CANCER EPIDEMIOLOGY

Epigenetics and Genetics

The idea that increased risk of disease originates from interactions among genes and environmental-lifestyle factors, infact, may not be driven by the genetic code. A hot debate has been the relative importance of genetic versus epigenetic processes. Although it is clear that inherited variation in deoxyribonucleic acid (DNA) sequence influences individual risk of cancer, this occurs in only a small percentage of the population.¹⁴ In addition, how structural variation of the genome increases cancer risk is unknown. An explosion of data now indicates the importance of epigenetic processes, especially those with resultant gene silencing of key regulatory genes (see Chapter 11). Epigenetic changes collaborate with genetic changes and environmental-lifestyle factors to cause the development of cancer. These changes are mitotically and meiotically heritable.^15,16

The three major areas of epigenetics are (1) methylation (the addition of methyl group [CH₃] to cytosine ring) (see Figure 11-16); aberrant methylation, which can lead to silencing of tumor-suppressor genes; (2) histone modifications (histone acetylation, alterations in chromatin); and (3) micro-ribonucleic acids (miRNAs), small RNA molecules that can target gene expression post-transcriptionally. The expression of miRNAs has been linked to carcinogenesis because they can act as either oncogenes or tumor-suppressor genes.¹⁷ An important feature of epigenetic mechanisms and their role in development and disease is that epigenetic processes can be modified by lifestyle, particularly diet and the environment, pharmacologic interventions, or both.¹⁸ Data on aging also have shown to affect DNA methylation in many cell types in various organisms.^19–21 Significant evidence for environment-lifestyle as the major contributor to these age-related effects on the “epigenome” involves a recent study of monozygotic (MZ) twins. Cell types and patterns of DNA methylation across the genome were similar in young MZ twins, but the patterns diverged in older twins.²² These data suggest that environmental-lifestyle factors act on individuals throughout life, changing gene expression through epigenetic mechanisms with subsequent implications for health.

Nutrition has become a major focus because it influences DNA methylation in several ways (see p. 405). Biologically active food components modify DNA methylation directly (see p. 406). Nutrition influences metabolic effects associated with energy balance. Because adipose tissue is endocrine tissue, obese individuals accumulate macrophages that secrete various proinflammatory signaling molecules and cytokines (see p. 414). Inflammation is strongly associated with cancer development, and inflammatory bowel disease is related to methylation in the colon.²³ The role of nutrition and diet is discussed on p. 405.

Tobacco Use

Cigarette smoking is carcinogenic and remains the most important cause of cancer. The risk is greatest in those who begin to smoke when young and continue throughout life.³³ Globally, tobacco use is greatest in developing countries, where 84% of 1.3 billion current smokers live.³⁴ The World Health Organization (WHO) World Cancer Report³⁵ reports that in the twentieth century approximately 100 million people died worldwide from tobacco-associated diseases (cancer, chronic lung disease, cardiovascular disease, and stroke). About 50% of regular smokers are killed by the habit. About 25% of smokers will die prematurely during middle age (35 to 69 years).³⁵

Cigarette smoking accounts for 1 of every 5 deaths each year in the United States.³⁶ About 21% of all U.S. adults smoke cigarettes. Estimates of cigarette smoking by age are 23.6% ages 18 to 24, 23.8% ages 25 to 44, 22.4% ages 45 to 64, and 8.8% ages 65 and older.³⁷ Cigarette smoking is more common among men (23.9%) than women (18.5%), and the prevalence of cigarette smoking is highest among Native Americans/Native Alaskans (32.4%) than whites (22.2%), blacks (20.2%), Hispanics (15%), and Asians (10.4%).³⁷ It is more common among adults living below the poverty level (30.6%) than those at or above the poverty level (20.4%).³⁷

Overall, cigarette smoking in developed countries is responsible for 30% of all cancer deaths, and an epidemic of cancer deaths is expected in developing countries.³⁵ Tobacco use is associated primarily with squamous and small cell adenocarcinomas. In addition, smoking causes even more deaths from vascular, respiratory, and other diseases than from cancer. Smoking tobacco is linked to cancers of the lower urinary tract (renal, penis, and bladder), upper aerodigestive tract (oral cavity, pharynx, larynx, nasal cavity, paranasal sinuses, esophagus, and stomach), liver, kidney, pancreas, cervix, and uterus, as well as myeloid leukemia.³⁸ Evidence is lacking that smoking causes breast, prostate, or endometrial cancer of the uterus.³⁵ However, tobacco smoke is known to cause mammary tumors in animals. In 2005, Japanese researchers reported that both active and passive smoking increased the risk of breast cancer in pre-menopausal women.^38a

Secondhand smoke, also called environmental tobacco smoke (ETS), is the combination of sidestream smoke (burning end of a cigarette, cigar, or pipe) and mainstream smoke (exhaled by the smoker). More than 4000 chemicals have been identified in mainstream tobacco smoke (250 chemicals as toxic)³⁹ of which 60 are considered carcinogenic.⁴⁰ Measuring secondhand smoke is difficult. Nonsmokers who live with smokers are at greatest risk for lung cancer as well as numerous noncancerous conditions.⁴⁰

Cigar or pipe smoking, or both, is strongly and causally related to cancers of the oral cavity, oropharynx, hypopharynx, larynx, esophagus, and lung. Cigar smokers who inhale deeply may be at increased risk for developing coronary heart disease and chronic obstructive pulmonary disease.⁴¹ Pipe smokers have a lower risk of dying from tobacco than cigarette smokers, but it is as harmful as and perhaps more harmful than cigar smoking.⁴² Bidi smoking, a small amount of tobacco wrapped in the leaf of another plant (used in South Asia), delivers higher amounts of nicotine per gram of tobacco and comparable or greater amounts of tar compared with cigarettes.³⁸ Case-controlled studies indicate bidi smoking can cause cancers of the respiratory and digestive sites. Epidemiologic data from the United States and Asia reveal an increased risk of oral cancer with smokeless tobacco products.⁴³ These data, however, are not confirmed in northern European studies.⁴³

Measures that prevent young adults from starting smoking would substantially avoid future disease burden. A public health approach is therefore needed that prevents young people from starting smoking and helps others stop smoking.

Diet

Understanding dietary factors that increase the risk for cancer can be difficult. The ways in which diet affects one’s likelihood of developing cancer are complicated by the variety of foods consumed, the many constituents of foods, the metabolic consequences of eating, and the temporal changes in the patterns of food use. Cancer risks in older adults may depend as much on diet in early life as on current eating practices.^33,44 In addition, studies in humans targeting diet and disease associations face a variety of challenges including measurements of specific nutrients, food types, and dietary patterns.

Humans are constantly exposed to a variety of compounds termed xenobiotics (Greek xenos, “foreign”; bios, “life”) that include toxic, mutagenic, and carcinogenic chemicals. Many of these chemicals are found in the human diet. Most xenobiotics are transported in the blood by lipoproteins and penetrate lipid membranes. These chemicals can react with cellular macromolecules, such as proteins and DNA, or can react directly with cell structures to cause cell damage.⁴⁵ The body has two defense systems for counteracting these effects: (1) detoxification enzymes and (2) antioxidant systems (see Chapter 2). Enzymes that activate xenobiotics are called phase I activation enzymes and are represented by the multigene cytochrome P-450 family, aldehyde oxidase, xanthine oxidases, and peroxidases. Phase II detoxification enzymes then protect further against a large array of reactive intermediates and nonactivated xenobiotics.⁴⁵ These enzymes are located predominantly in the liver and provide clearance of compounds through the portal circulation, thereby preventing the potentially carcinogenic agent(s) from entering the body through the gastrointestinal tract and portal circulation. These enzymes also occur in the skin epithelia and can be induced in other extrahepatic tissue, such as the lung.

Dietary sources of carcinogenic substances include compounds produced in the cooking of fat, meat, or protein, and naturally occurring carcinogens associated with plant food substances, such as alkaloids or mold byproducts.⁴⁵ The most studied and most relevant carcinogens produced by cooking are the polycyclic aromatic hydrocarbons benzo[a]pyrene and heterocyclic aromatic amines generated by meat protein. The greatest levels are found in well-done charbroiled beef. People, likewise, ingest xenobiotics that are found in environmental or industrial contaminants (e.g., particulate matter of diesel exhaust, contaminating pesticides in food and water supplies) and in certain prescribed and over-the-counter medicines.

Nutrition may directly influence epigenetic factors that silence genes that should be active or activate genes that should be silent.⁴⁶ Dietary components can act directly as mutagens or interfere with mutagen elimination. Nutritional factors may alter cellular environments by modulating hormonal axes or influencing cellular proliferation, or both.⁴⁶ Importantly, specific nutrients may directly affect the phenotype or expression of key genes, for example, epigenetically through abnormalities of methylation of the promoter regions of genes or histones. These alterations can affect DNA structure and mRNA for transcription.⁴⁶ Clearly, epigenetic events are susceptible to change, thus offering potential explanations of how environmental factors (e.g., diet) may modify cancer risk and tumor behavior. DNA methylation—the attachment of a methyl group to the 5-position of cytosine within cytosine guanine dinucleotides (CpGs)—is one of several epigenetic changes important in gene regulation and expression (Figure 12-2). CpGs are distributed evenly throughout the genome and remain in short stretches, or clusters, called CpG islands. These islands are located in the promoter region of genes found in half of all human genes.⁴⁷ DNA is also susceptible to hypomethylation, which can cause overexpression of transcription of proto-oncogenes, increased recombination and mutation (i.e., oncogenes), and failure to imprint. These alterations can all promote cancer.⁴⁸ Aberrant DNA methylation patterns occur in several cancers (colon, lung, prostate, and breast). Dietary factors may be related to DNA methylation in four ways: (1) they may influence the supply of methyl groups for the formation of S-adenosylhomocysteine (SAM) (see p. 411); (2) they may modify the use of methyl groups, e.g., by shifts in an important enzyme, DNA methyltransferase (DNMT) (see p. 411); (3) they may reduce methyl groups called demethylation; and (4) DNA methylation patterns may influence the response to a dietary factor.⁴⁹

Specific nutritional factors seem to influence susceptibility to cancer. Continuing studies are determining whether certain deficiencies, such as vitamin D and compounds found in fruits and vegetables, can increase cancer incidence.⁴⁸ Excess intake of alcohol can promote cancer (see p. 415). Aflatoxin (produced by mold) can contaminate corn, peanuts, and rice stored in hot, humid environments, and Chinese-style salted fish are known to cause cancer. With emphasis on epigenetic and aberrant methylation (Figure 12-3) the role of folic acid in cancer is prominent. The methyl group of 5-methylenetetrahydrofolate is the precursor of methyl group of methionine and eventually SAM (see Table 12-5, p. 410). Cancer cells reveal both genome overall (global) hypomethylation and regional hypermethylation (see Figure 12-2). Global hypomethylation in cancer is widely observed and can lead to genomic instability.⁵⁰ Regional hypermethylation has been observed in various cancers and when it involves tumor methylation can cause their inactivation or silencing (see Figure 12-2). Low intake of folate combined with high intake of alcohol is associated with global hypomethylation and colorectal cancer. Aberrant folate metabolism leading to DNA methylation is prevalent in the highly aggressive HER2/neu-positive breast cancers.⁵¹ Regional hypermethylation and gene silencing are found in the majority of invasive breast lobular carcinomas.⁵² Aberrant methylation is progressively acquired in the early stages of colorectal cancer.⁵³ The role of folic acid in cancer is complicated. For example, low intake of folic acid is correlated with an increased risk of colorectal cancer. Uracil is misincorporated into DNA as a result of folate deficiency.⁴⁸ However, it is important to note that once a cancerous lesion is present folate intake may increase tumor growth.⁵⁴

Selective dietary agents that inhibit histone deacetylase (HDAC) and, therefore, abnormal patterns of histone modification include sulforaphane (SFN). SFN is an isothiocyanate found in cruciferous vegetables, such as broccoli and broccoli sprouts. A growing body of evidence suggests that SFN acts through epigenetic mechanisms to inhibit HDAC activity in human colon and prostate cancer lines.⁵⁵ In human subjects, a single ingestion of 68 g (1 cup) of broccoli sprouts inhibited HDAC activity in circulating white blood cells 3 to 6 hours after eating.⁵⁶

In summary, epidemiologic and laboratory evidence suggests that diet is a significant factor in the cause, progression, and prevention of cancer (Table 12-3). Diet affects many pathways to cancer including cell cycle control, differentiation, DNA repair, gene silencing, inflammation, apoptosis, and carcinogen metabolism. Many of these processes are likely influenced, if not regulated, by DNA methylation, an epigenetic mechanism that affects gene function. Imbalances of nutrients can lead to global hypomethylation, and there is reason to believe that diet can affect gene-specific hypomethylation or hypermethylation, or both.⁴⁹ Much more research is needed to identify how specific nutrients can alter DNA methylation and restore gene function as well as other pathways (i.e., apoptosis, etc.) that can prevent tumor development. Studies on diet and cancer need testing in a variety of settings and among different population groups.

Alcohol Consumption

Chronic alcohol consumption is a strong risk factor for cancer of the oral cavity, pharynx, hypopharynx, larynx, esophagus, and liver.¹³⁷ Although evidence is inconsistent, alcohol consumption is less strongly related to breast cancer and colorectal cancer; however, it is known to increase cell growth of human breast cancer cells in vitro.¹³⁸ In addition, although the risk is lower, breast carcinogenesis can be enhanced with relatively low daily amounts of alcohol.¹³⁷ A meta-analysis showed no consistent relationship between alcohol and cancers of the pancreas, lung, prostate, or bladder.¹³⁹ Alcohol interacts with smoke, increasing the risk of malignant tumors, possibly by acting as a solvent for the carcinogenic chemicals in smoke products. In individuals who have never smoked, substantial alcohol consumption (i.e., three or more drinks per day) has been associated with head and neck cancers.¹⁴⁰ Inherited factors also put some individuals at increased risk in the ability to repair DNA, carcinogen metabolism, and cell cycle control.¹⁴¹ The strongest genetic associations to alcoholism are those with alcohol dehydrogenase (ADH) and mitochondrial aldehyde dehydrogenase (ALDH2). Specifically, individuals having the genes encoding 32-ADH or the dominant negative allele for ALDH2 are at reduced risk of alcoholism, despite being at much higher risk for oropharyngeal cancer.¹⁴²

Mechanisms involved in alcohol-related carcinogenesis include the effect of acetaldehyde, the first metabolite of ethanol oxidation; the induction of cytochrome P-450 2E1 (genetic variant CYP2E1) leading to the generation of reactive oxygen species (ROS); increased procarcinogen activation (e.g., nitrosamines) and modulation of cellular regeneration (cell cycle); and nutritional deficiencies (retinol, retinyl esters, folic acid, other vitamins). Nutritional deficiencies may give rise to altered mucosal integrity, enzyme and metabolic dysfunction, and other structural abnormalities. The median age for diagnosis is the early 60s, with a male predominance, especially in laryngeal cancer.¹⁴⁰

Ionizing Radiation

Much of the knowledge of the effects of ionizing radiation on human cancer has stemmed from observations of the Hiroshima and Nagasaki atomic bomb exposures, particularly the Life Span Study. These data provide the best estimate of human cancer risk over the dose range from 20 to 250 cGy for low linear energy transfer (LET) radiation, such as x-rays or γ-rays. Other data are derived from groups exposed for medical reasons (Table 12-6), underground miners exposed to radon gas, and workers exposed to high doses while in the nuclear weapons program of the former USSR. The atomic bomb exposures in Japan caused acute leukemias in adults and children and increased frequencies of thyroid and breast carcinomas. Lung, stomach, colon, esophageal, and urinary tract cancers and multiple myeloma have been added to the list. At Nagasaki and Hiroshima, leukemia incidence in individuals 15 years or younger reached its peak 6 to 7 years after the explosions and has steadily declined since 1952. People 45 years and older at the time of exposure had a latent period of 20 years before developing acute leukemia.

Human exposure to ionizing radiation includes emissions from x-rays, radioisotopes, and other radioactive sources. Health risks involve not only neoplastic diseases but also cardiovascular disease and stroke following high doses in therapeutic medicine and lower doses in A-bomb survivors (BEIR VII).^143,144 Late effects of radiation in A-bomb survivors show persistent elevations of inflammatory markers (e.g., interleukin [IL]-6, CRP, TNF-α, etc.) implying immunologic damage may be the cause of later cardiovascular effects.¹⁴⁵ Other risks include somatic mutations that may contribute to other diseases (e.g., birth defects and eye maladies) and from animal studies, inherited mutations that may affect the incidence of diseases in future generations (see What’s New? Radiation and Vulnerable Populations). Heritable mutations are of particular concern for women because the number of oocytes are presumably fixed at birth and mutations, if not repaired, are cumulative (see p. 421).¹⁴⁶ An important summary point in BEIR VII¹⁴³ is the concern from high-dose medical exposure, for example computed tomography (CT) (see What’s New? Increasing Use of Computed Tomography Scans and Risks). In 2009, the National Council on Radiation Protection and Measurements¹⁴⁷ reported Americans were exposed to more than seven times as much ionizing radiation from medical procedures compared to the 1980s (Figure 12-7).

The risks of low-dose radiation are being debated among radiobiologists, geneticists, physicists, and others because of the potential effect on the health of current and future generations.¹⁴⁶ Two opposing hypotheses have emerged: (1) there is no dose of radiation considered safe and the use of radiation must always be considered on the basis of risk versus benefit and (2) the health risks of diagnostic doses less than 10 cGy are not now measurable and may be nonexistent. Limiting is that general findings on the health risks of low-dose radiation are made by analyses of data on the risk of cancer alone.¹⁴⁶ The expression of radiation-induced damage depends not only on dose, fractionation, and protraction but also on repair mechanisms, bystander effects, radioprotective substances such as antioxidants, and how it is delivered.¹⁴⁶

Ultraviolet Radiation

Ultraviolet sunlight causes basal cell carcinoma and squamous cell carcinoma (i.e., photocarcinogenesis), two common skin cancers found in white individuals. Exposure to ultraviolet radiation (UVR) can emanate from natural and artificial sources; however, the principal source of exposure for most people is sunlight. With further depletion of the stratospheric ozone layer, people and the environment will be exposed to higher intensities of UVR. The degree of damage in skin depends on the intensity and wavelength content (i.e., ultraviolet A [UVA] or ultraviolet B [UVB]) and the depth of penetration. UV radiation is known to cause specific gene mutations; for example, squamous cell carcinoma involves mutation in the TP53 gene, basal cell carcinoma in the patched gene, and melanoma in the p16 gene.¹⁷³ In addition, UV light induces the release of TNF-α in the epidermis, which may reduce immune surveillance against skin cancer.¹⁷⁴

Skin exposure to UVR and ionizing radiation, as well as chemical (xenobiotic) agents/drugs, produces ROS in large quantities that can overwhelm tissue antioxidants and other oxygen-degrading pathways.¹⁷⁵ Uncontrolled release of ROS is an important contributor to skin carcinogenesis.¹⁷⁵ Imbalances in ROS and antioxidants can lead to oxidative stress, tissue injury, and direct DNA damage (see Figure 12-12). ROS can induce a number of transcription factors (e.g., activator protein-1 [AP-1] and NF-κβ).¹⁷⁶ In addition, UVA radiation of skin fibroblast releases iron, which is involved in activation of the transcription factor NF-κβ and other free radicals important in regulating genes that induce inflammation.^175,177 Inflammation is a critical component of tumor progression.

Healthy genes are needed to coordinate the levels of antioxidants and decrease harmful ROS. Antioxidants decrease ROS and oxidative stress and other protective mechanisms including DNA repair and apoptosis (see Figure 12-12). The genetic alterations in proto-oncogenes and tumor-suppressor genes may make epidermal cells resistant to signals for terminal differentiation.¹⁷⁷ With oxidative stress, DNA damage occurs and calcium-dependent enzymes (endonucleases) are activated that produce DNA strand breaks.¹⁷⁷ In addition, ROS are involved in the activation of procarcinogens, such as polycyclic aromatic hydrocarbons including 7,12-dimethylbenzene(a)anthracene (DMBA). DMBA is capable of initiating a point mutation in the ras proto-oncogene, which is evidenced to be the triggering event in mouse carcinogenesis.¹⁷⁸ The essential step appears to be the activation of DMBA by nicotinamide adenine dinucleotide dehydrogenase (NADH) and cytochrome P-450–dependent oxidases.¹⁷⁹ The pathophysiology of skin carcinogenesis is discussed further in Chapter 44.

Basal cell carcinoma commonly occurs on the head and neck. Individuals with these tumors generally have light complexions, light eyes, and fair hair. They tend to sunburn rather than tan and live in areas of high sunlight exposure. Usually these cancers arise on areas of the body that receive the greatest sun exposure, although they are not necessarily restricted to these skin sites. Squamous cell carcinoma is found more commonly in men who work outdoors. These tumors are distributed over the head, neck, and exposed areas of the upper extremities (see Chapter 44).

The incidence of melanoma has been increasing annually at rates of 2% to 7% for white populations.¹⁸⁰ The steady rise in incidence has resulted in an alarming 165% increase in mortality rate.¹⁸¹ Sun exposure and the risk of melanoma, a malignant pigmented mole, remain complex. Melanomas can appear suddenly without warning but can arise from or near a mole (melanocytic nevus). When detected in the early stages, melanoma is highly curable.¹⁸¹ About 20% of melanomas, however, are diagnosed at nonlocalized and advanced stages.¹⁸¹ The pathogenesis of melanoma is complex, involving genetic and environmental factors. The genetic factors can be inherited, for example, in high-susceptibility genes (i.e., cyclin-dependent kinase inhibitor 2A [CDKN2A]) or in low-susceptibility genes (i.e., melanocortin-1). Epidemiologic and case-control studies suggest that UVR exposure is the most significant factor for the development of melanoma. Other evidence, however, reports rates of melanoma are uncommon in persons with outdoor occupations.¹⁸² Although nonmelanoma skin cancers are related to cumulative exposure to UV radiation, melanoma is related to episodes of intense, intermittent exposure (measured as history of sunburn).¹⁸³ Melanomas more commonly occur in areas less continually exposed to sunlight, like the trunks in men and backs of the legs in women. Family history (i.e., genetic factors), skin type, and the density of moles are important in determining the risk of developing melanoma. For example, the incidence of melanoma in white populations is 10 times greater than in black, Asian, or Hispanic populations residing in the same area.¹⁸² Most importantly, the risk of melanoma from sunlight is certainly modified by risk factors.¹⁸² Traits associated with a high risk of melanoma are light-colored hair, eyes, and skin; an inability to tan; and a tendency to freckle, sunburn, and develop nevi.¹⁸⁴

Until 1998 a direct causal relationship between UVB light and melanoma in humans had not been established. Grafted newborn human foreskin (xenograft) onto RAG-1 immunodeficient mice showed such a relationship.¹⁸⁵ Melanocytic hyperplasia occurred in 73% of UVB-treated xenografts. One graft treated with DMBA and UVB light developed a human malignant melanoma. This was the first experiment to show that UVB light and an exogenous carcinogen could result in a new malignant melanoma.

A similar study using UVB light and overexpression of an endogenous growth factor, basic fibroblast growth factor (bFGF), also induced human melanoma.¹⁸⁶ Numerous local factors may result in increased cytokine production, including trauma, infection, diet, obesity, hormones, and other causes of inflammation. Sunburn reflects an overdose of UV light, triggering inflammation with an increase in cytokine production.

A very significant finding in 2002 jolted the melanoma field. Davies and colleagues¹⁷⁹ detected an activating point mutation in the B-raf (BRAF) proto-oncogene (i.e., somatic, not germline, mutation) in 60% to 70% of malignant melanomas. This mutation results in a marked increase in BRAF kinase activity, leading to activation of the mitogen-activated protein kinase (MAPK) pathway (see Table 1-4). This BRAF mutation and others have recently been linked to sun exposure.¹⁸⁷ Activation of MAPK in melanoma can occur through several mechanisms: (1) mutation in the B-raf gene, (2) stimulation of fibroblast growth factor (FGF) and hepatocyte growth factor (HGF), (3) exogenous stimulation by IGF-1, and (4) by adhesion molecule receptor signaling. The development of melanoma is associated with the loss of E-cadherin and the appearance of N-cadherin adhesion molecules. Cadherins are cell surface glycoproteins that promote calcium-dependent cell-to-cell adhesion. The major adhesion molecule between keratinocytes and normal melanocytes is E-cadherin, which disappears during melanoma progression,¹⁸⁸ and is expressed in melanoma cells, allowing them to adhere to fibroblasts and endothelial cells. Thus N-cadherin allows the melanoma cells to survive as they migrate through the dermis.¹⁸⁹ (For further discussion, see Chapter 44.)

Increased knowledge of the intricate cellular interactions in melanoma will increase knowledge of melanoma etiology and pathogenesis. This knowledge is essential for early detection and treatment.

Electromagnetic Radiation

Health risks associated with electromagnetic radiation (EMR) are very controversial. Exposure to electric and magnetic fields is widespread. EMRs are a type of nonionizing, low-frequency radiation without enough energy to break off electrons from their orbits around atoms and ionize (charge) the atoms. Microwaves, radar, and power frequency radiation associated with electricity and radio waves, fluorescent lights, computers, and other electric equipment create EMRs of varying strength. The major debate for more than four decades has focused on the association of exposure to EMR and resultant health consequences, including cancer. Scientific evidence has been accumulating slowly because it is hampered by methods to accurately measure exposure, the lack of a clear dose-response relationship, and the difficulty in reproducing effects. In addition, with competing priorities like convenience, financial interest, health necessity, a consensus of the risk/benefit ratio of EMR exposure may be difficult to achieve.¹⁹⁰ A recent case-control study in Japan linked high EMR exposure with a significantly higher risk of childhood leukemia.¹⁹¹ Other recent studies report the apparent link between cordless and cellular phone use with lymphoma and benign and malignant brain tumors.^192–195 Another case-control study reported a link between childhood leukemia and prenatal proximity to high-voltage powerlines.¹⁹⁶ Data from Sweden show adverse EMR has the potential to induce certain skin abnormalities and is a positive factor in the development of melanoma.^197,198 Yet another recent study denied an association between EMR exposure and female breast cancer.¹⁹⁹ A recent population-based study (N = 5400 women) linked residential EMR exposure from high voltage power lines to a 60% increased risk of breast cancer in Norwegian women of all ages.²⁰⁰ In 1998, however, a National Institute of Environmental Health Sciences Electric and Magnetic Fields Working Group recommended that low-frequency electromagnetic fields (EMFs) be classified as possible carcinogens.²⁰¹ Sweden has officially categorized electrohypersensitivity as a functional impairment.²⁰² The United Kingdom Childhood Cancer Study published in 1999 and updated in 2000^203,204 did not support a link between EMR exposure and childhood cancer. A pooled analysis from Europe showed no risk of childhood cancers with average exposures (less than 0.1 micro T), no increased risk at intermediate exposures, but at the highest average exposures (greater than 0.3 micro T American studies or 0.4 micro T European study) increased risk affecting few children (1.4%) with a significant relative risk of 2.²⁰⁵ In response to public concern, the WHO requested further studies in high-exposure areas like Japan. Thus a case-control study from Japan (N = 312 children) found acute lymphocytic leukemia (ALL) cases in the highest exposure category above 0.4 micro T.¹⁹¹

The controversy about potential health hazards associated with the exposure to EMFs has been stimulated by the increased use of mobile telecommunication devices and emissions from cell towers. Cell phones emit electromagnetic radiation in the range of 800 to 2000 MHz, which is in the microwave range (300 MHz to 300 GHz).

EMR from a cell phone can penetrate the skull and deposit energy 4 to 6 cm into the brain.²⁰⁶ This energy can result in thermal heating of the tissue. The debate therefore has been whether these thermal effects could induce carcinogenesis. One thermal mechanism proposed is change in protein phosphorylation.^207,208 Exposure of human peripheral blood lymphocytes to EMR associated with cell phones found a linear increase in chromosome 17 aneuploidy.²⁰⁹ Control experiments (without EMR) involving temperature changes from 24.5° to 38.5° C (76° to 101.3° F) showed that elevated temperature is not associated with genetic or epigenetic alterations. Thus these findings indicated a genotoxic effect of the EMRs is not elicited by a thermal pathway.²⁰⁹ Increasing evidence indicates that the mechanism of harm from EMR is induction of cell stress and damage of intracellular components (e.g., free radical formation and altered protein conformation).²¹⁰ Adverse EMR has been reported to affect DNA synthesis, alter cell division, alter electrical charge of ions, and alter molecules within cells.^211,212 Interference with cellular electrical charges may modify ionic structures, disturbing movement of ions across the membrane, including calcium ions.^188,213

In 2007, a meta-analysis of cell phones and brain tumors concluded that studies of individuals using cell phones for more than 10 years “give a consistent pattern of an increased risk for acoustic neuroma and glioma.”¹⁹³ The risk of a tumor is highest on the same side of the head that the phone is used. The studies reported are international including Sweden, Finland, the United Kingdom, Germany, Japan, and the United States. There are no studies of adults who have used cell phones as children or adolescents. Concern is for children in whom the effects may be compounded because of increased vulnerability to radiation and their longer use of cell phones into adulthood. Ongoing unbiased research is desperately needed. Absolute proof of causation may be hindered because of the ethical questions of exposing individuals to potentially harmful interventions.¹⁸⁹

Sexual and Reproductive Behavior: Human Papillomaviruses

The past decade has demonstrated that sexually transmitted infection with carcinogenic types of human papillomavirus (HPV), referred to as high-risk types of HPV, is required for the development of most cervical cancers. In addition, HPV is a newly identified causal factor for squamous cell carcinoma of the head and neck (SCCHN).¹⁴⁰ HPV infections, however, are very common in sexually active women, and the majority of these infections will resolve or only cause transient, minor problems.²¹⁴ Eighty HPV types have been sequenced—30 of these types infect the female and male genital tract and two thirds of these are classified as high-risk types. HPV-16, in most countries, accounts for 50% to 60% of cervical cancer cases, followed by HPV-18 (10% to 12%) and HPV-31 and HPV-45 (4% to 5% each).^215,216 HPV types correlated with genital warts, HPV-6 and HPV-11, are called low risk because they are rarely associated with cancer.²¹⁶ HPV-16 is directly mutagenic by inducing the viral genes E6 and E7. Persistence of infection with high-risk HPV is a prerequisite for the development of cervical intraepithelial neoplasia (CIN) (see Figure 23-17) lesions and invasive cervical cancers.²¹⁵ Biologic factors that determine persistence are not understood; controversial risk factors include long-term use of oral contraceptives and smoking.²¹⁷ Newer risk factors being studied include drug addiction and reproductive factors (i.e., age at menarche and menopause). In fact, it has been shown that a second peak of high-risk HPV prevalence occurs in postmenopausal women.²¹⁷ Smoking has been implicated in acquiring high-risk HPV (HR-HPV) but not as an independent risk factor for high-grade CIN.²¹⁸ Earlier reported risk factors, for example, number of sexual partners, are probably indicators of HPV exposure rather than independent risk factors. HPV can be transmitted by genital contact (oral, touching, or sexual intercourse); therefore, condoms are not necessarily protective (see Chapter 23).

About 500,000 cases of invasive cervical cancer are diagnosed each year worldwide—the majority in developing countries. Although HPV is the most prevalent sexually transmitted infection in the United States, less than one third of women and men in the general population have heard of it, and awareness is low among women in high school and college settings.²¹⁹ Cervical cancer mortality has decreased over the past five decades in the United States by more than 70%, probably due to screening with the Papanicolaou (Pap) test.²¹⁴ HPV vaccination programs have made it possible to eliminate about 70% of all invasive cervical cancers worldwide (see Chapter 23).²¹⁹ Human immunodeficiency virus (HIV)–infected individuals have demonstrated an increase in oral and anogenital pathologic conditions because of HPV infection.²²⁰

The incidence of invasive cervical cancer is substantially higher in women of low socioeconomic standing and is more common in Central and South America, eastern Africa, and the Caribbean.²²¹ Consensus is that newborn babies can be exposed to cervical HPV infection of the mother. The possible modes of transmission in children, however, are controversial.²²²

Other Viruses and Microorganisms

A discussion on viruses and bacteria and cancer is contained in Chapter 11. Other microorganisms include particular parasites, such as Opisthorchis viverrini and Schistosoma haematobium. Their specific roles in carcinogenesis are thought to be related to cofactors or carcinogens, or both.

Physical Activity

Physical activity reduces the risk of breast and colon cancers and may reduce the risk of other cancers. Several biologic mechanisms causing this effect have been proposed and include decreasing insulin and IGF levels; decreasing obesity; increasing free radical scavenger systems; altering inflammatory mediators; decreasing circulating sex hormones and metabolic hormones; improving immune function; enhancing cytochrome P-450, thus modifying carcinogen activation; and increasing gut motility.^222–226 For colon cancer, physical activity increases gut motility, which reduces the length of time (transit time) that the bowel lining is exposed to potential mutagens.²²⁷ For breast cancer, vigorous physical activity may decrease exposure of breast tissue to ovarian hormones, insulin, and IGF. A randomized trial found that after 12 months of moderate-intensity exercise, postmenopausal women had significantly decreased serum estrogens.²²⁸ Physical activity also helps prevent type 2 diabetes, which has been associated with risk of cancer of the colon and pancreas.^228,229

Many questions are unanswered regarding frequency, intensity, and duration of exercise. Much of the literature suggests that between 3.5 and 4 hours of vigorous activity per week are necessary to optimize protection for colon cancer.²²⁶ There is likely a dose-response relationship for colon cancer and breast cancer, and 30 to 60 minutes per day of moderate to vigorous intensity is proposed to decrease breast cancer risk.²³⁰ A randomized controlled trial (12 months) recently supported the Institute of Medicine and Department of Agriculture guidelines of 60 minutes per day of moderate to vigorous physical activity for decreasing weight, BMI, body fat, and intra-abdominal fat.²³¹

Chemicals and Occupational Hazards as Carcinogens

An estimated 80,000 synthetic chemicals are used in the United States. Of those, only about 7% have been tested for their health effects.²³² Disturbing is that another 1000 are added each year. Exposure to chemicals occurs everyday — they are present in air, soil, food, water, household products, toys, personal care products, workplaces, and homes. Table 12-1 provides a summary of the chemicals according to strong and suspected links to various types of cancer. Box 12-2 identifies known occupational carcinogenic agents classified by the International Agency for Research on Cancer (IARC), and Box 12-3 identifies probable occupational carcinogenic agents classified by the IARC. A substantial percentage of cancers of the upper respiratory passages, lung, bladder, and peritoneum are attributed to occupational factors; however, fewer studies of nonsmokers exist.²³³ One notable occupational factor is asbestos, which increases the risk of mesothelioma and lung cancer. Asbestos was used in homes and buildings built before the 1970s to insulate ceiling tiles, flooring, and pipe covers. In western Europe, the epidemic of mesothelioma in building workers and other workers born after 1940 did not become apparent until the 1990s because of long latency. Carcinoma of the bladder has been linked with the manufacture of dyes, rubber, paint, and aromatic amines, especially β-naphthylamine and benzidine. Benzol inhalation is linked to leukemia in shoemakers and in workers in the rubber cement, explosives, and dyeing industries. Other notable occupational hazards include heavy metals (e.g., high-nickel alloy, chromium VI compounds, inorganic arsenic), silica, polycyclic aromatic hydrocarbons, sulfuric acid, and chloromethyl ether. Studies of occupational exposure to diesel exhaust indicate an increased risk of lung cancer.²³⁴ Disentangling data related to lung cancer, air pollution, and occupational risks is complex, especially in combination with active and passive smoking and the interplay of environmental factors and genetic polymorphisms at multiple loci.

Air Pollution

A person inhales about 20,000 L of air every day; thus even modest contamination of the atmosphere can result in inhalation of appreciable doses of pollutants. Contaminants include outdoor and indoor air pollutants. Concerns include industrial emissions, including arsenicals, benzene, chloroform, formaldehyde, sulfuric acid, mustard gas, vinyl chloride, and acrylonitrile.²³⁵ Living close to certain industries is a recognized cancer risk factor, although it is difficult to determine cancer risk from outdoor pollution alone because investigators must accurately control for smoking and radon. Studies that controlled or stratified for smoking demonstrated associations between excess lung cancer rates and heavy metal and aromatic hydrocarbon emissions in polluted air. Evidence for cancers, other than lung cancer and childhood cancer, is inconsistent.²³⁶

Indoor pollution generally is considered worse than outdoor pollution, partly because of cigarette smoke. Environmental tobacco smoke (ETS; passive smoking) can cause the formation of reactive oxygen free radicals and thus DNA damage. The IARC has classified ETS as a human carcinogen. Another significant indoor air pollutant is radon gas. Radon is a natural radioactive gas derived from the radioactive decay of uranium that is ubiquitous in rock and soil; it can become trapped in houses and gives rise to radioactive decay products known to be carcinogenic to humans. The most hazardous houses can be identified by testing and then by being modified to prevent further radon contamination. Exposure levels are greater from underground mines than from houses. Most of the lung cancers associated with radon are bronchogenic; however, small cell carcinoma does occur with greater frequency in underground miners. Radon increases the risk of lung cancer in underground miners whether they smoke or not.

In China, some regions report very high levels of lung cancer in women who spend much of their time indoors. Exposures from heating and cooking combustion sources (e.g., oil vapors) are identified as risk factors for lung cancer.²³⁷ In addition, domestic coal use and ETS increase the risk of lung cancer in women and men.²³⁸

Inorganic arsenic (known as a carcinogen since the late 1960s), found principally in underground water (from 1000 to 4000 mcg/L), is found in many regions of the world. According to the IARC, strong evidence indicates an increased risk of bladder, skin, and lung cancers following consumption of water with high levels of arsenic (generally greater than 200 mcg/L).²³⁹ Evidence for cancers of the liver, colon, and kidney is weaker. Other sources of inorganic arsenic are related to occupational exposures (see Box 12-2).

The central hypothesis, based on rat studies, for the mechanisms related to particle-induced lung carcinogenesis is that insoluble particles cause pulmonary inflammation (e.g., cytokine release, ROS), which leads to genotoxic stress, proliferative response, and tissue remodeling progressing toward fibrosis and tumor development. Additional research is needed to understand the surface chemistry and lung tissue remodeling in relation to insoluble particles, lung carcinogenesis, and other respiratory problems.^240,241

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