animal models have led to the characterization of ionizing radiation as a “universal carcinogen.” Ionizing radiation can induce tumors in most tissues and in most species examined because of its unique ability to penetrate tissues and induce DNA damage via energy deposition.
Radon-222 is a radioactive gas that is produced by radioactive decay of uranium-238, which is found ubiquitously in soil, rock, and groundwater. Concern over accumulation of radon in indoor air, especially in underground spaces, has led to study of the health effects of inhaled radon. Radon decay results in the release of alpha particles (two protons and two neutrons), which do not deeply penetrate tissues but possess the capacity to damage DNA in areas of contact. Inhalation of radon has been associated with lung cancer incidence due to exposure of the bronchial epithelium to decay products. Uranium miners have been shown to succumb to lung cancer at a much higher rate than the general population because of their exposure to radon in underground air supplies. At the reduced exposure level detected in homes, radon carcinogenic potential is low, although not insignificant. WHO officials consider radon to be “the second most important cause of lung cancer second to tobacco in many countries” ( http://www.who.int/phe/radiation/backgrounder_radon/en/index.html ).
Biologic Carcinogens
Biologic carcinogens also play an important role in human carcinogenesis. Approximately 20% of human cancers are associated with infectious agents including bacteria, parasites, and viruses. These are discussed in more detail in Chapter 6 and are not discussed further in this chapter.
Chemical Carcinogens
Chemical carcinogens can be classified into one of four groups according to their chemical nature: organic carcinogens, inorganic carcinogens, fibers, and hormones. The first experimental confirmation of the existence of organic chemical carcinogens came in 1915, when Yamagiwa and Ichikawa demonstrated that multiple applications of coal tar could induce skin tumors on the ears of rabbits. It was later shown that the active carcinogenic agent was composed entirely of carbon and hydrogen. Since that time, numerous carbon-based carcinogens have been identified in studies using experimental animals and in epidemiologic studies of human populations. These organic compounds range from industrially produced and utilized solvents, to naturally occurring but chemically complex combustion products and mycotoxins, to simple alkyl halides such as vinyl chloride (see Figure 7-1 ).
Organic Carcinogens
Benzene
Benzene is a widely used solvent and is present in gasoline, automobile emissions, and cigarette smoke. Historically, high-level exposure to benzene was commonplace, and, in general, benzene exposure has been the cause of great concern due to its carcinogenic properties. Exposure to benzene occurs in industrial settings such as in rubber production, chemical plants, oil refineries, and shoe manufacturing. Because benzene is a volatile aromatic solvent, inhalation exposures predominate.
The carcinogenic properties of benzene have long been recognized; an increased risk of leukemia has been shown in workers exposed to high levels of benzene. Benzene exposure is associated with myelodysplastic syndromes. In addition, the strongest associations of benzene and cancer risk are found with risk of acute myeloid leukemia and non-Hodgkin’s lymphoma. Benzene is a recognized clastogen and induces oxidative stress upon metabolic activation. Along with mutagenic effects, benzene is believed to alter cell-signaling pathways that control hematopoiesis in hematopoietic stem cells. Workplace exposure restrictions have reduced human exposure to high levels of benzene. Current research is aimed at assessing risk associated with chronic low-level exposure scenarios.
Polycyclic Aromatic Hydrocarbons
Polycyclic aromatic hydrocarbons (PAHs) are a diverse group of intensively studied organic compounds including benzo[ a ]pyrene. Many PAHs can be metabolically activated to become highly reactive, electrophilic mutagens. PAHs are converted to “bay region” diol epoxides as depicted in Figure 7-2 . These diol epoxides covalently bind to DNA, forming a DNA adduct, and their overall reactivity is predictive of their carcinogenic potency. For example, benzo[ a ]pyrene diol epoxide reacts extensively with the exocyclic amino group of guanine to produce mutagenic DNA adducts ( Figure 7-3 , and see section entitled Initiation and Mutational Theory of Carcinogenesis). In addition, certain PAH metabolites may act synergistically with bay region diol epoxide metabolites to promote tumor formation in a manner unrelated to DNA adduct formation. PAHs are formed during combustion of organic matter such as coal, mineral oil, and oil shale. Therefore, PAH exposure occurs in the form of automobile exhaust, soot, coal tar, cigarette smoke, and charred food products. Many PAHs have been found to be carcinogenic in animal studies, and PAH exposure is associated in humans with lung, skin, and urinary cancers, among others. The carcinogenic potential of PAHs is highly variable. Examples of potent to moderately carcinogenic PAHs include 3-methylcholanthrene, B[ a ]P, dibenzo[ a , h ]anthracene, 5-methylchrysene, and dibenz[ a , j ]anthracene, whereas benzo[ e ]pyrene, dibenz[ a , c ]anthracene, chrysene, benzo[ c ]phenanthrene and fluoranthene are relatively weak or inactive carcinogens. Because humans are exposed to mixtures of PAH that are produced during combustion, estimates of carcinogenic potential associated with diverse exposure scenarios are highly variable.
Aflatoxin B 1
One of the most potent liver carcinogens is the fungal metabolite aflatoxin B 1 (AFB 1 ). AFB 1 and other aflatoxins are produced by Aspergillus mold species, such as Aspergillus flavus and Aspergillus parasiticus. Exposure to aflatoxins occurs via consumption of contaminated nuts and grain, such as peanuts and corn, on which Aspergillus species grow. Humid conditions and poor storage contribute to the growth of these molds. In numerous epidemiologic studies, the incidence of hepatocellular carcinoma (HCC) has been correlated with aflatoxin intake. AFB 1 is highly mutagenic in in vitro assays. AFB 1 is converted to an epoxide metabolite responsible for its mutagenic and carcinogenic action. The DNA base targeted by activated AFB 1 -epoxide is G (N7 position; see Figure 7-3 ), and the mutations induced are predominantly GC→TA transversions. Significantly, the TP53 gene is mutated (GC→TA point mutation in codon 249) in a high proportion of human HCCs that arise in areas where aflatoxin exposure is high. Evidence suggests that TP 53 mutation at codon 249 may occur as a result of combined exposure to HBV and AFB 1 , and studies have shown elevated risk of HCC in individuals exposed to both HBV and aflatoxin over individuals exposed to either agent alone.
Benzidine
Benzidine is a member of a large class of carcinogens referred to as aromatic amines. The carcinogenic nature of benzidine was discovered in the context of bladder cancer induction in workers in the dye industry. In the past, benzidine-based azo dyes were synthesized in vast quantities in the United States and abroad. In the 1970s, their use was significantly curtailed because of health concerns. However, numerous workers were exposed to these carcinogens before regulation. On activation, benzidine and certain benzidine-based dyes can covalently react with DNA, and benzidine has been shown to induce chromosomal damage in vivo. Benzidine is a bladder carcinogen in multiple species, including humans, dogs, mice, rats, and hamsters, although species differences in activation of the parent compound have made the study of benzidine-induced bladder cancer challenging.
Nitrosamines and Heterocyclic Amines
Shortly after the identification of benzo[ a ]pyrene, N -nitrosodimethylamine was shown to induce liver tumors in rats. These results were provocative at the time because of the stark differences in physical properties between the PAHs and the water-soluble N -nitroso compounds. Since the initial discovery of N -nitrosodimethylamine, a wide variety of N -nitroso compounds have been shown to be powerful carcinogens in multiple experimental models and suspected carcinogens in lung and gastrointestinal cancers in humans. Following metabolic activation, N -nitrosamines can react with DNA to initiate carcinogenesis. Exogenous and endogenous sources of N -nitroso compounds have been described. N -nitrosamines are present in smoked meats and in meats containing the antimicrobial and color-enhancing agent nitrite. In both cases, nitrogen oxides are formed, which react with the amines present in meat. Alternatively, the formation of N -nitroso compounds can occur endogenously because of low pH conditions in the gastric system or as result of the presence of intestinal bacteria that catalyze N -nitroso compound formation.
Heterocyclic amines are also formed in muscle meats on high-temperature processing. Most heterocyclic amines tested are mutagenic in in vitro assays, and several induce gastrointestinal tumors in rodents. The two heterocyclic amines found most abundantly in cooked meat and best absorbed into the circulation are 2-amino-1-methyl-6-phenylimidazo-(4,5- b )-pyridine (PhIP) and 2-amino-3,8-dimethylimidazo-(4,5- f )-quinoxaline (MeIQx). At high temperatures, these heterocyclic amines are formed via reactions among creatinine, creatine, sugars, and amino acids.
N -Nitrosamine exposure is also associated with tobacco use : 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), and N -nitrosonornicotine (NNN) are carcinogenic tobacco-alkaloid–derived N -nitrosamines present in unburned and burned tobacco products. PAHs and NNK are the most abundant pulmonary carcinogens in tobacco smoke. In contrast to PAHs, which induce SCCs, NNK induces adenocarcinoma of the lung in animal models. Furthermore, adenocarcinoma of the lung has become the most common lung cancer type in the United States. This fact may reflect changes in cigarette manufacturing in the past 30 to 40 years that have resulted in rising levels of NNK and falling levels of B[ a ]P. In addition, in smokeless tobacco products such as snuff, N- nitrosamines are prominent agents involved in the induction of oral cancer. These N -nitrosamines require metabolic activation for carcinogenic activity and form DNA adducts similar to other organic carcinogens discussed earlier.
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