Environmental Carcinogenesis

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Figure 7-1 Chemical structures of selected carcinogens.

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. 4 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. 5 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. 4,6 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 7 :

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. 8 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. 9,10 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

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[4,5f]quinoline
Aldehydes 2 Formaldehyde
Miscellaneous organic compounds 15 1,3-Butadiene
Ethyl carbamate
Inorganic compounds 7 Nickel
Chromium
Cadmium
Arsenic
Total 55

Adapted from Hecht SS. Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst 1999;91:1194.

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. 11 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. 12
In addition to excess calorie intake, certain dietary constituents may affect cancer risk. 13 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 B1 [AFB1]). 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. 14 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. 15

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. 1618 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, 19 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.

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 7-3

Exposures Associated with Human Cancers, as Identified by the IARC (Partial Listing)

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.

Adapted from Cogliano et al. Preventable exposures associated with human cancers. J Natl Cancer Inst 2011;103:1835.

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.

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 (monographs.iarc.fr/ENG/Monographs/PDFs/index.php) and additional references. 20,21

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.

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.

The incidence of skin cancers such as melanoma, basal-cell carcinoma, and squamous-cell carcinoma has risen dramatically in recent years. 22 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. 23,24 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. 25 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. 26
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.” 27 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. 28
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. 29 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” (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. 30 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. 31
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. 32 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. 2,33 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. 34 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.
image
Figure 7-2   Selected polycyclic aromatic hydrocarbon (PAH) bay region dihydrodiol epoxides.
Aflatoxin B1
One of the most potent liver carcinogens is the fungal metabolite aflatoxin B1 (AFB1). AFB1 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. AFB1 is highly mutagenic in in vitro assays. AFB1 is converted to an epoxide metabolite responsible for its mutagenic and carcinogenic action. The DNA base targeted by activated AFB1-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. 35,36 Evidence suggests that TP53 mutation at codon 249 may occur as a result of combined exposure to HBV and AFB1, and studies have shown elevated risk of HCC in individuals exposed to both HBV and aflatoxin over individuals exposed to either agent alone.
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Figure 7-3 Sites of adduct formation associated with carcinogenicity of selected agents.
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. 37 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. 38 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. 39
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. 40 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. 41,42 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 43 : 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.

Inorganic Carcinogens

Beryllium
In 1946, Hardy and Tabershaw reported “delayed chemical pneumonias” in workers exposed to beryllium. In that same year, Gardner and Heslington reported experimentally induced osteosarcomas in beryllium-injected rabbits. Subsequent studies in the 1950s demonstrated that inhalation exposure of rodents resulted in induction of lung tumors. Since that time, beryllium has been recognized as a human carcinogen capable of inducing lung cancer in exposed workers. Occupational exposures to beryllium include inhalation of beryllium-containing dusts during processing of ores, machining of beryllium metal and alloys, and manufacturing of aerospace materials, ceramics, sports equipment, and electronics. Beryllium is weakly mutagenic in bacterial and mammalian mutagenesis test systems; however, it shows strong transformation capacity in Balb/3T3 and Syrian hamster secondary embryo cells. 44 In addition to genotoxic effects, beryllium has been shown to alter the expression of numerous cancer-related genes (i.e., c-fos, c-jun, c-ras, MAP kinases, DNA repair genes,). Despite these reports, the carcinogenicity of beryllium has recently been called into question. 45,46 Current occupational exposure levels are much lower than historical values, and previous reports of beryllium’s effects may have been confounded by inadequate smoking history information.
Cadmium
Cadmium is a heavy metal present in soil, air, and water and is listed as a priority pollutant by the U.S. EPA. Occupational exposures to cadmium occur during the manufacture of nickel-cadmium batteries, pigments, and plastic stabilizers as well as electroplating processes, metal smelting, and electronic waste recycling. 47 In addition, cigarette smoke contains cadmium. Release of industrial cadmium waste into the environment is of particular concern because of its long biologic half-life. On absorption, cadmium can accumulate in the body because it is poorly excreted and effectively stored in liver and kidney as a result of binding to metallothionein. Furthermore, once absorbed, no effective detoxification pathways for cadmium exist. The half-life of cadmium in humans is estimated at 15 to 20 years.
Cadmium exposure has been linked to human lung cancer and may affect the risk of prostate and kidney cancers. Although the carcinogenicity of cadmium has been confirmed in rodent models, the precise mechanism is unknown. 47 Cadmium binds only weakly to DNA and is only weakly mutagenic in bacterial and mammalian assays, and high concentrations are required to induce oxidative stress. Cadmium may act via non-genotoxic mechanisms to activate proto-oncogenes and disrupt normal cellular processes. For example, cadmium has been shown to alter E-cadherin–mediated cell adhesion, inhibit DNA repair, and alter expression of numerous genes in vitro including c-fos, c-myc, metallothionein, and genes encoding heat shock proteins.
Arsenic
Arsenic is widely distributed in the environment, being found in the earth’s crust in both inorganic [arsenite-As(III) and arsenate-As(V)] and methylated forms [monomethylated arsenic (MMA) and dimethylated arsenic (DMA)]. As(III), as well as MMA(III) and DMA(III), have been associated with skin, lung, urinary bladder, kidney, and liver cancers. 48 Human exposure to arsenic occurs via contaminated drinking water, diet, or contact with wood preserved with arsenicals; during mining of tin, gold, and uranium; and during application of arsenical pesticides. Signs of chronic exposure to arsenic in drinking water include altered skin pigmentation and hyperkeratosis of the palms of the hand and soles of the feet, which may ultimately lead to skin lesions and skin cancer.
Much attention has been given to assessing the health impact of arsenic contamination in drinking water sources. The current WHO guidelines for arsenic exposure recommend no more than 10 μg/L arsenic in water intended for human consumption. Since the 1980s, millions of people in China, India, Bangladesh, the United States, Chile, and Argentina have been exposed to arsenic in the drinking water far in excess of this limit. Already, numerous epidemiologic studies in Taiwan, the United States, Chile, and Argentina have demonstrated excess cancer risk in areas with known high exposure to arsenic in drinking water. 49 Unfortunately, identifying a safe level of arsenic in drinking water has been difficult because most epidemiologic studies show adverse effects at high doses; data concerning health risk at low exposures are unavailable. After intense debate, the limit in the United States was lowered to 10 μg/L in 2006.
For years, the study of arsenic and cancer was hindered by a lack of experimental evidence of carcinogenicity in animals. Only recently have studies of methylated arsenic and early life exposures provided adequate validation in vivo. As(III) and As(V) are transported into cells, As(III) more readily than As(V). On absorption, As(V) is reduced to As(III); As(III) can then be methylated. Historically, methylation of As(III) was considered to be a detoxification reaction, but recent evidence contradicts this dogma. 50 MMA(III) and DMA(III) are at least as cytotoxic, mutagenic, and clastogenic as As(III). Nonetheless, when methylated, arsenic is readily excreted in urine. DMA can be detected in urine shortly after exposure; also, because of the wide distribution of arsenic, exposure can be assessed via hair and fingernail deposits months or years after exposure. Therefore, methylated arsenic in hair and fingernail samples serves as a useful biomarker of exposure.
Numerous mechanisms of action have been proposed for arsenic carcinogenicity. 48 Arsenic exposure is known to generate reactive oxygen species. Like many transition metals, arsenic can participate in Fenton reactions that produce oxidative stress. Furthermore, arsenic may activate superoxide-generating NAD(P)H oxidase. In this way, arsenic is thought to induce DNA and protein damage that may initiate carcinogenesis. Arsenic has also been shown to elevate the total level of tyrosine phosphorylation in cells. Specifically, arsenic may alter phosphorylation-dependent epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase (MAPK) signaling. In addition, arsenic has been shown to alter NFκ signaling, apoptosis rates, cell cycle regulation, DNA repair, and genome stability. More recent evidence suggests that epigenetic dysregulation may underlie these adverse effects of arsenic exposure. 51
Chromium
Chromium in the hexavalent state [Cr(VI)] is a human carcinogen. The carcinogenic properties of chromium have been identified via epidemiologic studies of exposed workers in industries such as chrome plating, welding, leather tanning, and stainless steel production. Exposure to chromium generally occurs via inhalation and primarily affects risk of lung cancer. Because of environmental contamination, consumption of chromium in drinking water is also possible; however, the health consequences of the low-level exposure are unclear. 52
The oxidation state of chromium determines not only its bioavailability but also its cellular reactivity. 53 Cr(VI) readily enters cells via anion channels, whereas Cr(III) only slowly crosses the cell membrane. On entry to the cell, Cr(VI) is likely reduced, as Cr(VI) does not readily react with DNA in in vitro analyses. Chromium in lower oxidation states [Cr(III), Cr(IV), and Cr(V)] is more reactive; Cr(III) is believed to be the ultimate DNA reactive form. The reduced forms of chromium can also induce oxidative stress. In addition to or as a result of oxidative stress, chromium alters cell signaling pathways. Signaling molecules affected include NFκB, AP-1, p53, and HIF-1.

Fibers

Asbestos
The term asbestos refers to a group of naturally occurring silicate mineral fibers. There are numerous types of asbestos fibers that are classified according to their morphologic characteristics, including whether the fibers are curly (serpentine) or straight (amphibole). The shape and length-to-width ratio are important determinants of whether a particular asbestos fiber type will be carcinogenic. 54 This is likely because the size of the fiber determines the ability of the fiber to reach the deep lung tissues and penetrate the lung. Long (>4 μm) and thin (<0.5 μm diameter) fibers are the most carcinogenic. Extensive exposure to asbestos has occurred because the flame-resistant and durable characteristics of asbestos have led to its use as an insulating agent in schools, factories, homes, and ships, as construction material, and as a raw material for automobile brake and clutch parts. A large cohort of workers was exposed to high levels of asbestos when ship building peaked during World War II.
The toxic effects of asbestos exposure have been known for many years. 54 For example, more than 40 years ago, crocidolite asbestos exposure of South African miners was linked to mesothelioma incidence. Mesothelioma is a rare cancer of the membranous lining of the abdomen and chest. Numerous animal studies and in vitro experiments support the conclusion that asbestos can induce tumors. In fact, few cancer cause-effect relationships are as striking as asbestos and mesothelioma; most cases of mesothelioma can be related to asbestos exposure. In addition to mesothelioma, asbestos exposure has been associated with lung and laryngeal cancers. The initial accumulation of evidence of asbestos carcinogenicity was obscured by the differences in carcinogenicity of asbestos fibers of varying shape and by the long latency for the development of tumors following exposure. Since identification of asbestos as a cancer-causing agent, asbestos usage in the United States has greatly declined because of the introduction of a replacement material (fiberglass) and OSHA regulation of asbestos exposure. Nonetheless, mesothelioma rates have not declined in the United States in the past 15 years.
Numerous biologic hypotheses concerning the mechanism(s) by which asbestos induces tumors have been proposed. 55 Because long, thin fibers are the most carcinogenic, asbestos fibers may penetrate the lung and irritate the lining of the chest wall. The chronic inflammation and scarring would then contribute to tumor formation. Alternatively, the fibers may pierce spindle fibers during mitosis and thereby induce chromosome damage. Finally, asbestos fibers may induce oxidative stress and/or alter EGFR and MAPK cell signaling. Significantly, epidemiologic studies show that cigarette smoking acts synergistically with asbestos exposure to induce lung tumors. In addition to asbestos, exposure to other fibers such as plant-derived silica fibers (biogenic silica) has been shown to be carcinogenic. 56

Hormones

The etiology of numerous cancers is believed to be influenced by hormonal or dietary factors, and hormones under certain conditions are considered to be known human carcinogens (see Table 7-5). As previously mentioned, overweight and obesity are associated with elevated cancer risk. This effect may be mediated by endocrine dysregulation such as altered adiponectin, leptin, insulin, and IGF-1 levels. In addition, prostate, ovarian, breast, testicular, and endometrial cancers are hormonally driven. 57,58 A role for hormones in cancer etiology was established when castration and ovariectomy studies revealed that hormone-dependent cancers could be prevented by removing the primary hormone-synthesis organs. As an example of the action of hormones in cancer formation, estrogen activates hormone-responsive receptors. Stimulation of these receptors, such as the estrogen receptors, can increase the cellular proliferation rate to promote tumorigenesis. Endogenously synthesized hormones and administered hormones have been shown to influence cancer formation. Hormone replacement therapy and estrogen-only birth control therapy have been associated with increased risk of hormone-dependent cancers. An even more dramatic example of synthetic hormone-induced cancer is that of women who were exposed to estrogenic diethylstilbestrol (DES) in utero. DES was taken by pregnant women to prevent abortion; however, a large percentage of their female offspring developed clear-cell carcinomas of the vagina and cervix after the onset of puberty.

Mechanisms of Chemical Carcinogenesis

Multistage Nature of Carcinogenesis and the Multistage Model of Mouse Skin Carcinogenesis

In the early days of carcinogenesis research, it was noted that wounding of the skin of mice previously treated with mutagenic coal tar led to skin tumor formation. To explain these findings, a multistage model of carcinogenesis was proposed. 59 The model holds that tumors arise in cells that have first undergone a mutating event initiated by an electrophilic metabolite such as that formed from benzo[a]pyrene found in coal tar. Subsequently, cell proliferative stimuli promote the initiated cell population to expand, resulting in premalignant clonal outgrowths. Finally, additional genetic alterations accumulate in these lesions, leading to the development of a neoplasm that becomes invasive and ultimately metastatic. Over the years, this model has been refined to encompass the fundamental role of stem cells as the targets of initiation, the importance of stemlike characteristics in the plasticity of developing tumors, and the critical role of tumor microenvironment in carcinogenesis. 60 In addition, the mechanistic importance of DNA methylation changes and histone modifications in the initiation, promotion, and progression phases has been acknowledged.
Numerous animal models have been developed to study the multistep manner in which various epithelial and other tumors develop and progress. In one of the best-characterized models, the mouse two-stage skin carcinogenesis model, a subcarcinogenic dose of a mutating agent is delivered. 61 This is followed by multiple exposures to growth-promoting stimuli and the appearance of tumors on the dorsal skin (Figure 7-4 ). This model has provided an excellent paradigm in which to examine the carcinogenic potential of environmental agents and has been used to reveal the mechanistic bases of multistage carcinogenesis by environmental agents.

Initiation and Mutational Theory of Carcinogenesis

During the first stage of multistage carcinogenesis, DNA mutations result as a consequence of electrophilic carcinogen exposure, oxidative damage to DNA, DNA strand breaks, or other DNA insults. Mutations are believed to occur in multipotent stem cells and are inherited by daughter cells. Theodor Boveri first proposed the concept that cancer arises as a result of damage to genetic material at the turn of the 20th century. In the 1950s and 1960s, James and Elizabeth Miller, after observing that a wide variety of structurally diverse chemicals could induce cancer in animal models, suggested that chemical carcinogens required metabolic activation to electrophilic intermediates. These electrophilic intermediates could then covalently bind to proteins, RNA and DNA. The term electrophile theory of chemical carcinogenesis

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