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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

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Holland-Frei Cancer Medicine. 5th edition.

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Chapter 26Nutrition in the Etiology and Prevention of Cancer

, MD, PHD, , MS, RD, LD, and , MD, DPH.

Throughout human evolution, the often-precarious food supply was typically low in fat and high in complex carbohydrates and fiber. Over the last two centuries, improvements in food production, processing, storage, and distribution have led to major changes in diet composition within the economically developed nations. During this period, life expectancy also dramatically increased in these countries because of a combination of factors including public health measures, improved occupational safety, and major reductions in nutrient deficiency syndromes. As the population has aged, we have seen a shift in the major causes of morbidity and mortality toward chronic diseases, such as cancer and cardiovascular disease. These changes have been associated with an increasingly overweight and sedentary population. Although nutritional deficiencies still plague subpopulations in the developed nations, such as the poor, the aged, alcoholics, and the chronically ill, we now recognize that the affluent diet contributes to the pathogenesis of chronic diseases that afflict the vast majority of the population. Efforts to understand the etiologies of various cancers have led to epidemiologic and laboratory studies that strongly implicate certain dietary patterns and specific nutrients.

The diet not only is a source of nutrients, it serves as a vehicle for many other substances that may participate in promoting or inhibiting carcinogenesis. Although frequently implicated by the lay press and public, food additives, such as dyes, artificial sweeteners, and flavoring agents appear to contribute very little to the overall cancer burden.1–3 The potential risks of man-made contaminants, such as pesticides, herbicides, and industrial wastes, that enter the food chain have not yet been clearly defined. Many natural carcinogens that are produced by plants or fungi (e.g., aflatoxins in moldy grains) probably play a role in the etiology of some human cancers. Increasing evidence also implicates food processing or cooking methods (e.g., salt-pickling, charcoal-broiling) as sources of carcinogens or tumor-promoting substances.1,2 A rapidly expanding area of research focuses on the identification of natural substances in foods, such as phytochemicals, which are not nutrients but have anticarcinogenic properties that ultimately may be used in chemoprevention programs.1,2,4–6

This review is devoted to the role of nutrients and foods in the etiology of cancer. Laboratory studies have proven that nutritional status has a major influence on host susceptibility to oncogenic events. Nutrients are classified into six main categories: protein, carbohydrate, fat, vitamins, minerals, and water. The only components providing energy are protein, carbohydrates, and fat, at approximately 4, 4, and 9 kilocalories per gram, respectively. Vitamins and minerals provide no energy but function as structural components or cofactors in numerous vital metabolic processes. Dietary fiber has not been considered an essential nutrient category, although considerable efforts have been devoted to understanding its complexities and role in human health and disease. Alcohol also has been a component of the human diet throughout recorded history and has numerous metabolic and physiologic effects in addition to its contribution to energy intake (7 kcal/g). The potential complex interactions among the dozens of established nutrients and the genetic as well as environmental factors participating in human carcinogenesis have precluded precise quantification of the risks and benefits associated with any single nutrient. Recent publications have provided comprehensive overviews of the nutrition and cancer field.1–3,7–12 Rather than detailing here the complex, often incomplete, and occasionally contradictory literature concerning the role of nutrients in the etiology of human cancer, this chapter is a general guide to this rapidly expanding discipline, emphasizing the major emerging concepts in the area.

Methodologic Issues in Diet, Nutrition, and Cancer Studies

Several approaches are used by epidemiologists and laboratory-based scientists to study the effects of diet and nutrition on the development of cancer. Each type of study has its strengths and limitations that need to be understood in order to interpret individual studies within the context of a large body of data. Nutritional epidemiology poses some unique obstacles, in that food is an exposure that is universal, which is in stark contrast to other cancer-causing environmental exposures, such as cigarette smoke.13–16 The unbiased detection and quantification of risks that are associated with variations in nutrient intake would ideally be achieved through randomized, prospective trials. Unfortunately, the enormous costs of long-term nutrition studies and the scientific difficulties in controlling or measuring nutrient intake limit their feasibility. Current nutritional guidelines for disease prevention and future refinements, therefore, will be based on the integration of information derived from a variety of different epidemiologic approaches and laboratory investigations. The etiologies of most chronic diseases, including cancer, are multi-factorial. Human cancers show striking variations based on factors such as age, sex, race, socioeconomic status, and genetics as well as many occupational and lifestyle factors. The potential for complex interactions between these factors and nutrients is enormous, and this emphasizes the difficulties in demonstrating causal associations with the same clarity as is demonstrable for high-risk environmental exposures, such as cigarette smoking.

Assessment of the Human Diet

The critical limiting feature of most human studies designed to examine the role of nutrients in cancer is the imprecision of quantifying nutrient intake. Estimating the usual intake of foods or nutrients as well as accounting for intraindividual variation over time is a critical area of research.17,18 An estimate of human nutrient intake is derived from a two-step process. First, the amounts and types of foods that are consumed must be determined by interviews, questionnaires, or food diaries. This information can then be used to calculate nutrient intake if an accurate database has been established that quantifies the amount of each nutrient contained in the foods that are consumed by the population under investigation. Each step can be associated with significant error and makes nutrient and cancer associations difficult to detect.

There are four basic methodologies for assessing intake: dietary recalls, food records, diet histories, and food-frequency questionnaires. Dietary recalls and food records focus on current intake, whereas diet histories and food-frequency questionnaires focus on usual intake over a period of time. For recall studies, participants are contacted and asked to list all the foods they have ingested over a defined period of time, usually 24 hours; multiple 24-hour recalls collected over a period of time for different days of the week will more fully assess current intake. The food-record method requires that subjects record their intake as they consume their meals over a period of time, such as a week or a month. This methodology may incorporate the estimation or measurement of portion size and the method of food preparation. Diet histories are obtained by interviews using open-ended questions regarding usual intake, which may include portion size, and food models. A number of food-frequency questionnaires, which vary in length and complexity, have been developed. Subjects record the frequency of intake for each item on the list, typically using a format that allows for rapid coding into computerized databases. Self-administered food-frequency questionnaires typically are used in large-cohort or case-control studies.

There are several potential advantages and disadvantages to each diet-assessment technique. A very active and critical area of research involves improving the design and subsequent validation of dietary questionnaires and interview techniques to measure both long- and short-term dietary intake.13,14 Investigators in this field must address several issues. The human diet is a complex array of foods that exhibits significant day-to-day and seasonal variations. The complexity of diet also differs widely among populations, cultures, and geographic areas. This often requires the development of different assessment methods for each population. For example, food variety in specific counties within the People’s Republic of China is very homogeneous and may be limited to less than 25 items produced locally.19 In contrast, 90% (by weight) of the diet in the United States is derived from over 500 different food items.20 An efficient and accurate assessment tool that was designed for China would be useless in the United States. Within a nation or geographic area, food selections among individuals also show significant variations with age, gender, ethnicity, and social and economic status; specific assessment tools may be necessary for certain subgroups within a population. Most human cancers have a long latency period, and the methodologic difficulties associated with estimating the intake of foods or nutrients consumed many years before the diagnosis are a major concern for retrospective studies.21

Once an estimate of food choices has been obtained, estimation of nutrient intake depends on a database that defines the nutrient composition of the chosen foods. The U.S. Department of Agriculture handbook provides an estimate of the nutrient composition of most foods consumed in North America.22 However, the nutrient content of foods in many developing nations has not been as precisely defined. The content of some nutrients in a food may be relatively constant and even regulated by law in some nations (e.g., the amount of fat in whole milk); however, the contents of other nutrients in food items may be highly variable. For example, the selenium concentration in grains and vegetables will vary greatly, depending on the soil selenium content. In nations where foods are shipped to large distances, an estimate of selenium intake may require direct measurement of its content in food samples from the study population. A very important area of research also concerns how to accurately measure energy intake in the participants of the studies.23

In many studies, the consumption of certain foods that account for the greatest variance in the nutrient of interest serves as a surrogate indicator of nutrient intake. For example, many investigators present an analysis of meat intake relative to the risk of certain cancers as a surrogate indicator of saturated fat intake. Similarly, the consumption of certain vegetables and citrus fruits often is used as an estimate of β-carotene or vitamin C intake. Studies using surrogate measures for nutrient intake, however, can greatly underestimate or fail to detect a real association between a nutrient and cancer because of imperfect exposure data. In addition, most foods are a source of more than one potentially active nutrient; for example, many fruits and vegetables are not only sources of vitamin C but also contribute significantly to carotenoid and fiber intake. Caution should be used in making assumptions concerning the role of specific nutrients, when investigators use food items or groups as the primary focus of the analysis.

Biochemical Assessment of Nutrient Intake

Future progress will depend, in part, on innovative epidemiologic strategies employing accurate biochemical and molecular indicators for the intake of many nutrients.13,24 Identifying biomarkers of nutrient exposure offers the promise of improved precision in epidemiologic studies because of reduced misclassification of participants according to intake estimates. An additional application will be in the measurement of compliance with dietary regimens during prospective intervention trials. For some nutritional factors, such as total fat intake, we have no useful screening test that can be applied to a large population. For other factors, such as cholesterol consumption, the measurement of serum cholesterol only provides a crude indictor of intake and is modulated by many other genetic and dietary factors. Serum retinol as a measure of vitamin A status is buffered by tissue stores and reflects nutrient status only at the extremes of deficiency or excess.25 In contrast, measuring the selenium content of hair or toenail clippings provides an integrated measure of selenium intake over an extended period of time and can be used in epidemiologic studies.26 Because the presence of a disease may alter dietary intake and the metabolism of specific nutrients, the biochemical or molecular assessment of nutrient intake will be less useful in retrospective and case-control studies; they will be most informative in prospective and cohort studies, geographic correlational investigations, and studies of migrant populations.

Correlation and Ecologic Studies

In correlational and ecologic studies, the unit of observation is a group of people. Cancer incidence or mortality among groups is compared with estimates of the average group intake of foods or nutrients. Often quoted examples are the studies showing a relationship between dietary fat intake and breast cancer.27,28 Armstrong and Doll27 reported a correlation of 0.89 between the estimated average per capita fat intake and breast cancer mortality rates in nations around the world. Ecologic studies also can be conducted within a single country. One example is a study in China based on an analysis of data from 65 Chinese counties.29 Per capita fat intake varied from 6 to 45% of energy and was positively, but weakly, associated with risk of breast cancer. These two examples illustrate that researchers must be particularly careful in making strong or quantitative conclusions on the basis of correlations between cancer rates and single nutrients. Nations showing large differences in cancer incidence often exhibit dietary patterns so dramatically different that conclusions concerning the contribution of individual dietary components or nutrients are impossible. For example, the Chinese exhibit an overall age-adjusted breast cancer mortality rate that is approximately 10 to 20% of that found in the United States, and they consume a diet that is lower in total fat, animal protein, refined carbohydrates, vitamin A, and calcium but higher in carotenoids, starches, and fiber (Table 26.1).19 In addition to variations in dietary content, populations also exhibit significant differences in food processing and preparation that are associated with the shift from an agrarian society to an industrial society. Inaccuracies in the available data on food consumption also may limit these studies. In many nations, data are crude and based on food-disappearance information of varying accuracy. Furthermore, spoilage or waste may affect food-disappearance data.

Table 26.1. Estimated Average Intake of Several Dietary and Nutritional Factors in the Peoples Republic of China and the United States.

Table 26.1

Estimated Average Intake of Several Dietary and Nutritional Factors in the Peoples Republic of China and the United States.

The major strength of international correlational studies is that the contrast in a dietary variable much larger than likely will be found within geographically restricted populations. For example, dietary fat intake varies over a wide range between nations, but it is relatively homogeneous within a nation, such as the United States. Despite the inherent difficulties in interpretation, ecologic studies also will continue to provide a very important resource for the generation of nutrition and cancer hypotheses.

Case-Control Studies

Many weaknesses of correlational studies are potentially avoidable in case-control investigations, in which information about previous diets is obtained from patients with disease and compared with that from subjects without the disease. Because the populations tend to be more homogeneous in various ways than those in international studies and detailed information on a variety of potentially confounding factors, such as smoking, can be obtained, positive results from these studies may provide more convincing evidence regarding a particular nutrient and cancer. These studies can be conducted over a relatively short period of time, and they are particularly useful in studying relatively rare cancers, if a mechanism for identifying cases in a large geographic area is established.

These studies have been useful in many situations, but they have some limitations when studying diet and cancer. This is particularly true if serum markers of nutrient intake are being evaluated. For example, if blood β-carotene concentrations are different between subjects with and without lung cancer, it is difficult to know whether the difference reflects a true variation in intake or a change that is related to the disease. In addition, the possibility of selection or recall bias must be considered in evaluating case-control studies. Selection bias occurs if a nonrepresentative control group is selected or if some of the cases or controls refuse to participate and have characteristics that may bias the results. Recall bias could occur if subjects having a specific cancer remember and report their diet differently from controls. The magnitude of this source of bias has been examined in two studies. One was conducted among members of the Nurses’ Health Study cohort,30 and among participants in 1986, who prospectively completed food-frequency questionnaires, 398 were subsequently diagnosed with breast cancer in the following 2 years. The investigators attempted to contact these women and 798 age-matched controls, and they asked responders to complete a second food-frequency questionnaire inquiring about their diet in 1985 (before the diagnosis of breast cancer) to mimic a case-control study. Using the prospective data, no appreciable association was seen between total fat intake and risk of breast cancer, but a 43% higher risk was observed through the questionnaires completed after the diagnosis.

A similar study that focused on recall bias,31 however, found no significant differential error in the recall of past diet by patients with cancer and controls. Recall bias is more likely in situations where participants may be familiar with a particular hypothesis, such as fat and breast cancer. Another limitation is that only dietary factors that are etiologically relevant relatively shortly before the diagnosis of cancer can be studied. Whereas many studies indicate that diet within the past few years can be recalled with reasonable accuracy, it is less likely that diet in past decades can be assessed with any degree of precision. In addition, study populations in case-control investigations may be highly homogeneous relative to the intake of certain nutrients, and differences between patients with cancer and matched controls may not be demonstrable using current assessment techniques. Case-control studies may prove to be most useful in migrant populations moving to areas that exhibit dramatic differences in dietary content (e.g., migrants from countries exhibiting a low-risk of colon cancer, such as China, moving to high-risk areas, such as the United States).32 Cases and controls can then be evaluated according to the degree of adaptation to the high-risk diet in the United States.

Prospective or Cohort Studies

The prospective approach defines a study population and monitors the incidence of disease over time as well as exposure to potential risk factors. These studies avoid some of the inaccuracies of estimating dietary intake retrospectively and the recall bias typically found in case-control studies because a description of dietary exposures can be obtained before the development of the disease. A disadvantage is the enormous costs that are associated with a large number of participants and long periods of follow-up. A potential problem that investigators must address is the loss of participants over time because of inefficient follow-up. If disease incidence or specific dietary exposures are related to a loss to follow-up, then estimates of risk are biased or may not be detected. An additional consideration for some cancers (e.g., breast cancer) is that nutrients acting during childhood and adolescence may be very crucial, and a prospective study initiated in adult women may not accurately identify critical dietary risk factors. One important advantage is that dietary intake can be updated periodically so that long-term intake can be more precisely estimated. For example, in the Nurses’ Health Study of approximately 88,000 women,33 dietary intake was assessed in 1980, 1984, 1986, 1990, and 1994. Recent technologic advances, such as self-administered, computer-scannable dietary questionnaires, allow these studies to become more efficient and cost effective. There are currently at least six large dietary cohort studies underway, ranging in size from 17,000 to over 89,000 women.

Prospective studies are especially useful when evaluating biochemical markers for nutrient intake, using samples of blood, urine, feces, or tissue that may ultimately correlate with cancer risk. One approach, referred to as a nested case-control study, requires that biologic specimens be collected from all members of the cohort. Because it may not be cost effective to measure nutrient markers in samples from all individuals, the experiment can be limited to those who develop a specific cancer and matched controls from the cohort. For example, several studies have used this technique to examine the relationship between serum β-carotene and risk of lung cancer.34 Prospectively collected sera from those developing lung cancer were analyzed and compared with controls matched by age, sex, time of serum collection, and smoking history. In each study, serum β-carotene was observed to be lower among individuals who subsequently developed lung cancer, compared with controls.

Randomized Trials and Intervention Studies

Oncologists routinely use randomized trials to assess the utility of therapeutic interventions in the treatment of cancer or the prevention of relapse. Despite the scientific advantages, this method is difficult to implement for the evaluation of many nutrition and cancer hypotheses. Experiments in otherwise healthy individuals can only be justified when considerable observational data have been collected and supported by studies from the laboratory. It is critical that the potential benefits be well defined, and that adverse outcomes are unlikely. Because of the length of the induction period for most cancers, intervention trials will require large numbers of participants and many years of follow-up to detect the effects of most dietary interventions. Use of individuals who are at high risk of cancer from a genetic marker or premalignant condition (i.e., colonic polyps) may increase the frequency with which an outcome of interest occurs over time.

For some nutritional variables, compliance may be an issue. It may be difficult to ensure that a large population adheres to a strict diet, such as a low-fat regimen, over a long period of time. The biochemical methodology to assess compliance with a low-fat diet does not currently exist. Trials of dietary change cannot be blinded. The control group may change nutrient intake over time on the basis of societal adaptation to currently publicized recommendations or dietary fads, thus limiting the power of the study. Randomized trials will be most useful in the testing of potential cancer inhibitors, such as certain vitamins, minerals, and other chemopreventive agents, that can be incorporated into pills or capsules and provided in a double-blind fashion over a period of years.35

Because the length of time between a dietary intervention and a measurable effect on cancer may be years or decades, an intermediate end point may be used as an earlier indicator of efficacy. For example, the ability of supplemental wheat bran to decrease colon mucosa cell proliferation rates36 and reduce polyp formation37 in patients who are at high risk for colon cancer have been completed. However, intermediate end points may not completely predict cancer risk. Efforts to define intermediate markers for common cancers that can be used in prospective studies is of major importance to the nutrition and cancer fields.

The manipulation of single dietary components in large-scale intervention studies is difficult. For example, increasing fruit and vegetable intake or reducing the proportion of calories from fat alters the intake of many food items and a number of nutrients. Although these studies may provide useful information regarding public health recommendations, interpretation of the precise role a specific nutrient plays may be problematic. Even when scientifically and ethically feasible, the large costs of randomized trials limit their implementation. In addition, negative results in intervention studies often are difficult to interpret. They could be explained by a lack of treatment effect, inappropriate dose of supplement, dietary intervention of ineffective magnitude, failure of participants to comply with the intervention, or insufficient duration of treatment and follow-up.

Laboratory Animal Models

The effects of nutrients and their interactions on carcinogenesis can be rigorously tested in animal models. Although the information derived from animal models must be extrapolated to humans with caution, it does provide important evidence for the biologic plausibility of relationships suggested by epidemiologic studies. The nutrient requirements of most laboratory animals have been precisely defined, and purified ingredients can be used to formulate diets for cancer studies.38–41 Unfortunately, many published studies do not provide useful information because of the investigators’ failure to appreciate two critical observations derived from decades of experimentation.12 The first is the strong, positive correlation between energy intake and the incidence or growth of tumors in virtually every animal model system.1–3,1242–48 The second issue is the frequent observation that animals fed nutritionally complete diets that are composed of unrefined foods, usually referred to as “chow,” often exhibit a reduction in tumorigenesis, compared with those fed a complete diet derived from purified nutrients.1,2,35

Because energy intake has a major influence on tumorigenesis (Fig. 26.1), recording food consumption and body weight is an essential aspect of all rodent studies.49 Unfortunately, failure to document the effects of dietary treatments on feed (i.e., energy) intake frequently limits the interpretation of published experiments. Nutritional deficiencies, imbalances, or excesses can significantly alter energy intake. For example, vitamin A deficiency or supplementation of the diet with selenium at high concentrations can inhibit carcinogenesis through an indirect effect on energy intake. Readers of nutrition and carcinogenesis literature must carefully evaluate dietary treatments, identify the variables that are present, and determine if energy intake has confounded interpretation of the data. In some cases, pair-feeding and other methods of compensating for treatment-induced differences in energy intake can be used.

Figure 26.1. The effects of low- and high-fat diets at different levels of caloric intake on spontaneous mammory tumorigenesis in C3H female mice.

Figure 26.1

The effects of low- and high-fat diets at different levels of caloric intake on spontaneous mammory tumorigenesis in C3H female mice. Adapted from Tannenbaum A. The dependence of tumor formation on the composition of the calorie-restricted diet as well (more...)

Another problem frequently found in the literature is the inappropriate use of cereal-based commercial laboratory chows. Some investigators use these products as the control or normal diet for comparison against synthetic diets with a different concentration of a specific nutrient. Although commercial laboratory chows provide excellent nutrition, they vary over time and between companies in the sources of natural ingredients. Chow diets contain varying concentrations of cereals, vegetables, legumes, fishmeal, and milk products that are a function of local market availability and cost. Although the nutrient content of these diets satisfies the established minimum requirements for mice and rats, the concentrations of individual nutrients may vary substantially. For example, the vitamin A and β-carotene content of different batches of the National Institutes of Health (NIH)-07 chow diet varied over 6- and 20-fold, respectively.50 In addition, detectable levels of aflatoxins, nitrosamines, antioxidants, pesticides, herbicides, and heavy metals are observed.50 Many undefined substances found in grains and vegetables are thought to have anticarcinogenic activity and contribute to the tumor-preventive properties that are associated with chow diets. In general, natural-ingredient diets are inconsistent and therefore inadequate for use in experiments to quantify the subtle effects of specific nutrients on carcinogenesis. Diets must be precisely defined in publications and confounding variables eliminated, whenever possible.

Nutrition and the Etiology of Common Cancers

It is unlikely that any food, nutrient, or dietary pattern will influence all cancers uniformly.3,51 In reviewing the relationships between nutrition and cancer, it is convenient to examine the data for each tissue or organ separately; however, this approach will ultimately prove to be inadequate. A key feature of human cancer is interindividual heterogeneity in biologic characteristics and response to treatment. Clearly, cancer of the breast, colon, or any tissue represents a family of diseases. As laboratory methodology improves, we will be able to subclassify cancers according to molecular, biochemical, genetic, and biologic characteristics. Coupled with future improvements in nutritional assessment, the more precise classification of human cancers will allow a more accurate quantification of the relationship between nutrients and specific neoplasms.

Lung

Lung cancer is currently the most common worldwide malignancy and the leading cause of cancer-related death.3,52 Cigarette smoking accounts for the vast majority of cases and incidence rates continue to climb in parallel with the globalization of the manufacture, marketing, and advertising of cigarettes.3,53 Certain occupational exposures, such as to asbestos or radiation, may act synergistically with cigarette smoking to increase the risk.53 Compared with the role of tobacco, the contribution of diet and nutrition almost seems trivial. However, the inverse relationship between the greater intake of fruits and vegetables and lower risk of lung cancer has been one of the most consistent findings in human nutritional epidemiology.3,8,54–56 The active agents in a diet rich in these food items remain to be determined. Many have hypothesized that carotenoids, particularly β-carotene, or vitamin A may be important.3 Prospective studies also have compared serum β-carotene levels in individuals subsequently developing lung cancer to matched controls and have found them to be correlated inversely with risk.3,34

Several ongoing intervention trials may help to determine if β-carotene supplementation has anticancer properties. A recent evaluation of a Finnish study57 found no reduction, and perhaps an increase, in the incidence of lung cancer among male smokers after 5 to 8 years of supplementation with β-carotene at 20 mg/d. Similarly, an American study from Seattle tested 30 mg of β-carotene and 25,00 IU of vitamin A in over 1,800 men and women at high risk for lung cancer. The intervention group had a relative risk (RR) of 1.36 for lung cancer incidence, compared with the placebo group. This study was stopped early when it became clear that the supplements were not cancer protective and possibly harmful.58 These reports emphasize that β-carotene is probably not the only component in diets rich in fruits and vegetables that contribute to some degree of protection from tobacco-related cancer of the lung.59

A number of other nutrients including vitamin E, selenium, vitamin C, fat, and retinoids are undergoing continuing evaluation regarding a protective role against lung cancer;3,60,61 however, their roles remain obscure. Overall, elimination of cigarette smoking and occupational risk factors will have the greatest impact on decreasing the incidence of lung cancer. Among high-risk individuals, the frequent consumption of a diverse array of fruits and vegetables may provide some degree of protection against lung cancer.

Oral Cavity, Larynx, and Oropharynx

Like lung cancer, cancers of the oral cavity and the larynx are strongly related to the use of tobacco products.3,62–67 Case-control studies completed over several decades also have documented associations between the consumption of alcoholic beverages and cancers of these tissues.68–73 A dose–response relationship of alcohol and oral cancer, independent of tobacco usage, has been observed in a number of studies (Fig. 26.2).74–81 Additional evidence is derived from studies of populations, such as alcoholics, who exhibit increased risk, and Seventh-Day Adventists and Mormons in the United States, who abstain from alcohol and have lower risk.82,83 It is of interest that feeding pure alcohol as part of a nutritionally sound diet does not produce oral cancers in experimental animals.66 The extent that this represents biochemical differences between man and rodents, the lack of a direct carcinogenic effect of ethanol, the presence of carcinogens in alcoholic beverages consumed by man, the passive inhalation of ambient tobacco smoke in the places where ethanol is consumed, or the importance of other interacting carcinogens and nutritional deficits must be further evaluated.

Figure 26.2. The interactions between alcohol intake and cigarette smoking on the relative risk of oral cancer.

Figure 26.2

The interactions between alcohol intake and cigarette smoking on the relative risk of oral cancer. Adapted from Rothman K, Keller A. The effect of joint exposure to alcohol and tobacco on risk of cancer of the mouth and pharynx. J Chronic Dis 1972;25:711. (more...)

Both epidemiologic and laboratory studies support a role of vitamin A as a modulator of carcinogenesis of the oral and respiratory epithelia. Vitamin A deficiency leads to squamous metaplasia of these tissues that is corrected by treatment with vitamin A and a number of related retinoids. The metaplasia that is associated with vitamin A deficiency is similar histologically to the premalignant changes that are observed following exposure of the oral mucosa to chemical carcinogens. Several animal studies have suggested that vitamin A, carotenoids, or synthetic retinoids may retard carcinogenesis of the oral cavity, and case-control studies occasionally have reported increased risk associated with lower estimated vitamin A intake.84 A number of chemoprevention trials have been undertaken using leukoplakia, a premalignant condition of the oral mucosa, as the surrogate end point. In a randomized trial, Stich and colleagues85 treated patients having leukoplakia with β-carotene, β-carotene plus vitamin A, or placebo for 6 months. On follow-up evaluation, the complete remission rates were 15, 28, and 3%, respectively. A subsequent study reported a 57% complete remission rate in a group treated with vitamin A at 200,000 IU/wk, compared with only 3% in the placebo group.85 Several nonrandomized studies using synthetic retinoids also have suggested dramatic reversals in oral leukoplakia. Subsequent randomized studies using 13-cis-retinoic acid also showed significantly lower relapse rates in the treated groups.86

The beneficial effects of vitamin A and synthetic retinoids in preventing premalignant changes of the oral mucosa led to a landmark clinical chemoprevention trial designed to determine its effectiveness in preventing second primary tumors of the aerodigestive tract.87 Second cancers occur at a rate of 3 to 4% per year in patients who have received potentially curative treatment of their initial, early stage cancer. Patients rendered disease-free after primary treatment of their head and neck cancer were randomized to placebo or 13-cis-retinoic acid. There were no significant differences in the local, regional, or distant recurrences of the primary cancers (Table 26.2). However, the treated group had significantly fewer second primary tumors compared with placebo controls, at 4% and 24%, respectively, after 32 months (see Chapter 105).88 This study suggests that vitamin A or retinoids influence early stages in carcinogenesis, and that these compounds probably have little utility for the treatment of established cancers of the oral pharynx.

Table 26.2. The Effects of 13-cis Retinoic Acid on the Incidence of Primary-Treatment Failure and the Incidence of Second Primary Tumors in Squamous Cell Carcinoma of the Head and Neck.

Table 26.2

The Effects of 13-cis Retinoic Acid on the Incidence of Primary-Treatment Failure and the Incidence of Second Primary Tumors in Squamous Cell Carcinoma of the Head and Neck.

It is also possible that dietary carotenoids derived from diets rich in fruits and vegetables, some of which are precursors to vitamin A, are protective.3 A recent study monitored nearly 7,000 American men of Japanese ancestry and found a significant relationship between low prediagnostic serum carotenoids and the risk of esophageal, laryngeal, and oral pharyngeal cancer.89 It is important, however, to be cautious when interpreting these results because serum levels of carotenoids may simply be a surrogate marker for diets rich in fruits and vegetables with a variety of other phytochemicals possibly involved. Frequent consumption of fruits and vegetables has been shown to be protective by a large series of studies.3,84,90–93

In summary, tobacco products are major contributors to cancers of the mouth and pharynx. Convincing evidence is now available that diets rich in fruits and vegetables will decrease the risk of mouth and pharyngeal cancer.3 In addition, consumption of alcoholic beverages increases the risk of these cancers, especially among smokers.3 Further efforts to better define the role of vitamin A and synthetic retinoids as possible chemopreventive agents for high-risk groups is warranted.3

Esophagus

Cancer of the esophagus varies several-hundred-fold between nations and between geographic regions within nations.3,52 The incidence is particularly high in an area extending from the southern border of the Caspian Sea in Iran across central Asia to China. Within nations, such as China or Iran, there frequently are large differences in risk between different locations and population groups.94 For example, age-adjusted annual mortality in the Caspian region of Iran is 165 and 195 per 100,000 for males and females, respectively, but it is 10- and 20-fold lower in other areas of the country.94 The incidence of esophageal cancer in the United States is relatively low, at less than 7 per 100,000.52

In most developed nations, correlational analyses and case-control studies indicate that the major risk factors are ethanol and cigarette smoking.1–3,66,95 Risk increases in proportion to the amount of alcohol consumed.3,67,71,81,96,97 A number of studies have shown an alcohol dose–response relationship after controlling for cigarette smoking, although the two factors may show a significant additive effect.3,71,97,98 In the United States, mortality from esophageal cancer in the Caucasian population has decreased gradually over recent decades, whereas the mortality has doubled for African American men in the last 25 years.99,100 It has been postulated that the three-fold greater risk in African Americans compared with Caucasians may result from differences in alcohol intake, tobacco smoking, and undefined dietary or nutritional factors.100–102 One study which found a protective effect of dietary fruit and vegetables as well as the use of vitamin supplementation also reported that African American men were significantly less likely to adhere to such dietary habits.103

Increasing consumption of alcohol generally is associated with the marginal intake of many nutrients, which is thought to predispose individuals to greater risk.104,105 For example, alcohol may interact with folate, vitamin B12, and methyl group metabolism to modulate risk. One study106 found significantly lower concentrations of B12 and folic acid in the blood of patients with cytologic dysplasia or malignancy of the esophagus; there also was a reduction in DNA methylation of nucleated blood cells of individuals whose esophagus displayed signs of folic acid–related deficiency. As has been suggested for lung cancer, a number of studies have accumulated evidence showing an inverse relationship between risk of esophageal cancer and the consumption of fresh fruits and vegetables.3,8,61,91,107,108 For example, the RR was increased 4.5-fold among Americans eating less than 40 servings of fruits and vegetables per month, compared with those eating over 80 servings.108

Alcohol consumption does not explain the high risk for esophageal cancer in certain parts of Asia.1 Populations in these areas frequently consume diets that are marginal or deficient in a number of nutrients.109–112 Low intakes of fresh fruits, vegetables, and animal products are noted, and the estimated intakes of vitamin A, vitamin C, riboflavin, zinc, and several trace elements, such as molybdenum, frequently are cited as being low as well.105,109,110,112,113 It has been postulated that dietary deficiencies may alter susceptibility to carcinogens that are indigenous to these populations. Although not firmly established, a role for N-nitroso compounds in pickled foods and mycotoxins from moldy grains has been postulated.109,110,112,114 In some areas, associations have been found with the intake of foods consumed at high temperatures.109,112,115,116

In summary, cigarette smoking and alcohol consumption are the most important etiologic factors in affluent nations. The possibility that marginal intakes of one or more nutrients may contribute to risk in affluent populations has been suggested but not firmly established. In some areas of the world, such as the high-risk area between Iran and China, micronutrient deficiencies coupled with the exposure to carcinogenic substances in salt-pickled vegetables or moldy foods may be contributing factors. The most important protective dietary intervention is the frequent consumption of fruits and vegetables.3

Adenocarcinoma of the Esophagus and Gastric Cardia

The incidence of adenocarcinoma of the distal esophagus and gastric cardia have been increasing rapidly over the last two decades in the United States and Western Europe.117,118 Among Caucasian men, adenocarcinoma of the distal esophagus has increased > 350% since the mid-1970s.119 Current or past cigarette smoking may be one of the contributing factors.119,120,121 However, one of the most consistent observations has been a positive association between risk and body mass index (BMI).117,122,123 As the prevalence of obesity has increased in the United States, a similar trend can be observed in the incidence of adenocarcinoma of the esophagus and gastric cardia.124 One study found that BMI was more strongly associated with esophageal and gastric cardia cancer in nonsmokers and younger age groups.125 The mechanism is unknown; however, it has been speculated that obesity may increase intra-abdominal pressure and predispose to gastroesophageal reflux disease.

Other nutritional factors which have been investigated relative to the increased adenocarcinoma risk include diets high in animal sources of fat, low in fiber, and low in fruits and vegetables.121,126 While alcohol intake is a well-established risk factor for squamous cell carcinoma of the upper esophagus, the association between alcohol and adenocarcinoma is less well established.117,120,121 Further efforts are needed to clarify the risk factors responsible for the dramatic increase in the incidence of adenocarcinoma of the esophagus and to devise effective intervention strategies.

Stomach

Gastric cancer is the second most common cancer worldwide (Fig. 26.3).52 The incidence varies dramatically among countries and is highest in parts of Asia (e.g., Japan) and South America. A dramatic decrease in the incidence of stomach cancer in many affluent nations has been observed over the last 50 years. In the United States, the current rate is among the lowest in the world, whereas in 1930, gastric cancer was the most frequently diagnosed cancer in Americans.127 In recent years, investigators have identified a divergent incidence pattern for cancers of the gastric cardia and distal stomach, which suggests different etiologies. Adenocarcinomas of the cardia are typically grouped etiologically with those arising from the metaplastic distal esophagus showing a similar histology and will be discussed under the heading of esophageal cancer.

Figure 26.3. Age-adjusted death rates per 100,000 population from gastric cancer in selected countries.

Figure 26.3

Age-adjusted death rates per 100,000 population from gastric cancer in selected countries. Adapted from Boring CC, Squires TS, Tong T, Montgomery S. Cancer Statistics, 1994. CA 1994;44:7.

Although general agreement exists that diet and nutrition play a role in gastric carcinogenesis, the mechanisms that account for the geographic and temporal incidence patterns have not been firmly established.1,3,40,128 The efforts to identify the causes of stomach cancer have proceeded in several major directions: (1) the protective role of diets rich in fruit and vegetables, (2) the benefits of vitamin C, (3) the protective effects of modern food processing and storage, (4) the role of Helicobacter pylori and interactions with dietary factors, (5) identification of natural carcinogens or precursors such as nitrates, found in foods, (6) the production of carcinogens during grilling or barbecuing of meats, (7) the synthesis of carcinogens from dietary precursors in the stomach.

Populations consuming abundant quantities of fresh fruits and vegetables experience a significantly lower risk of stomach cancer and efforts to identify components of these foods that have protective properties are underway.3,8,128–136 Several possibilities have been proposed, including vitamin A, carotenoids, tocopherols, vitamin C, and other bioactive phytochemicals.128,137,138 Perhaps the data regarding a protective effect of vitamin C is most consistent.3 The majority of case-control studies, cohort studies, or investigations of plasma ascorbic acid have detected statistically significant benefits of vitamin C.3 However, it is not yet possible to completely dissect the independent effects of vitamin C from other substances in vitamin C–containing fruits and vegetables. Intervention studies with vitamin C supplements have not yet demonstrated chemopreventive activity. Greater estimated carotenoid exposure and lower bloods levels of carotenoids are also associated with lower risk, but it is not yet possible to determine if they are serving as proxies for other protective constituents in fruits and vegetables.3

Widespread refrigeration within homes and sanitary food processing, shipping, and storage parallel the reduced risk of gastric cancer over time. These developments contribute to the year-round consumption of fruits and vegetables. Furthermore, the dependence on salt as a preservative is reduced by modern food processing technology and thereby may also contribute to a lower risk.3,128,139

Infection of the gastric mucosa with Helicobacter pylori (previously known as Campylobacter pylori) has been strongly associated with chronic atrophic gastritis and gastric carcinoma.140,141 In the vast majority of infected individuals, the infection is harmless and does not lead to the development of peptic ulcer disease, atrophic gastritis, or gastric cancer.142 The dietary and environmental factors that interact with H. pylori infection to modulate risk are a critical and very active area of investigation.3 For example, in animal models, a high-salt diet induces gastric epithelial hyperplasia and parietal cell loss, thereby enhancing H. pylori colonization.143

Epidemiologic studies have consistently identified an increased risk associated with greater consumption of salt, which is used in many cultures as a preservative of dried meats and pickled vegetables.131,135,139,144–148 Salt-cured foods induce gastric irritation in humans and rodents,149–151 and although salt alone will not induce stomach tumors in experimental models, increased intake potentates tumorigenesis induced by other agents.152,153

The polycyclic aromatic hydrocarbons are a heterogeneous class of lipophilic compounds, many of which are carcinogenic and mutagenic. When administered orally, several have been reported to produce forestomach tumors in mice and hamsters.154,155 These compounds are produced during the heating of foods to high temperatures or incorporated into foods that are cooked over a flame or smoked. They are found in high quantities in grilled, charbroiled, and smoke-cured meats.156–158 For example, the quantity of polycyclic aromatic hydrocarbons in a large, well-done charbroiled steak is equivalent to that found in the smoke of 600 cigarettes.157 Hot-air drying and roasting of grains and coffee also produces polycyclic aromatic hydrocarbons.159 Subpopulations at high risk for gastric cancer in Iceland, Hungary, and Latvia were found to have greater exposure to polycyclic aromatic hydrocarbons in smoked meats.160–163 Overall, dietary exposure to polycyclic aromatic hydrocarbons has not been fully evaluated in large populations that differ in gastric cancer risk.1

Continuing efforts are directed toward the identification of dietary factors that may accentuate the endogenous production of mutagens. It has been postulated that nitrosamines found in food or produced in the stomach from precursors may play a role in gastric carcinogenesis.1,128,164,165 Many nitrosamines are potent mutagens and stomach carcinogens in experimental animals, and several studies have suggested an association between increased levels of nitrate in the diet or drinking water and risk of gastric cancer.1,144 Nitrate itself is not carcinogenic, however. Dietary nitrate first must undergo reduction to nitrite, which, in turn, nitrosates other compounds in the stomach contents, thus producing nitrosamines. Factors that modulate the conversion of dietary nitrate to nitrite probably are more important than the amount of nitrate in the diet.128 Human epidemiologic studies have not consistently observed a relationship between dietary nitrate and gastric cancer. While several studies show a relationship between dietary nitrates and gastric cancer, a recent prospective cohort study analyzed food and water nitrate and nitrate content in 120,000 men and women. Mean follow-up was 6.3 years, and in the 282 cases of gastric cancer, there was no association with dietary nitrate intake.166 One hypothesis suggests that disruption of the gastric mucosa by surgery, dietary irritants, or nutritional deficits produces focal areas of gastritis or atrophy, leading to colonization by bacteria that are known to produce nitrate reductases.167 These changes are thought to promote increased formation of nitrosamines and to initiate the malignant cascade. For example, pernicious anemia is a well-known metabolic disease of nutrient metabolism that leads to atrophic gastritis and increased risk of carcinoma.168 A number of food items and drugs have been found to yield mutagens after nitrosation; for example, nitrosation of a substance in fish consumed in Japan yields a carcinogen for the stomach of rats.169 A compound in fava beans, which are consumed by high-risk populations in Colombia, also yields a potent mutagen after nitrosation.170 Bile acids can be nitrosated and may contribute to carcinoma at the anastomotic site following partial gastrectomy.171 Laboratory studies suggest that vitamins C or E and other antioxidants may protect against the formation of nitrosamines.137,138

Although risk of gastric cancer has been associated with several dietary variables, it is not possible at this time to quantitate the individual contribution of each component or its mechanisms of action. In general, the diet of high-risk populations is low in animal products, high in complex carbohydrates derived from grains, high in salt-preserved and pickled foods, and low in fresh fruits and leafy green vegetables.1,2,8,128 In some populations, additional risk may derive from diets high in smoked foods or nitrates.

Liver

Primary hepatocellular carcinoma is very rare in the United States and Northern Europe.52 In contrast, it is one of the most frequent types of cancer in the developing nations of sub-Saharan Africa and Asia and is now ranked as the third most common cancer worldwide.3,52 Hepatitis B and C infections appear to be the major etiologic factors in many high-risk areas, where the carrier state imparts an RR of approximately 200-fold.172 Contamination of foods with carcinogenic fungal products, such as certain aflatoxins, also may contribute to risk in some populations.1,2,173–175 Aflatoxins are found in geographic areas where food processing and storage are not optimal. Some aflatoxins induce hepatocellular carcinoma in rodent models at the concentrations found in the diet of high-risk populations.176 Quantifying the contribution of aflatoxins to the incidence of hepatocellular carcinoma in many nations is limited by the difficulties of accurately assessing aflatoxin intake and the actual incidence of cancer in these populations. In addition, groups with high aflatoxin exposure often have high rates of hepatitis B infection, parasitic infections, and nutritional deficiencies, which may interact to determine risk.

In low-risk nations, it has been concluded that the regular and high consumption of alcohol is an important dietary factor in the pathogenesis of liver cancer.3,27,66,96,177,178,The data also suggest that other cofactors may act in an additive or synergistic fashion.90,179 It has been hypothesized that liver cancer primarily occurs in those whose cumulative experiences with ethanol, viral hepatitis, and toxin exposure lead to cirrhosis. The cellular and molecular events that are associated with cirrhosis and regenerative nodules that may participate in the initiation and progression to cancer are under investigation. Additional evidence suggests that vinyl chloride, oral contraceptives, and androgenic-anabolic steroids also may participate in liver carcinogenesis in susceptible individuals.

Animal studies using various carcinogens, including aflatoxin, have shown that a number of dietary factors modulate experimental liver carcinogenesis. Diets that are high in protein, energy, or lipid or deficient in lipotropes generally enhance hepatocarcinogenesis.1,2,12,180 The role of these and other nutrients in modulating hepatocellular carcinoma in humans, however, has not been defined.

Pancreas

The association between increased risk of pancreatic cancer and cigarette smoking has been firmly established.3,181 The RR of smoking at least a pack per day is approximately four-fold, compared with that of nonsmokers.3,181 The important roles for nutrients in regulating normal pancreatic growth and function suggest that diet and nutrition may contribute to the pathogenesis of pancreatic cancer.182 The exocrine pancreas, which is the origin for 90% of pancreatic cancers, readily alters the pattern of digestive enzyme secretion in response to the nutrient content of the diet.183 Dietary restriction produces acinar cell atrophy, reduces DNA synthesis,184 and inhibits experimental pancreatic carcinogenesis.185 Pancreatic cell replication and differentiation are modulated by a number of gastrointestinal hormones, such as cholecystokinin and gastrin, and many dietary factors are potent mediators of gastrointestinal hormone secretion.182 Non-nutritive components, such as trypsin inhibitors, frequently found in certain vegetables and legumes, have dramatic stimulatory effects on pancreatic cell DNA synthesis, induce hyperplasia and hypertrophy, and enhance pancreatic carcinogenesis in laboratory studies.182 The strong evidence supporting a role for dietary and nutritional factors in modulating pancreatic cell replication and differentiation suggests that diet may be important in pancreatic carcinogenesis.

The descriptive epidemiology of pancreatic cancer is complicated by the fact that estimates of incidence depend on conventions of medical care that vary in different geographic areas and socioeconomic conditions.186 The symptoms of pancreatic cancer often are vague, and significant cost and risk are associated with obtaining tissue for histologic diagnosis in many nations. Errors in clinical impressions and the difficulty of accurately reporting clinical diagnoses from medical records by cancer registries suggest that extreme caution should be used when comparing rates from populations with different standards of medical care or living in different times and places. Meaningful clues from epidemiologic studies concerning diet and nutrition in the pathogenesis of pancreatic cancer likely will be obscured by inconsistencies in diagnoses among different geographic and socioeconomic population groups. Overall, reports have suggested a higher incidence in the affluent populations of North America and Northern Europe.52 Descriptive studies have suggested associations between an increased risk for pancreatic cancer and a number of components that are characteristic of the affluent diet, such as meat, fat, protein, eggs, milk, and alcohol.1,2,3,27,182,186,187 In contrast, however, the majority of epidemiologic studies suggest that the frequent consumption of fruits and vegetables may reduce the risk of pancreatic cancer.3,8,188

Several animal models for pancreatic cancer have been characterized and used to examine the roles of dietary and nutritional components in modulating carcinogenesis under precisely controlled conditions.43,189,190 Energy restriction dramatically reduces the number of pancreatic cancers in rodent models,43,185 which is consistent with many studies showing a strong inhibitory effect of diet or energy restriction on carcinogenesis in other tissues.43,47 A human case-control study analyzed the diets of 436 cases and 2,003 controls and found a 70% higher cancer risk in subjects who consumed the most calories versus those who consumed the least (highest quartile versus lowest quartile). Additionally, obesity was associated with a 50 to 60% higher risk of pancreatic cancer.191 Thus, both animal and human studies support a relationship between total energy intake and pancreatic cancer risk.

Trypsin inhibitors found in many legumes and vegetables may contribute to the pathogenesis of pancreatic cancer.182 The heat-labile trypsin inhibitors are thought to be the factors responsible for pancreatic acinar hyperplasia and the spontaneous carcinomas that are observed in rats fed diets containing raw soy flour.192–194 Diets containing trypsin inhibitors also enhance the progression of pancreatic carcinomas that are induced by carcinogens such as azaserine.189,194,195 The ability of trypsin inhibitors to enhance pancreatic carcinogenesis probably is closely related to an increased production of trophic hormones and growth factors that contribute to acinar cell hyperplasia. It is unlikely, however, that the average cooked diet that is characteristic of high-risk nations contains significant concentrations of active trypsin inhibitors. Additional information concerning the risk associated with various amounts and durations of exposure to the wide variety of different trypsin inhibitors is necessary.

Some studies have reported a positive association between high coffee intake and pancreatic cancer risk while other studies show that moderate amounts of coffee (1 to 3 cups per day) pose no risk or may be protective.196–199 However, most studies that controlled for smoking history have not found an association. Overall, the evidence is most consistent with the conclusion that coffee has little contribution to the risk of pancreatic cancer.3

A role for alcohol intake remains speculative.3,182 Ethanol does produce toxic injury to pancreatic cells, and the recurrent injury and regeneration may enhance risk in a fashion similar to partial pancreatectomy200 and other chemical injuries.201 However, laboratory202,203 and epidemiologic studies182,186,187 remain inconsistent, and it is concluded that alcohol probably plays a minor role.3

In summary, laboratory studies clearly indicate that pancreatic carcinogenesis is sensitive to a number of dietary and nutritional components. For some nutrients, the limited data from laboratory and epidemiologic studies are in agreement. The most consistent epidemiologic data have been generated concerning reduced risk with diets rich in fruit and vegetables.3,8 However, additional investigations designed to define more clearly the associations identified and the mechanisms involved must be completed to develop dietary recommendations that will significantly decrease the risk of this devastating cancer.

Colon and Rectum

Colorectal cancer is a major public health problem in affluent westernized societies.3,52 In the United States and Western Europe, up to 5% of the population may develop cancer of the large bowel by the age of 75 years.204 The international variation in large bowel cancer is large (Fig. 26.4), and although diagnostic differences may account for some of the international variation, it is unlikely to account for the > 10-fold variations that are observed between many nations.52 The lower rates in Japan suggest that cultural and lifestyle variables rather than industrialization are the critical factors.52 The geographic incidence patterns for colon and rectal cancer also generally vary in concert, suggesting that some similarity in etiology exists.205,206 Studies in immigrant populations, such as Chinese migrants to the United States,32 clearly indicate that international variations primarily result from environmental influences rather than genetic background.207–209 Japanese migrants to the United States also show a definite shift toward the colorectal cancer rates of the adopted country within the first generation.207 Examination of time trends in colorectal cancer incidence also suggests major contributions from environmental and lifestyle factors.208 Increases in the rate of large bowel cancer have been particularly striking within Japan in the recent decades (Fig. 26.5).207,210 The desire to understand these variations in incidence and to institute preventive measures has prompted efforts to identify specific substances that are initiators or promoters of colon cancer.211

Figure 26.4. Age-adjusted death rates per 100,000 population from colon and rectal cancer in selected countries.

Figure 26.4

Age-adjusted death rates per 100,000 population from colon and rectal cancer in selected countries. Adapted from Boring CC, Squires TS, Tong T, Montgomery S. Cancer statistics, 1994. CA 1994;44:7.

Figure 26.5. Age-standardized colon and rectal cancer incidence per 100,000 men in Japan from 1960 through 1977.

Figure 26.5

Age-standardized colon and rectal cancer incidence per 100,000 men in Japan from 1960 through 1977.

The dietary pattern most frequently associated with increased risk of colorectal cancer have several characteristics: rich in total fat, rich in total or animal protein, rich in meat products, a high proportion of saturated fats, low in fruits and vegetables, and low in plant sources of fiber.1–3,8,207,212–214 A sedentary lifestyle with little physical activity is emerging as one of the strongest lifestyle factors associated with increased risk of colon cancer.3,212 In addition, excessive caloric intake and obesity have been implicated in some, but not all, studies.212,215,216 The relative contribution of each variable alone and the potential interactions among them are currently under investigation in both human and laboratory studies.

Energy Balance and Physical Activity

Energy intake, metabolic efficiency, physical activity, and various measures of body size or obesity are intimately inter-related. It is difficult to quantitate or ascertain the role of each component in cancer risk without considering them as a group. An inverse association between physical activity and risk of colon cancer has been observed in studies limited to occupational activity177,217–225 and those examining both job-related and recreational activity.32,226–237 In addition, many studies have found an association between BMI and elevated risk of colon cancer in men, although this relation is weaker among women.93,209,238–244 The association with a sedentary lifestyle appears stronger but is not limited to the distal colon. One study indicated that waist or waist-to-hip ratio and indicators of central or abdominal obesity are strongly associated with risk of colon cancer,245 perhaps explaining the stronger association in men. These associations between obesity and inactivity with risk of colon cancer have been observed in several countries (United States, China, Sweden, and Japan), among men and women, and for both occupational and recreational activities. Obesity also has been directly associated with risk of colon adenoma.245,246,247 Some evidence suggests that height (perhaps a proxy of the net energy intake during childhood and adolescence) also is related to a higher risk of colon cancer.248–250 Studies in rodent models of colon carcinogenesis have reported enhanced tumorigenesis with greater ad libitum intake251 and reduced risk with restricted intake.252–254 Overall, the evidence is becoming fairly convincing that physical activity and appropriate energy balance will decrease risk of colon cancer.255

Insulin-like growth factor-1 (IGF-1) is one hormone that may be modulated by dietary energy balance, and the relationship between changes in the IGF-1 axis and colorectal cancer risk is currently being investigated. A recent nested case-control study found a significant increase in risk in 193 men who had high baseline plasma levels of circulation IGF-1 prior to the development of colon cancer.256 The complex dietary, lifestyle, and genetic factors that determine bioactive IGF-1 levels throughout the life cycle relative to colon cancer risk remains to be elucidated.

Fat

The relationship between total fat intake, fat saturation, or different sources of fat and risk of colon cancer remain an active area of research but definitive conclusions are not yet possible. However, when the data from epidemiologic and experimental studies are taken together, the possibility that some aspects of dietary fat intake influence colon cancer risk is quite possible.3,212 Food consumption data from geographically defined populations have shown striking correlations between estimated fat intake, especially saturated fat, and colorectal cancer incidence.27,28,257 Many32,233,240,259–269 but not all12,208,270–275 report a positive association between dietary fat and risk of colon cancer. Most of these studies also show a direct association between total energy intake and risk of colon cancer, which is not surprising, given the high correlation between fat and energy intake. Moreover, at least some of the studies indicate that nonlipid sources of energy contribute to the association between energy intake and colon cancer, which raises the question of the relative contribution of total energy consumed or of the fat composition of the diet that is etiologically relevant. For most of the studies, the investigators have been able to separate the influence of dietary fat from that of total energy intake.

A population-based case-control study suggests that dietary fat accounts for 60% of colorectal cancer risk among Chinese migrants to the United States (Fig. 26.6). The relative risk of a high-fat diet, however, depends on the level of physical activity and on gender. Several other cohort studies report that fat from red meats, rather than total fat, may be more important. A recent prospective study in a cohort of 88,000 American nurses supports a role for animal fat in colon cancer.276 An increased RR of 1.89 (95% confidence interval, 1.13–3.15) was observed for the highest quintile (65 g/d), compared with the lowest quintile (39 g/d) of animal fat intake. Other cohort studies have supported a positive association with red meat, particularly processed meats, but not with total fat, animal fat, or saturated fat.238,260,277–279

Figure 26.6. The risk of colorectal cancer in Chinese migrants to the United States according to dietary fat intake and level of physical activity.

Figure 26.6

The risk of colorectal cancer in Chinese migrants to the United States according to dietary fat intake and level of physical activity. From Whittemore AS, Wu-Willaims AH. Lee Metal Diet, physical activity, and colorectal cancer among Chinese in North (more...)

Most studies in carcinogen-induced rodent models for colon cancer have observed increased tumor incidence and multiplicity in rats fed diets containing fat concentrations similar to those observed in the high-risk human diet.43,214,280 A promotional effect has been observed for both saturated and unsaturated fats;43 however, several wellcontrolled rodent studies have failed to document an increased tumor incidence with greater dietary fat,251,281 suggesting that the effect of fat may not be a simple direct relationship and may depend on other variables not yet clearly defined, such as the timing of carcinogen exposure relative to dietary intervention, type of carcinogen and its mechanism of action, and consumption of other interacting nutrients.

Potential mechanisms whereby fat may enhance colon cancer have been postulated on the basis of both human and rodent studies.3,212 A popular, but unproven, hypothesis suggests that dietary fat increases the concentration of bile acids in the colon contents and alters the metabolic activity of the intestinal microflora in a manner that favors production of certain bile-acid metabolites. These metabolites may be weak carcinogens, increase the susceptibility of the mucosa to other carcinogens, or act directly as promoters.214 Low-risk populations in Asia and Africa have lower concentrations of bile acids and their metabolites in stool, compared with high-risk populations in North America.214 Similar results have been observed in rats fed diets that vary in fat content.214 The intrarectal administration of bile-acid metabolites also has been reported to increase carcinogen-induced colon cancer in some studies214 but not in others.282

Protein

A role for dietary protein or specific amino acid patterns in colorectal cancer has been postulated but remains to be established.1,2,3,283–285 The international variation in total protein intake is much less than for fat intake. The source of protein does vary significantly, however, and is primarily derived from vegetable sources among low-risk populations in many nations and from meat and dairy products in those areas exhibiting high-risk.1,2

Few rodent studies have investigated the role of dietary protein in colon carcinogenesis. Increasing protein intake enhanced 1,2-dimethylhydrazine–induced intestinal carcinogenesis in rats, whereas no effect of protein source was observed.284,286 It has been proposed that high-protein diets may enhance colon carcinogenesis by increasing colonic ammonia concentrations.282 It is interesting that in several prospective cohort studies of colon cancer and in studies of adenomatous polyps, protein intake has been associated with a reduced risk of colon cancer. This is even more remarkable, given that red meat, which is a good source of protein, has been associated with an increased risk. A protective effect of dietary protein may relate to increased consumption of the amino acid methionine, which is required for normal methyl group metabolism and DNA methylation.278 Aberrant DNA methylation may be one step in the cascade of genetic defects associated with colon cancer development and progression that is influenced by methionine.288–292 Others have postulated that soy protein may inhibit colon cancer on the basis of both epidemiologic and experimental data.294,295

Fiber

Burkitt and Trowell296 popularized the hypothesis that low dietary fiber intake may be a critical variable enhancing the risk of colon cancer. Trowell297 provided a useful definition of fiber as a component of plant cells that resists digestion by secretions of the human gastrointestinal tract; however, the precise definition continues to be debated and refined among nutritional scientists.1,2 In general, dietary fiber is a complex collection of substances, including cellulose, hemicelluloses, pectin, lignin, gums, some polysaccharides, and mucilages. It is possible to expand the definition to include indigestible substances that are not derived from plant sources, such as chitins from fungi and crustaceans, aminopolysaccharides from animals, or nonenzymatic browning products that form during food processing. The chemistry of dietary fiber is exceptionally complex, and standardization of analytic techniques is a dynamic and evolving field of nutritional science. The different fiber components have widely varying physical and chemical properties, such as water-holding capacity or ion-exchange characteristics. At present, our limited understanding of these physical and chemical characteristics has not allowed adequate insight into the biologic properties of high-fiber foods, which makes it particularly difficult to understand their roles in such diseases as colon cancer.1,2

Studies of several populations consuming diets similar in fat but differing in total fiber intake suggest a protective role for fiber;205,298–300 however, most international and intracountry studies have provided little insight.27,301–303 This should not be surprising because there is a lack of complete analytic data concerning the content of fiber components in foods consumed by many populations. Superimposed on the analytic difficulties, the epidemiologic methodology for estimating fiber intake exhibits tremendous imprecision. Inverse associations between total fiber intake and risk of colon cancer have been observed in some, but not all, case-control studies.261,262,264,265267,276,304–307 A meta-analysis of case-control studies of colon cancer found a combined odds ratio (OR) of 0.58 between the highest and lowest quintiles on the basis of fiber intake but an even stronger OR of 0.48 on the basis of vegetable consumption.96 Prospective data regarding fiber intake and risk of colon cancer generally have been less convincing, with only one study300 showing a clear inverse association and others being only suggestive.55,238,308

A recent, large prospective study of almost 90,000 women enrolled in the Nurses Health Study found no protective effect of fiber against colorectal cancer or adenoma.309 When the data were stratified according to the food source of fiber (cereal, fruit or vegetable), only fiber from fruit showed a trend toward risk reduction, although this trend was not statistically.309 In contrast, the Seven Countries Study in Europe310 examined over 12,000 men and found that fiber intake was inversely associated with colorectal cancer mortality with an increase of 10 grams of daily intake of fiber associated with a 33% lower 25-year risk of death.

Among the case-control and cohort studies that examined sources of fiber separately, intake of fruits or vegetables generally is protective, whereas grain fiber or cereal intake either is unrelated or positively associated with risk of colon cancer. Studies of colorectal adenomas also tend to more consistently support a beneficial effect of fruit and vegetable fiber and, possibly, cereal fiber.3,270,311–315 Overall, epidemiologic data suggest that some component of dietary fiber, particularly from vegetables, or a factor associated with diets rich in fiber, may reduce risk. In addition, some characteristic of highly refined, fiber-depleted foods may enhance the risk for colon cancer.3,238,316–318

The chemical complexity of fiber suggests that estimated total fiber intake might not be an adequate measure for epidemiologic studies attempting to determine its role in colon cancer, thus emphasizing the need for standardized analytic techniques in fiber chemistry. A number of case-control studies have not attempted to calculate fiber intake per se; rather, they use the frequency of consumption of high-fiber foods as an indirect indicator. In general, these studies suggest a protective effect of fiber-rich diets and especially vegetable consumption.300,304,313,319–322 Intervention trials with dietary fiber are now beginning to yield results relative to the risk of colon cancer.323 For example, a recent double-blind, placebo-controlled study showed that a daily supplement of 22.5 g of wheat bran significantly reduced the number of adenomatous polyps in the sigmoid colon and rectum of patients with familial polyposis.37 A subsequent single-arm study reported a reduction in rectal mucosa cell DNA synthesis rates in patients with a history of resected colon or rectal cancer who were fed wheat-bran fiber.36 Future randomized studies will determine if supplements of wheat-bran fiber prevent the development of colon cancer in a high-risk population. Studies to determine the validity of colon cell proliferative rates as a marker of carcinogenic risk also are needed. An intermediate marker will be especially useful for rapid assessment of the chemopreventative effects of various types of dietary fiber.

Animal studies have reinforced the concept that fiber nutrition may play a role in colon carcinogenesis, but that the relationship is not simple.1,2,324–326 Studies have observed the lack of effect and the increased or decreased tumorigenesis being dependent on the amount, type, and source of fiber, its particle size, the amount of other nutrients, type of carcinogen, timing of fiber feeding relative to carcinogen administration, and the strain and species of animal. The results of rodent studies reflect the complexities of fiber nutrition and emphasize the importance of avoiding strong conclusions based on single laboratory or epidemiologic studies. Among the fiber sources evaluated, wheat bran has shown a relatively consistent ability to inhibit experimental colon carcinogenesis.1,2,326,327

A number of mechanisms may contribute to the protective effect of dietary fiber against colon cancer.1,2,326 Fiber may increase fecal bulk and reduce the concentration of colon mutagens or promoters. Many high-fiber diets decrease transit time, thus providing another mechanism to reduce exposure of the colon to genotoxic agents or tumor promoters in the fecal stream. Many fibers also may bind carcinogens in the diet, further limiting exposure.328 Most fibers are metabolized to varying degrees by the bacterial flora, which may lead to the production of metabolites that can either increase or decrease risk. In summary, each type of fiber has unique properties, which may modulate carcinogenesis by different mechanisms. Evidence suggests that diets containing foods that have varying amounts and sources of fiber probably influence the risk of colon cancer, although the details of this relationship remain to be defined.

Alcohol

An association between alcohol intake and risk of colon cancer is consistent with many ecologic329 cohort211,234,241,277330–334 and population-based case-control studies.332,335–337 As further evidence, alcohol is consistently related to higher risk of colorectal adenoma.250,315,337–340 Extensive reviews3,329 concluded that a positive association between alcohol intake and colorectal cancer was found in a majority of human studies, whereas others found no association. The inconsistencies across studies may be a consequence of the small number of cases in some studies or due to variations in the subjects examined, differences in methodology used to quantitate consumption, and variations in beverages preferred in different cultures.3 Overall, the effects seem to be related more to total alcohol intake rather than to the source of alcohol.3 Studies suggest that the elevated risk associated with alcohol occur predominantly in the rectum or distal colon.329 Recent studies indicate that high intakes of folate or methionine, both of which are crucial for normal methyl group metabolism and, particularly, DNA methylation, appeared to mitigate the influence of alcohol. The risk of colorectal adenoma and cancer was elevated in individuals with high intakes of alcohol and low intakes of methionine and folate, and the excess risk was particularly high among those with deleterious combinations, such as high-alcohol and low-folate intakes.127,341 This suggests that alcohol, which has a well-known adverse effect on methyl group metabolism, increases the risk of colorectal cancer via this mechanism.342

Colon Carcinogens

The recent characterization of a series of very specific mutational events in human colon cancer ultimately must be linked with etiologic agents that participate in the accumulation of genotoxic events. At present, no definitive data implicate specific ingested carcinogens for human large bowel cancer; however, the potential for the generation of DNA-damaging compounds or promoters during cooking and food processing has not been thoroughly investigated.343 Food preparation varies among different cultures and could be a critical factor contributing to the large geographic differences in cancer incidence. For example, in China, many foods are prepared with steam, whereas Chinese migrants to the United States more frequently fry similar foods. These differences in food preparation may lead to a different pattern or concentration of pyrolysis products in food. A number of mutagenic pyrolysis products are produced during cooking, and several have been found to be carcinogenic in laboratory animals, even if very few have been found to be specific for the colon.343 Short-term studies that examine nuclear aberrations and microadenoma formation in the colonic mucosa have been used as an indirect measure of carcinogenic potential,343 and rodents fed diets containing cooked food items, such as fried bacon or hamburger, show a higher frequency of nuclear aberrations in the colon mucosa than do controls.343,344 Heterocyclic amines are one class of potent carcinogens formed during the cooking of meat, particularly under conditions of high temperature for prolonged periods of time.345,346 Well-done grilled red meat has recently been associated with the risk of colorectal adenomas.347

Other investigations have focused on the production of mutagens within the digestive tract as a result of bacterial metabolism.343 Human feces contain substances that are mutagenic in bacterial test systems,343 and correlational studies have indicated that fecal mutagenicity is greater in populations that are at high risk for colorectal cancer.348,349 For example, the concentration of stool mutagens in rural black South Africans at low risk of colon cancer was lower than in urban blacks and whites who experience greater risk.348 Human subjects fed a high-risk diet rich in protein, fat, energy, and animal products showed greater concentrations of fecal mutagens than those fed a low-risk diet.350

In summary, increased risk of colorectal cancer is strongly associated with an affluent dietary pattern, which is rich in high-fat foods (especially from animal products) and low in fruits, whole grain products, and especially a variety of vegetables.3,212 The individual contributions of alcohol, energy intake, folate, methionine, meats, and specific fiber components require further investigation.3,212 The potential interactions among these components and other factors contributing to risk, such as exercise and genetics, are numerous. At present, it is prudent to consider the impact of the total diet and greater physical activity when making recommendations for colon cancer prevention rather than focusing on a single factor.

Breast

In women, breast cancer is the most common malignancy and cause of death from cancer throughout the world. In general, breast cancer incidence and mortality continue to increase on a worldwide basis. Cancer of the breast is most common in the affluent nations of North America and Western Europe and much less common in many parts of Asia and Africa.3,52 Migrants from low-risk nations show increasing risk after moving to a high-risk nation,1,2,3,12,207,351 particularly in succeeding generations. This observation suggests that nutritional or other environmental factors that are active during youth and adolescence may have a long-term and major impact on subsequent risk of breast cancer.352 These findings are consistent with the hypothesis that some dietary patterns established early in life are associated with increased height and weight, leading to a hormonal environment contributing to an earlier age of menarche, which, in turn, is associated with an increased risk of breast cancer.353

A number of dietary and nutritional factors have been proposed to enhance or protect against breast cancer. Geographic studies have identified associations between national breast cancer rates and diets high in fat, protein, milk, eggs, refined sugar, and animal products.1–3,27,28,354–356 All these components are characteristic of the Western diet, and the individual contribution of each factor to breast cancer risk cannot be determined by correlational studies alone. Case-control studies frequently have supported associations between breast cancer and components of the affluent diet, but results have not been uniform.3,15,357–364

Energy Balance, Weight, and Obesity

The role of energy intake as a stimulator of mammary carcinogenesis has been well established by rodent studies using diet or energy restriction.49,365 or by regression analysis of ad libitum feeding.44,45 Higher body weight or BMI in women has been associated with greater risk;3,42 furthermore, adult weight gain is associated independently of body weight with enhanced risk of postmenopausal breast cancer.366–370 Overall, higher levels of adult physical activity seem to be associated with a modest protection against breast cancer risk.3,371 However, the precise relationships between energy intake, energy expenditure, anthropometrics, and risk of breast cancer must be examined for different critical periods in a woman’s life cycle. The effects of these factors may vary during adolescence, the reproductive years, and the postmenopausal period.

Fat

The controversy concerning the contribution of dietary fat to risk of breast cancer can best be appreciated through examination of the representative data presented in Figure 26.7 and Tables 26.3 and 26.4. Geographic studies show strong correlations between national rates of breast cancer and the estimated per capita fat consumption.28,372,373 There are wide international variations in breast cancer rates as well as per capita fat consumption or the percentage of calories derived from fat. Breast cancer rates have been observed to increase significantly in populations migrating from low-risk areas, such as Japan, where diets are low in fat, to high-risk areas, such as the United States, where populations consume diets high in fat.1,2,12,207,351 Time-trend studies also support a dietary fat and breast cancer association. Within Japan, estimates of per capita daily fat intake rose from 23 to 52 g/d over the 15-year period before 1973.87 During this period, breast cancer mortality increased in Japan by over 30%.210 Correlation does not prove cause and effect, and many investigators argue that fat intake may be an indicator of some other unidentified combination of diet and environmental components that are the truly critical risk factors. The strong correlations observed might indicate the overall effect of many dietary factors that change simultaneously.

Figure 26.7. International corrrelation of A.

Figure 26.7

International corrrelation of A. estimated dietary fat intake (percentage of calories as fat) and B. estimated carbohydrate intake (percentage of calories as carbohydrate) and age-adjusted breast cancer mortality. From Carroll KK. Carbohydrate and Cancer. (more...)

Table 26.3. Dietary Fat and the Risk of Breast Cancer*.

Table 26.3

Dietary Fat and the Risk of Breast Cancer*.

Table 26.4. The effects of dietary fat intake (12, 24, 48% of calories) on 7, 12-dimethylbenz (a) anthracene (DMBA)-induced mammary carinogenesis in female rats*.

Table 26.4

The effects of dietary fat intake (12, 24, 48% of calories) on 7, 12-dimethylbenz (a) anthracene (DMBA)-induced mammary carinogenesis in female rats*.

The relationship between fat intake and risk of breast cancer has been examined in many case-control studies with inconsistent results.3,374 Prospective cohort studies have not provided compelling evidence for the high dietary fat/breast cancer association.3,269 In the largest cohort study, the Nurses’ Health Study, there was375 no significant relationship between a low fat-diet or specific types of fat and breast cancer risk (see Table 26.3).

Although the epidemiologic data have not provided definitive results concerning dietary fat and breast cancer, accumulated evidence from over 100 animal studies using chemical carcinogens, hormones, irradiation, or viruses to induce breast cancer indicate that as a single variable, fat enhances mammary carcinogenesis.46 For example, a large study in rats, using diets containing fat concentrations ranging from 12 to 48% of calories, clearly indicates a strong enhancement of mammary carcinogenesis over the range of fat intake observed in human populations.44,45,376 Well-controlled rodent studies also have shown that dietary fat enhances the risk of breast cancer independently of caloric intake (see Figure 26.1 and Table 26.4).3,44,45 In addition, both saturated or polyunsaturated fats will similarly enhance mammary carcinogenesis, once the minimal amounts of essential fatty acids have been provided.372 The possibility that omega-3 fatty acids have a unique ability to reduce breast carcinogenesis or growth rates requires additional investigation.

Overall, the large body of data from animal investigations and human geographic epidemiologic studies supports the hypothesis that dietary fat may be one component of an affluent diet that contributes to an increased risk of breast cancer. The negative findings from recent analytic epidemiologic studies, however, have led many to revise the hypotheses. Perhaps the effect of fat is most important early in life, when breast development is most pronounced.377,378 Additional efforts should be directed toward defining how dietary fat interacts with other nutrients to modulate breast development and risk of initiating the carcinogenic cascade. The possibility that achievable reductions in fat intake during adulthood will cause an appreciable reduction in breast cancer risk remains uncertain; several intervention trials are ongoin to evaluate low-fat dietary patterns on breast cancer risk.

Alcohol

Recent reviews of the accumulated evidence concerning alcohol intake and risk of breast cancer suggest a positive association.3,33,258,379–382 The RR from the consumption of one typical serving of beer, wine, or liquor (approximately 12 g of ethanol) per day was estimated to be 1.4, whereas three drinks per day would approximately double the risk. A recent meta-analysis which pooled studies from Canada, the Netherlands, Sweden, and the United States found a linear relationship between breast cancer risk and each 10-g increase in daily alcohol consumption.383 Most investigators have not yet concluded that the association is definitely causal, however, because of the possibility of residual confounding, given that the causes of breast cancer are poorly understood.3

Other Dietary Factors

Overall, diets high in vegetables and fruits probably decrease the risk of breast cancer,3 with some evidence supporting a protective role of carotenoids.3,384,385 There are no consistent relationships for the consumption of specific vitamins and breast cancer risk,3 and recommendations regarding supplement use for prevention remain to be defined. Selenium has been extensively studied relative to breast cancer prevention in animal models.1,2,43 However, the evidence on selenium and breast cancer risk in humans is limited,3 in part due to the difficulty in assessing intake.3 Other bioactive compounds found in the diet, such as soy isoflavones, lignins, and fiber, may play a role in breast cancer, but evidence remains insufficient for recommendations.3

In summary, geographic epidemiologic data, studies of migrant populations, and rodent experiments strongly suggest that diet may have a significant impact on the risk of breast cancer. However, the contribution of individual components of the diet and the time period during a woman’s life when they may be most active are not well understood. The possible risks associated with an affluent dietary pattern and alcohol consumption as well as the benefits of fruits and vegetables warrant further study.

Prostate

Cancer of the prostate has become one of the most frequently diagnosed malignancies in American men, and it is especially common among the African American population.3,386–389 Prostate cancer is a disease of aging men and is rare under the age of 45 years. The international distribution of prostate cancer is similar to that of colon and breast cancer; therefore, it correlates with Western culture and affluent diets.3,52,387

Detailed investigations of diet, adolescent growth and development, adult energy balance, and prostate cancer risk clearly are needed, on the basis of intriguing, but not convincing, evidence from a variety of sources. Although many dietary assessment tools employed in epidemiologic studies inadequately measure energy intake, some have suggested a positive association between estimated intake and risk.387 Higher body weight, BMI, or other measures of obesity have been associated with risk of prostate cancer in some, but not all studies.243,387,390–393 Data regarding physical activity and prostate cancer are relatively sparse and inconclusive.3,287 Laboratory studies in experimental models have shown a striking ability of modest dietary energy restriction to inhibit tumor growth.394 Energy restriction was associated with reduced tumor growth rates, reduced tumor angiogenesis, and greater tumor cell apoptosis.394 The effects of energy balance on hormone status may underlie some of these relationships.387 Reduced energy intake is associated with lower concentrations of several hormones known to stimulate prostate tumor progression, such as growth hormone, prolactin, testosterone, and IGF-1.387,394,395 Human and laboratory studies suggest that IGF-1 may be a key hormone related to prostate cancer risk. Prostate cells have receptors for IGF-1, and IGF-1 stimulates proliferation in the presence of androgens. The findings from a large cohort study document that circulating IGF-1 concentrations adjusted for its binding protein in prospectively collected samples are positively related to future risk of prostate cancer.396

International and intracountry correlational studies have suggested associations between prostate cancer mortality and the per capita intake of total fat.3,387 Similarly, several analytic epidemiologic studies have reported associations between total fat or the consumption of high-fat foods and prostate cancer.3,387 For example, a correlational analysis based on diet history data conducted within Hawaii showed that both animal and saturated fat intake had a high correlation with prostate cancer incidence.390 Within Italy, strong positive correlations exist between prostate cancer mortality and the consumption of foods rich in fat, such as milk and cheese.3,387 The majority of the case-control studies support an association between some component of diets rich in fat, particularly saturated or animal fats, and risk of prostate cancer.3,387,397 Several of the earlier prospective or cohort studies have been inconsistent regarding fat intake and prostate cancer risk. Some of this variation may relate to the design of the studies; for instance, some studies that found a positive association did not control for total energy intake. Several of the null studies had a very long time interval between dietary assessment and diagnosis of cancer and a limited dietary assessment or were conducted in Japan, which has a low fat-consumption level.398,399 Studies of Seventh-Day Adventists provide suggestive evidence that animal fat consumption increases the risk of prostate cancer, particularly fatal cancers.356,392 Several recent cohort studies found similar positive associations between prostate cancer and red meat consumption, total animal fat consumption, and intake of fatty animal foods.400–402 The recent studies assessed dietary intake over a relatively short period before diagnosis (mostly within 5 years). Thus, excluding the studies from Japan, where the overall intake of animal fat is quite low, most cohort studies have supported a positive association between some component of dietary fat, especially animal fat, and risk of prostate cancer.3,387 Few rodent models of prostate cancer have been used to investigate the role of dietary fat. Even so, essential fatty acid deficiency was found to inhibit the growth rate of a transplantable prostate adenocarcinoma, whereas dietary fat concentrations over the wide range of intake observed in human populations had no significant effect.403 Others observed a stimulation of tumor growth with increased dietary fat concentration.404 The possibility that specific fatty acids and prostaglandin metabolites may modulate tumor growth and metastatic spread are also under investigation.405,406

Few studies have examined the role of vitamin E in prostate cancer risk. The most provocative data is derived from a randomized intervention trial conducted in Finland among men at high risk of lung cancer.407 A significantly lower risk of prostate cancer was noted among men randomized to vitamin E supplementation.407 However, this finding has only modest support from laboratory investigations and many other human intervention studies evaluating vitamin E supplementation and other disease end points.

The overall consumption of fruits and vegetables has not shown a consistent reduction in risk of prostate cancer.3,387 However, a reduced risk of prostate cancer associated with the consumption of tomatoes and processed tomato products has been observed in the prospectively evaluated Health Professional’s Follow-up Study.408 On the basis of these findings, it has been hypothesized that the carotenoid lycopene may account for some of the anticancer properties of tomato products.409,410 Lycopene is found in the prostate of men at concentrations that may be biologically active.411 Lycopene is the carotenoid providing the red color to tomato products and is a potent antioxidant.409 Recently, blood lycopene concentrations obtained prior to diagnosis were inversely related to the risk of prostate cancer.412 However, it is premature to conclude that lycopene mediates a protective effect against prostate cancer or that lycopene is the only component of tomato products that may contribute to the association.

The possibility that calcium, phosphorus, and vitamin D are interacting components of a complex network of dietary and endocrine factors modulating prostate cancer risk is under investigation.387 Prostate cells have vitamin D receptors that tend to induce patterns of differentiation. In a large, prospective, case-control study, mean serum 1,25-dihydroxy vitamin D levels were lower in cases than in matched controls.385 A recent study found those diets high in calcium, either from foods or supplements, were positively associated with advanced prostate cancer.414 These studies and others have led to the hypothesis that a dysregulation of vitamin D metabolism may relate to risk of prostate cancer.387 Further epidemiologic and laboratory-based studies are clearly needed.

The possible role of selenium in the prevention of prostate cancer has been hypothesized on the basis of a chemoprevention study completed by Clark and colleagues.415 The study was designed to examine the effects of supplemental selenium on recurrence of skin cancer in populations of geographic areas having low soil selenium. Selenium treatment did not influence the risk of skin cancer, although selenium supplementation was associated with a nonsignificant reduction in all-cause mortality and a statistically significant reduction in total cancer mortality or risk of prostate cancer.415 A protective effect was also suggested by a study reporting that low concentrations of toenail selenium are related to a greater risk of prostate cancer.416 Additional studies designed to further investigate the hypothesis that selenium can prevent prostate cancer are ongoing.

In summary, epidemiologic studies and a limited number of laboratory investigations have suggested a role for diet in prostate cancer. Rates of prostate cancer are higher in nations consuming an affluent dietary pattern and sedentary lifestyle, although the contribution of specific components, such as fat and energy intake, have not been well defined. The possibility that selenium, vitamin E, calcium, vitamin D, lycopene, and other dietary factors influence the risk of prostate cancer are being actively investigated.

Endometrium

In general, endometrial cancer shows an international distribution similar to that of other cancers of affluence, such as breast, colon, and prostate cancers.52 Evidence for association between endometrial cancer and excess energy intake and body weight continues to accumulate.1,12,394,417,418 The roles of fruits and vegetables in decreasing risk and of saturated fat in stimulating endometrial cancer is supported by some data but remain speculative.3 One established risk factor is the use of exogenous estrogens at high dosages.1,419 It has been postulated, although the evidence is minimal, that dietary factors contributing to obesity may influence risk through changes in the hormonal environment. The potential interactions between dietary components and supplemental estrogens should be thoroughly investigated.

Ovary

There are considerable international and geographic variations in the incidence and mortality rates of ovarian cancer. The disease is more common in nations exhibiting Western culture, especially among the higher socioeconomic groups.1,3,12,52,419,420 Although some of the geographic variation may result from reproductive variables, there also are suggestive relationships to dietary components.1,2,12 Several studies have implicated fat, particularly from animal sources.293,420,421 In contrast, the consumption of vegetables and grain products was associated with lower risk.420,422 At present, no conclusive role for dietary components in the pathogenesis of ovarian cancer has been established, but additional studies are needed, particularly in conjunction with known risk factors of low parity and specific inherited genetic abnormalities.3

Bladder

Bladder cancer is more frequent in industrialized nations, especially among smokers and those in urban areas and of lower socioeconomic status.52,420 Bladder cancer is clearly associated with cigarette smoking as well as with certain occupational exposures to specific industrial chemicals and parasitic bladder infections with Schistosoma haematobium.3,420 Overall, there have been limited efforts to investigate the role of diet in bladder cancer etiology and how specific dietary or nutritional variables may interact with known environmental risk factors.1–3,8,12,27,423

The majority of epidemiologic and case-control studies support the hypothesis that the frequent consumption of fruits and vegetables will reduce risk.3,8,423–425 Recently, prospective investigations of fruit and vegetable intake and bladder cancer risk in over 47,000 men enrolled in the Health Professionals Follow-up Study have been reported.425 A diet rich in cruciferous vegetables, such as broccoli, but not other classes of fruits and vegetables, was associated with a significantly reduced bladder cancer risk in both smokers and nonsmokers.425

The role of fluid intake in bladder cancer risk has frequently been proposed, but with two divergent hypotheses.3,423 One theory favors a positive association with bladder cancer since water and other fluids may serve as a vehicle for bladder carcinogens. In contrast, greater fluid intake may dilute the concentration of carcinogens or tumorpromoting agents excreted in the urine and increase the frequency of urination, thereby protecting the bladder mucosa. The prospective evaluation of fluid intake in the Health Professional’s Follow-up Study found a significant inverse association between total daily fluid intake and bladder cancer risk, with no evidence for a benefit or risk from specific sources of fluid.426 Several case-control studies, however, have found either no association or a positive association between total fluid intake and bladder cancer risk.3

Laboratory studies have found that the non-nutritive sweeteners cyclamates and saccharine may be weak initiators or promoters of bladder carcinogenesis in rodents,427 but their contribution to human cancer probably is very small.1,3,423,427,428 Although some studies have suggested an association between coffee consumption and bladder cancer,248,331,429,430 most of the investigations do not support a meaningful relationship.2,3,423,431,432

Summary of Research Efforts Focusing on Specific Nutrients

Energy Balance and Physical Activity

Striking and consistent inhibitory effects of reduced energy intake on most types of cancer have been observed in rodent studies.1–3,12,43–47,251,394,433 An understanding of the diverse mechanisms underlying these observations should be relevant to human cancer prevention. Experimental evidence suggests that energy intake modulates a range of metabolic, endocrine, and immunologic processes that influence cellular proliferative rates, proto-oncogene expression, and DNA repair capabilities.47

Because of the complex interrelations among total energy consumption, energy expenditure and genetic differences in energy metabolism, and limitations of current assessment methodologies, the associations between energy balance and cancer are not easily interpretable in human studies.398 Accurate measures of energy intake are difficult to obtain with current food-frequency questionnaires. Variation in energy expenditure among individuals within a population can be attributed to three general sources: physical activity, body size, and metabolic efficiency.23 The balance between energy intake and expenditure will determine whether an individual gains or loses weight; even small differences between intake and expenditure over time can lead to appreciable differences in body weight. Surrogate measures, such as the development of obesity or weight change in adulthood, may reflect an imbalance between energy intake and expenditure. In human studies, obesity is associated with endometrial cancer, cancer of the biliary system, and colon cancer, particularly in men. More modest associations are evident for breast and renal cell cancers. Attained adult height, which is another surrogate marker of energy balance, may reflect, in part, dietary patterns during in utero development, childhood, and adolescence. In some developed countries, however, there may be a paucity of individuals who were sufficiently energy restricted during development to have experienced a failure to obtain their full potential adult height. Mean national heights, perhaps as an index of energy balance during development, have a strong correlation with international rates of breast cancer.434,435 Similar associations with height have been observed for colon and, possibly, prostate cancers. Greater physical activity, the other component of the equation, has been consistently related to lower risk of colon cancer and possibly breast cancer. Overall, the epidemiologic evidence supports animal studies that an imbalance of energy consumption versus requirements could be an important risk factor for a variety of cancers. Furthermore, regular exercise is likely to inhibit the risk of several common malignancies, particularly cancer of the colon and rectum.3,433

Protein

Like energy intake, dietary protein has dramatic effects on many physiologic and biochemical processes that may participate in carcinogenesis.285 The Western diet typically is greatly in excess of the recommended protein requirement. The major change in protein intake as nations develop economically is a shift from plant to animal products as the major source of protein. At this time, it is not possible to precisely delineate the specific contribution of protein quality and quantity to human cancer risk;3 however, it is recommended that red meats be consumed in moderation, and that a diverse array of protein sources from poultry, fish, and plant products be consumed. Laboratory studies generally have found minimal effects of dietary protein content, except at the extremes of feeding.1,12,285 Experimental studies of the breast,437 colon,282,284 and liver1,2 have provided some evidence for an increased risk of carcinogenesis with greater protein intake.

Lipids

Defining the contribution of dietary fat in the etiology of many cancers, especially those of the breast, colon, pancreas, endometrium, and prostate, is an active area of investigation.1,2,3,12,280,433 Improved epidemiologic and biochemical methods are needed for the accurate assessment of past and current lipid intake in humans. Many previous studies lack the sensitivity and specificity that are necessary to quantify the risk associated with high-fat diets. Human studies at this time are not consistent, and a convincing role for dietary fat, independent of other factors in human cancer, remains to be demonstrated. In contrast, precisely controlled laboratory studies in rodent models support a contribution of dietary fat concentration and source in the pathogenesis of several malignant neoplasms, such as breast and colon cancers. Dietary fat modulates many metabolic and endocrine processes that may alter tissue susceptibility to transformation and tumor progression. In addition, dietary lipids influence the lipid composition of cell membranes and thereby may modulate the cellular response of many growth-stimulating and -inhibitory pathways by altering ligand-receptor binding and signal transduction.

Cholesterol

Dietary cholesterol derives from meat and dairy products and therefore is correlated with cancers that are frequent in affluent nations. The close association of cholesterol with other nutrients, such as fat, has made it difficult to establish its independent contribution to the risk of breast, colon, or prostate cancers.3 Several long-term prospective studies originally designed to evaluate cardiovascular disease have reported an inverse relationship between overall cancer risk and serum cholesterol levels at the start of the study.438 These observations have created a potentially difficult problem for those concerned with public health and dietary guidelines. At present, however, it is not clear if the information relative to a pre-existing low serum cholesterol level can be extrapolated to a population with deliberately lowered serum levels to reduce the risk of cardiovascular disease. Overall, the relationship between dietary cholesterol, serum cholesterol, and cancer risk in humans is far from clear.

Carbohydrates

Carbohydrates are the major energy component of diets throughout the world and are composed of a chemically diverse array of starches and sugars. Very few studies have examined the relationship between carbohydrates and cancer.3 The few laboratory studies have suggested that carcinogenesis in some models can be modulated to a limited degree by the source of carbohydrate, although the mechanisms remain obscure.

Fiber

The complexities of dietary fiber chemistry and in vivo physiologic effects have made it impossible to define the overall contribution of total fiber intake or specific fractions to cancer risk at this time.1–3,326 Data concerning the inhibition of colon polyp formation by specific fiber supplements suggest potential benefits for high-risk individuals. However, prospective epidemiologic studies have not supported a role of fiber in colon cancer risk.309 This remains an expanding area of nutrition research, and significant improvements in our understanding of various types of dietary fiber in health and disease should be forthcoming.

Fruits and Vegetables

Several hundred studies have examined the relationship between fruit and vegetable intake and cancer risk.1,3,8,384,433 The vast majority suggests a significant protective effect of diets rich in fruits and vegetables relative to cancer risk at many sites. How these associations are mediated has not been clearly established, however, but it may involve many interacting factors. For example, the protective effect of fruits and vegetables may relate, in part, to an associated reduction in the consumption of risk-enhancing foods and nutrients, such as fat or energy. Perhaps the increased dietary fiber derived from fruits and vegetables contributes to reduced risk of some cancers; however, specific fruits and vegetables likely will prove to have unique protective effects for certain cancers. The critical task for investigators is to identify the specific foods and the chemical constituents that may have the potential to inhibit carcinogenesis in specific organs. This information will allow us to target more precisely high-risk individuals with specific fruits and vegetables, food extracts, or even purified chemical components in rational, preventive studies.

Vitamins

The public perceives vitamin supplements as an important form of self-therapy for the prevention and treatment of many ailments, including cancer.3,10 Vitamin supplements are inexpensive, easy to consume, relatively free of side effects when taken at the recommended dosages, and can be obtained without a prescription. A particularly attractive aspect of vitamin supplementation is the belief that these nutrients may counteract the adverse effects of diet or lifestyle that are much more difficult to change.439 These issues emphasize the importance of scientifically sound studies to define the risks and benefits of vitamin nutrition in the origins of human cancer. It is important to stress that major organizations providing dietary guidelines emphasize the importance of obtaining proper vitamin nutrition through the consumption of vitamin-rich foods rather than the use of supplements. Caution is advisable because vitamin supplementation may not be uniformly beneficial, and enhanced tumor promotion may occur in some situations.

The role of vitamin A in the normal growth and development of epithelial tissues has been known for decades. Vitamin A is provided in the diet as retinol and its esters, primarily from milk and organ meats, and as β-carotene and a few other carotenoids in yellow and leafy green vegetables. Interest in vitamin A and related compounds in the etiology, prevention, and treatment of cancer is rapidly expanding. A protective effect of consuming foods rich in vitamin A has been suggested for several types of cancer;1–3,8,10,12 however, at this time, there is no clear evidence that vitamin A supplementation will decrease the risk of cancer in populations consuming a healthy diet. Although many studies in laboratory models indicate that vitamin A deficiency increases the susceptibility of many tissues to chemical carcinogenesis, these observations should not suggest that supplements might reduce this risk in those with adequate vitamin A status. The role of vitamin A excess has not been frequently assessed in rodent models. The use of vitamin A and synthetic retinoids as pharmacologic agents in chemoprevention trials to determine their efficacy in specific high-risk populations is an important area of research.5,6 Although evidence to support the use of vitamin A supplements is lacking, the consumption of foods that are rich in provitamin A carotenoids is supported by a large body of data.8

Very few studies have investigated the role of vitamin D in human cancer,2,10 but several studies have suggested a relationship between lower vitamin D intake and colon cancer.2,390 Cancer cells derived from many human tumors have been shown to express the receptor for 1,25-dihydroxy vitamin D3 and respond to this agent in vitro, but the pathophysiologic significance in human cancer remains to be determined.10 The development of vitamin D analogues that do not have hypercalcemic effects but continue to interact with receptors on many epithelial tissues may lead to the development of novel chemopreventive or therapeutic agents.

Vitamin E is a family of eight compounds that are collectively referred to as tocopherols. Vegetable oil, eggs, and whole grains are the major sources of dietary vitamin E. The antioxidant and free radical scavenger properties of vitamin E have suggested a possible role as an antineoplastic vitamin;10 however, few rodent or epidemiologic studies have provided strong evidence to support the consumption of vitamin E supplements to prevent cancer. Additional studies focusing on cancers of the lung, cervix, and prostate are particularly worthy of additional investigation.

Vitamin C, which includes ascorbic acid and dehydroascorbic acid, functions as a general antioxidant and a component of several enzymatic reactions in intermediary metabolism.10 Citrus fruits, leafy vegetables, tomatoes, and potatoes are rich sources of vitamin C. Despite the large volume of publications in the last decade, very little evidence supports a critical role of vitamin C in the etiology of most human cancers.1,2,10 Some provocative evidence concerns the ability of vitamin C to inhibit the formation of carcinogenic nitrosamines, which ultimately may reduce the incidence of cancers that are thought to be associated with nitrosamines, such as gastric cancer. At present, there is no evidence to suggest that consumption of vitamin C supplements at levels higher than can be achieved in a well-balanced diet containing ample fresh fruits and vegetables is useful in the prevention or treatment of human cancer.3

Folate is essential for the normal metabolism of amino acids, methyl groups, and nucleotides, and folate plays a role in the methylation of DNA, which may be critical for the normal regulation of gene expression and tissue differentiation. Epidemiologic and laboratory studies are beginning to accumulate evidence suggesting that insufficient folate may relate to the risk of several malignancies, particularly colon cancer.3,127,433,437 Folate primarily is derived from fruits and vegetables and may be one component contributing to the reduced risk of cancer associated with the consumption of these foods. Unlike many other nutrients, mild to moderate folate deficiency is relatively prevalent in the American population.

Minerals

A number of minerals are required for normal structural development of the skeleton and soft tissue and for numerous biochemical and physiologic reactions. Those that are required in large amounts, such as calcium, phosphorus, and magnesium, are to be considered macrominerals. The trace elements are needed in much smaller amounts and include zinc, selenium, fluoride, iron, copper, iodine, manganese, and molybdenum. The contributions of variations in the dietary intake of minerals to carcinogenesis have not been clearly defined,1–3,10,12 and specific recommendations concerning supplemental intake should be made with caution. Among the minerals, roles for selenium and calcium in human cancer are most actively investigated.

Recent evidence suggests a role for calcium in colon carcinogenesis. A prospective, cohort study in the United States found that those who develop colon cancer had a significantly lower intake of calcium and vitamin D;239 however, case-control studies have been inconsistent. Calcium supplementation of 1.2 g/d reduced the proliferative rate of colonic cells in patients who are considered to be at an increased risk of colon cancer.440 Laboratory studies have reported that calcium reduces the loss of superficial epithelial cells and the proliferation of basal crypt cells.441 Clinical trials to determine the effects of calcium supplementation on polyp formation are currently ongoing.

Selenium is an essential constituent of glutathione peroxidase, and it participates in the destruction of hydrogen peroxide and organic hydroperoxides, using reducing equivalents from glutathione. Selenium, thus, participates in cellular and tissue defense against oxidative damage. Marginal selenium intake does not produce major physiologic changes, but it may predispose to injury by other agents, such as chemical carcinogens. A major obstacle for epidemiologic studies is that estimates of dietary selenium intake are unreliable, especially in the developed nations where foods are extensively processed and shipped to large distances, since food content is very sensitive to soil concentrations. An inverse association between the selenium levels in forage crops and mortality rates from certain cancers in different geographic areas has been suggested.2,3,442 Other studies have compared blood selenium levels in patients with cancer and in controls.2 Although these studies frequently are small and do not control for other risk factors, many have observed lower selenium levels in patients with cancer. Prospective studies, where serum has been obtained before the onset of disease, have provided inconsistent results.2 Recent studies from intervention trials and prospective evaluation of toenail selenium support a hypothesis that selenium may have a role in protection against prostate cancer.415,416 Animal studies also have provided variable results concerning the effects of excess selenium or selenium deficiency and carcinogenesis.2,3 Overall, conclusions concerning a role for selenium in human cancer cannot be justified, and dietary supplementation with a mineral that has a significant risk of toxicity cannot be supported. However, further studies are warranted to define the degree to which risk may be modulated and the conditions under which adjustments of selenium intake may be beneficial.

Alcohol

Chronic consumption of alcohol is strongly associated with cancers of the oropharynx, larynx, and esophagus.2,3,12 Tobacco smoking acts synergistically with alcohol in the pathogenesis of these cancers. Ethanol beverages probably contribute to liver cancer, and they may have a role in gastric, pancreatic, colon, and breast cancers. Even so, additional studies are necessary to firmly establish and quantify risk for the latter tissues. The risks associated with moderate alcohol intake and cancer are not well established but have been suggested in some studies.2,3,12 Ethanol itself probably is not a carcinogen, and a number of mechanisms are under investigation whereby ethanol may modulate carcinogenesis.421 Ethanol may have direct effects on the target tissue, altering cell turnover, permeability to carcinogens, or carcinogen metabolism. Ethanol may alter nutrient requirements of the target tissue, thereby disrupting the normal structure and function and altering carcinogenic risk. Some alcoholic beverages may contain chemical substances that are carcinogens or tumor promoters. The systemic effects of alcohol on hepatic carcinogen or hormone metabolism may indirectly alter the risk of cancer in many tissues. Ethanol may contribute to malnutrition with regard to a number of nutrients by altering absorption and metabolism or through the poor dietary habits that are associated with excessive consumption of alcoholic beverages.

Dietary and Nutritional Recommendations

Considerable controversy exists within the lay public, scientific community, food industry, and government regulatory agencies concerning the establishment of dietary guidelines to prevent cancer. Some argue that dietary changes should not be recommended until the scientific uncertainties have been resolved. Others believe that the associations observed justify instituting changes in the diet while more definitive data are obtained. Because cancer ranks as the second leading cause of death in affluent nations, there is a large public demand for nutritional remedies to prevent cancer. Without sound guidelines, the public will overinterpret inconclusive studies and pursue dietary habits, including supplements that are useless and even harmful. Unfortunately, absolute proof for many diet and cancer hypotheses will be difficult to obtain because of the expense that is required to support long-term studies with large numbers of subjects. The decision to formulate recommendations must take into account several factors, including strength of the evidence, potential benefits to society if the disease could be prevented, likelihood and severity of an adverse effect, and the feasibility of reducing exposure to the risk factor. In addition, economic issues relative to the food and agricultural industry are factors that may influence the decisions of committees to define nutritional guidelines. Although much remains to be learned before the impact of the proposed recommendations on health can be precisely quantified, most experts agree that a number of recommendations can be made with a reasonable degree of certainty, with the likelihood of minimal risk, and the potential for significant public health benefits.2,3,433,443,444

In general, there are two different, but complementary, approaches to reducing dietary risk factors for cancer and other chronic diseases. One focuses on individuals or groups and is aimed at identifying those who are at high risk and providing dietary intervention. The second addresses the population as a whole and is the public health approach. For some cases, we can, with a very high degree of certainty, identify individuals who will develop a specific cancer and institute preventive measures. For example, those with familial polyposis have a very high incidence of colon cancer, and a prophylactic colectomy frequently is performed before the age at which tumor risk increases. Most future patients with cancer, however, cannot be identified with a similar degree of certainty before the onset of their disease. The eventual application of sophisticated, individually based nutritional or chemopreventative interventions will be greatly facilitated by the identification of susceptible genotypes and additional environmental risk factors.

The public health approach is a preventive strategy to decrease the overall disease incidence by reducing the adverse dietary habits of the entire population. Implementation of dietary recommendations requires cooperation among the media, food industry, nutritional scientists, public health personnel, medical practitioners, educators, and the government.2,3 To achieve success, dietary recommendations must be simple and feasible to implement and have minimal risk, low cost to society, and the potential to benefit many people.2,3 Past efforts have been successful in the area of nutrition. For example, iron fortification of cereals benefits a large number of children and adult women, while risk is limited to a small number of individuals with hemochromatosis.

Tables 26.5 and 26.6 present population-based dietary recommendations consistent with those published by several organizations to lower the risk of chronic diseases.1–3,180,433,445 Most groups recommend reducing total fat intake to 30% or less of calories, with saturated fats reduced to less than 10% of calories and cholesterol limited to less than 300 mg/d. Although the roles of fat level, saturation, and cholesterol in cancer have not been precisely quantified, a large body of evidence supports a contribution of these dietary factors to cardiovascular diseases. These goals can be accomplished by substituting fish, poultry without skin, lean meats, and low- or nonfat dairy products for fatty meats and whole-milk dairy products, and by selecting more fruits, vegetables, cereals, and legumes in conjunction with limiting fats and oils in cooking, spreads, and dressings.2 With a decrease in lipid calories, carbohydrates should increase to approximately 55% of total energy through increased consumption of green and yellow vegetables, citrus fruits, and whole-grain cereals and breads, which typically are low in fat and rich in many vitamins, minerals, and fiber. Most groups suggest moderation in protein intake. Protein is an essential nutrient, but in many affluent nations, intake is two-fold in excess of the established recommended daily allowance.RDA The contribution of protein to the risk of cancer and other major diseases is less clear than that of lipid intake. The National Academy of Sciences has recommended protein intake at levels lower than twice the RDA for all age groups. Consumption of meat frequently is associated with certain cancers and cardiovascular disease; however, at this time, it is not possible to implicate meat per se, other than through its contribution to high total or saturated fat and cholesterol intake. Lean meats can remain a component of a low-fat diet.

Table 26.5. Summary of Public Health Nutrition Guidelines*.

Table 26.5

Summary of Public Health Nutrition Guidelines*.

Table 26.6. Population Nutrient Goals Established by the World Health Organization to Prevent Diet-Related Chronic Diseases.

Table 26.6

Population Nutrient Goals Established by the World Health Organization to Prevent Diet-Related Chronic Diseases.

Excess weight has been associated with increased morbidity and mortality from a number of diseases, including diabetes, hypertension, cardiovascular disease, and some forms of cancer.1–3,180,433,445 Laboratory studies indicate a strong relationship between energy intake and carcinogenesis, but the relevance of these studies, which frequently use severely restricted diets, to the human situation is unknown. The increasingly sedentary populations of many affluent nations exhibit higher average body weight or other indices of body mass even while total energy intake is slightly decreasing. It is recommended that food intake and physical activity be balanced to maintain an appropriate body weight.

Most expert committees do not recommend alcohol consumption on the basis of its role in cancer, other diseases, accidents, and birth defects. For those who drink, the National Academy of Sciences has suggested limiting intake to less than 1 ounce of alcohol per day, which is equivalent to two cans of beer or two small glasses of wine.2 Salt intake should be limited to less than 6 g/d, primarily by reducing its use in cooking and at the table.2 The evidence linking salt intake to hypertension is strong. The consumption of salt-preserved or -pickled foods should be limited on the basis of its frequent association with stomach cancer, although the causative agents in these foods have not been identified. The National Academy of Sciences does not recommend calcium intake above the current RDA.2 Benefits of intake above these levels to prevent osteoporosis, hypertension, or colon cancer have not been adequately documented. It is recommended that fluoride intake be optimized, especially during the years of tooth formation.2 There is no substantial evidence linking fluoride intake to cancer risk.

An increasing proportion of the American population consumes some type of self-prescribed nutritional supplement on a daily basis. The benefits of nutrient supplements that are in great excess of the RDA have not been proven, although significant risks are well known. The appropriate mechanism to obtain the recommended concentrations of nutrients is through a diverse and varied diet. It is important to view these guidelines as reflecting an overall dietary pattern rather than individual recommendations. Most of the evidence suggests that a major impact on cancer incidence would require the combination of changes recommended in these guidelines.

References

1.
National Academy of Sciences. Committee on Diet, Nutrition, and Cancer. In: Diet, nutrition, and cancer. Washington, DC: National Academy Press; 1982.
2.
National Academy of Sciences, Committee on Diet and Health, Food and Nutrition Board, Commission on Life Sciences, National Research Council. In: Diet and health: implications for reducing chronic disease risk. Washington, DC: National Academy Press; 1989.
3.
World Cancer Research Fund and American Institute for Cancer Research. Food, nutrition and the prevention of cancer: a global perspective. Washington, DC: American Institute for Cancer Research; 1997.
4.
Birt DF, Bresnick E. Chemoprevention by nonutrient components of vegetables and fruits. In: Alfin-Slater RB, Kritchevsky D, editors. Human nutrition: a comprehensive treatise. Vol 7: Cancer and nutrition. New York, NY: Plenum; 1991. p. 221.
5.
Greenwald P, Nixon D W, Malone W F. et al. Concepts in cancer chemoprevention research. Cancer. 1990;65:1483. [PubMed: 2178765]
6.
Greenwald P, Sondik E, Lynch B S. Diet and chemoprevention in NCI's research strategy to achieve national cancer control objectives. Annu Rev Public Health. 1986;7:267. [PubMed: 3013230]
7.
Alfin-Slater RB, Kritchevsky D. Human nutrition: a comprehensive treatise. Vol 7: Cancer and nutrition. New York, NY: Plenum; 1991.
8.
Block G, Patterson B, Subar A. Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence. Nutr Cancer. 1992;18:1. [PubMed: 1408943]
9.
Doll R, Peto R. The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J Natl Cancer Inst. 1981;66:1191. [PubMed: 7017215]
10.
Merrill AH, Foltz AT, McCormick DB. Vitamins and cancer. In: Alfin-Slater RB, Kritchevsky D, editors. Human nutrition: a comprehensive treatise. Vol 7: Cancer and nutrition. New York, NY: Plenum; 1991. p. 262.
11.
Reddy BS, Cohen LA. Diet, nutrition and cancer. A critical evaluation. Vol 1: Macronutrients and cancer. Boca Raton, FL: CRC; 1986.
12.
Rogers A E, Longnecker M P. Biology of disease. Dietary and nutritional influences on cancer: a review of epidemiological and experimental data. Lab Invest. 1988;59:729. [PubMed: 3059048]
13.
Colditz GA, Willet WC. Epidemiologic approaches to the study of diet and cancer. In: Alfin-Slater RB, Kritchevsky D, editors. Human nutrition: a comprehensive treatise. Vol 7: Cancer and nutrition. New York: Plenum; 1991. p. 51.
14.
Freudenheim J L. A review of study designs and methods of dietary assessment in nutritional epidemiology of chronic disease. J Nutr. 1993;123:401–405. [PubMed: 8429394]
15.
Howe G R. The use of polytomous dual response data to increase power in casecontrol studies: an application to the association between dietary fat and breast cancer. J Chronic Dis. 1985;38:663. [PubMed: 4019703]
16.
Johansen H L, Neutel C I. Epidemiological studies in nutrition: utility and limitations. J Nutr. 1988;118:137. [PubMed: 3335936]
17.
Block G. A review of validations of dietary assessment methods. Am J Epidemiol. 1982;115:492. [PubMed: 7041631]
18.
Medlin C, Skinner J D. Individual dietary intake methodology: a 50-year review of progress. J Am Diet Assoc. 1988;88:1250. [PubMed: 3049748]
19.
Junshi C, Campbell TC, Junyao L, Peto R. Diet, life-style, and mortality in China. Oxford, U.K.: Oxford University Press; 1990.
20.
Pennington J A T. Revision of the Total Diet Study food list and diets. J Am Diet Assoc. 1983;82:166. [PubMed: 6822702]
21.
Zaridze DG, Muir CS, McMichael AJ. Diet and cancer: value of different types of epidemiological studies. In: Joossens JV, Hill MJ, Geboerst J, editors. Diet and human carcinogenesis. New York, NY: Excerpta Medica; 1985. p. 221.
22.
Watt BK, Merrill AL. Composition of foods. Agriculture Handbook, No. 8. Washington, DC: U.S. Department of Agriculture; 1975.
23.
Willett W, Stampfer MJ. Total energy intake: implications for epidemiologic analyses. Am J Epidemiol 11986;24:17.
24.
Olson J A. Nutrition monitoring and nutrition status assessment: an overview. J Nutr. 1990;120:1431–1432. [PubMed: 1978726]
25.
Willett W C, Stampfer M J, Underwood B A. et al. Vitamin A supplementation and plasma retinol levels. A randomized trial among women. J Natl Cancer Inst. 1984;73:1445. [PubMed: 6595452]
26.
Morris J S I, Stampfer J J, Willet W C. Dietary selenium in humans. Toenails as an indicator. Biol Trace Element Res. 1983;5:529. [PubMed: 24263672]
27.
Armstrong B, Doll R. Environmental factors and cancer incidence and mortality in different countries, with special reference to dietary practices. Int J Cancer. 1975;15:617. [PubMed: 1140864]
28.
Carroll K K, Khor H T. Dietary fat in relation to tumorigenesis. Prog Biochem Pharmacol. 1975;10:308. [PubMed: 165553]
29.
Marshall J R, Yinsheng Q, Junshi C. et al. Additional ecological evidence: lipids and breast cancer mortality among women aged 55 and over in China. Eur J Cancer. 1992;28A:1720. [PubMed: 1389494]
30.
Giovannucci E, Stampfer M J, Colditz G A. et al. A comparison of prospective and retrospective assessments of diet in the study of breast cancer. Am J Epidemiol. 1993;137:502. [PubMed: 8465802]
31.
Friedenreich C M, Howe G R, Miller A B. An investigation of recall bias in the reporting of past food intake among breast cancer cases and controls. Ann Epidemiol. 1991;1:439. [PubMed: 1669524]
32.
Whittemore A S, Wu-Williams A H, Lee M. et al. Diet, physical activity, and colorectal cancer among Chinese in North America and China. J Natl Cancer Inst. 1990;82:915. [PubMed: 2342126]
33.
Willett W C, Stampfer M J, Colditz G A. et al. Moderate alcohol consumption and the risk of breast cancer. N Engl J Med. 1987;316:1174. [PubMed: 3574368]
34.
Menkes M S, Comstock G W, Vuilleumier J P. et al. Serum beta-carotene, vitamins A and E, selenium, and the risk of lung cancer. N Engl J Med. 1986;315:1250. [PubMed: 3773937]
35.
Wattenberg LW. Inhibitors of chemical carcinogens. In: Burchenal JH, Oettgen HF, editors. Cancer: achievements, challenges, and prospects for the 1980s. Vol 1. New York, NY: Grune and Stratton; 1981. p. 517.
36.
Alberts D S, Einspahr J, Rees-McGee S. et al. Effects of dietary wheat bran fiber on rectal epithelial cell proliferation in patients with resection for colorectal cancers. J Natl Cancer Inst. 1990;82:1280. [PubMed: 2165179]
37.
DeCosse J J, Miller H H, Lesser M L. Effect of wheat fiber and vitamins C and E on rectal polyps in patients with familial adenomatous polyposis. J Natl Cancer Inst. 1989;81:1290. [PubMed: 2549261]
38.
American Institute of Nutrition. Report of the American Institute of Nutrition ad hoc committee on standards for nutritional studies. J Nutr. 1977;107:1340. [PubMed: 874577]
39.
American Institute of Nutrition. Second report of the AIN ad hoc committee on standards for nutritional studies. J Nutr 1980; 110:1726.
40.
National Academy of Sciences, National Research Council. Nutrient requirements of laboratory animals, No. 10. Washington, DC: National Academy Press; 1978.
41.
Newberne P M, Bieri J G, Briggs G M, Nesheim M C. Control of diets in laboratory animal experimentation. ILAR News. 1978;21:A3.
42.
Albanes D. Caloric intake, body weight and cancer. A review. Nutr Cancer. 1987;9:199. [PubMed: 3299283]
43.
Angres G, Beth M. Effects of dietary constituents on carcinogenesis in different tumor models: an overview from 1975 to 1988. In: Alfin-Slater RB, Kritchevsky D, editors. Human nutrition: a comprehensive treatise. Vol 7: Cancer and nutrition. New York, NY: Plenum; 1991. p. 51.
44.
Clinton S K, Alster J M, Imrey P B. et al. Effects of dietary protein, fat and energy intake during an initiation phase study of 7, 12-dimethylbenz[a)anthracene-induced breast cancer in rats. J Nutr. 1986;116:2290. [PubMed: 3098937]
45.
Clinton S K, Imrey P B, Alster J M. et al. The combined effects of dietary protein and fat on 7,12-dimethylbenz(a)anthracene-induced breast cancer in rats. J Nutr. 1984;114:1213. [PubMed: 6429293]
46.
Freedman L S, Clifford C, Messina M. Analysis of dietary fat, calories, body weight, and the development of mammary tumors in rats and mice: a review. Cancer Res. 1990;50:5710. [PubMed: 2203521]
47.
Ruggeri B. The effects of caloric restriction on neoplasia and age-related degenerative processes. In: Alfin-Slater RB, Kritchevsky S, editors. Human nutrition: a comprehensive treatise. Vol 7: Cancer and nutrition. New York, NY: Plenum; 1991. p. 187.
48.
Tannenbaum A. Nutrition and cancer. In: Homburger F, editors. The physiopathology of cancer. New York, NY: Hoeber-Harper; 1959.
49.
Tannenbaum A. The dependence of tumor formation on the composition of the calorie-restricted diet as well as on the degree of restriction. Cancer Res. 1945;5:616. [PubMed: 8878181]
50.
Rao G N, Knapka J J. Contaminant and nutrient concentrations of natural ingredient rat and mouse diet used in chemical toxicology studies. Fundam Appl Toxicol. 1987;9:329. [PubMed: 3653575]
51.
Byers T E, Graham S. The epidemiology of diet and cancer. Adv Cancer Res. 1984;41:1. [PubMed: 6375293]
52.
Boring C C, Squires T S, Tong T, Montgomery S. Cancer statistics, 1994. CA Cancer J Clin. 1994;44:7. [PubMed: 8281473]
53.
Department of Health, Education, and Welfare (DHEW). Smoking and health: a report of the Surgeon General. DHEW Publ. No. (PHS) 79-50066. Rockville, MD: Office on Smoking and Health, Office of the Assistant Secretary for Health, Public Health Service, U. S. Department of Health, Education and Welfare; 1979. p. 1164.
54.
Ocke M C, Bueno-de-Mesquita H B, Feskens E J. et al. Repeated measurements of vegetables, fruits, beta-carotene, and vitamins C and E in relation to lung cancer. The Zutphen Study. Am J Epidemiol. 1997;145:358. [PubMed: 9054240]
55.
Steinmetz K A, Kushi L H, Bostick R M. et al. Vegetables, fruit, and colon cancer in the Iowa Women’s Study. Am J Epidemiol. 1994;139:1. [PubMed: 8296768]
56.
Steinmetz K A, Potter J D, Folsom A R. Vegetables, fruit, and lung cancer in the Iowa Women’s Health Study. Cancer Res. 1993;53:536. [PubMed: 8425185]
57.
The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study Group. The effect of vitamin E and beta-carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med. 1994;330:1029–1035. [PubMed: 8127329]
58.
Omenn G S, Goodman G E, Thornquist M D. et al. Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial. J Natl Cancer Inst. 1996;88:1550. [PubMed: 8901853]
59.
Mayne S, Janerich D, Greenwald P. et al. Dietary beta carotene and lung cancer risk in U.S. nonsmokers. J Natl Cancer Inst. 1994;86:33. [PubMed: 8271280]
60.
Bandera E V, Freudenheim J L, Marshall J R. et al. Diet and alcohol consumption and lung cancer risk in the New York State Cohort. Cancer Causes Control. 1997;8:828. [PubMed: 9427425]
61.
DeStefani E, Deneo-Pellegrini H, Mendilaharsu M. et al. Dietary fat and lung cancer: a case-control study in Uruguay. Cancer Causes Control. 1997;8:913. [PubMed: 9427434]
62.
Austin DF. Larynx. In: Schottenfeld D, Fraumeni Jr JF, editors. Cancer epidemiology and prevention. Philadelphia, PA: W.B. Saunders; 1982. p. 554.
63.
Hinds M W, Kolonel L N, Lee J, Hirohata T. Associations between cancer incidence and alcohol/cigarette consumption among five ethnic groups in Hawaii. Br J Cancer. 1980;41:929. [PMC free article: PMC2010370] [PubMed: 7426317]
64.
Mahboudi E, Sayed GM. Oral cavity and pharynx. In: Schottenfeld D, Fraumeni Jr JF, editors. Cancer epidemiology and prevention. Philadelphia, PA: W.B. Saunders; 1982. p. 583.
65.
Mashberg A, Garfinkel L, Harris S. Alcohol as a primary risk factor in oral squamous carcinoma. CA Cancer J Clin. 1981;31:146. [PubMed: 6784891]
66.
Rogers AE, Conner MW. Interrelationships of alcohol and cancer. In: Alfin-Slater RB, Kritchevsky D, editors. Human nutrition: a comprehensive treatise. Vol 7: Cancer and nutrition. New York, NY: Plenum; 1991. p. 51.
67.
Tuyns AJ. Alcohol. In: Schottenfeld D, Fraumeni Jr JF, editors. Cancer epidemiology and prevention. Philadelphia, PA: W.B. Saunders; 1982. p. 293.
68.
Graham S, Dayal H, Rohrer T. et al. Dentition, diet, tobacco, and alcohol in the epidemiology of oral cancer. J Natl Cancer Inst. 1977;59:1611. [PubMed: 926184]
69.
Keller A Z, Terris M. The association of alcohol and tobacco with cancer of the mouth and pharynx. Am J Public Health. 1965;55:1578. [PMC free article: PMC1256548] [PubMed: 5890556]
70.
Kirchner J A, Malkin J S. Cancer of larynx: 30-year survey at New Haven Hospital. Arch Otolaryngol. 1953;58:19. [PubMed: 13057448]
71.
Martinez I. Factors associated with cancer of the esophagus, mouth and pharynx in Puerto Rico. J Natl Cancer Inst. 1969;42:1069. [PubMed: 5793187]
72.
Schwartz D, Lellouch J, Flamant R, Denoix P F. Alcohol and cancer. Results of a retrospective investigation. Rev Fr Etud Clin Biol. 1962;7:590. [PubMed: 13987358]
73.
Wynder E L, Hultberg S, Jacobson F, Bross I J. Environmental factors in cancer of the upper alimentary tract: a Swedish study with special reference to Plummer-Vinson (Paterson-Kelly) syndrome. Cancer. 1957;10:470. [PubMed: 13460941]
74.
Burch J D, Howe G R, Miller A B, Semenciw R. Tobacco, alcohol, asbestos, and nickel in the etiology of cancer of the larynx: a case-control study. J Natl Cancer Inst. 1981;67:1219. [PubMed: 6947107]
75.
Flanders W D, Rothman K J. Occupational risk for laryngeal cancer. Am J Public Health. 1982;72:369. [PMC free article: PMC1649897] [PubMed: 7065314]
76.
Herity B, Moriarty M, Daly L. et al. The role of tobacco and alcohol in the aetiology of lung and larynx cancer. Br J Cancer. 1982;46:961. [PMC free article: PMC2011218] [PubMed: 7150489]
77.
Olsen J, Sabreo S, Fasting U. Interaction of alcohol and tobacco risk factors in cancer of the laryngeal region. J Epidemiol Community Health. 1985;39:165. [PMC free article: PMC1052426] [PubMed: 4009100]
78.
Rothman K, Keller A. The effect of joint exposure to alcohol and tobacco on risk of cancer of the mouth and pharynx. J Chronic Dis. 1972;25:711. [PubMed: 4648515]
79.
Tuyns A J. Oesophageal cancer in non-smoking drinkers and in non-drinking smokers. Int J Cancer. 1983;32:443. [PubMed: 6618707]
80.
Tuyns A J, Pequignot G, Gignoux M, Valla A. Cancers of the digestive tract, alcohol and tobacco. Int J Cancer. 1982;30:9. [PubMed: 7118300]
81.
Wynder E L, Bross I J, Feldmann R M. A study of the etiological factors in cancer of the mouth. Cancer. 1957;10:1300. [PubMed: 13489682]
82.
DeLint J, Levinson T. Mortality among patients treated for alcoholism: a 5-year follow-up. Can Med Assoc J. 1975;113:385. [PMC free article: PMC1956646] [PubMed: 168951]
83.
Lyon J L, Klauber M R, Gardner J W, Smart C R. Cancer incidence in Mormons and non-Mormons in Utah 1966–1970. N Engl J Med. 1976;294:129. [PubMed: 1244508]
84.
Marshall J, Graham S, Mettlin C. Diet in the epidemiology of oral cancer. Nutr Cancer. 1982;3:145. [PubMed: 7134009]
85.
Stich H F, Rosin M P, Hornby A P. et al. Remission or oral leukoplakias and micronuclei in tobacco/betel quid chewers treated with beta-carotene and with beta-carotene plus vitamin A. Int J Cancer. 1988;42:195. [PubMed: 3403064]
86.
Hong W K, Endicott J, Itri L M. et al. 13 cis-Retinoic acid in the treatment of oral leukoplakia. N Engl J Med. 1986;315:1501. [PubMed: 3537787]
87.
Hirayama T. Epidemiology of breast cancer with special reference to the role of diet. Prev Med. 1978;7:173. [PubMed: 674105]
88.
Hong W K, Lippman S M, Itri L M. et al. Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N Engl J Med. 1990;323:795. [PubMed: 2202902]
89.
Nomura A M, Ziegler R G, Stemmermann G N. et al. Serum micronutrients and upper aerodigestive tract cancer. Cancer Epidemiol Biomarkers Prev. 1997;6:407. [PubMed: 9184773]
90.
Brechot C, Nalpas B, Courouce A. et al. Evidence that hepatitis B virus has a role in liver-cell carcinoma in alcoholic liver disease. N Engl J Med. 1982;306:1384. [PubMed: 6281640]
91.
DeStefani E, Deneo-Pellegrini H, Mendilaharsu M, Ronco A. Diet and risk of cancer of the upper aerodigestive tract. I. Foods. Oral Oncol. 1999;35:17. [PubMed: 10211305]
92.
Munoz N, Wahrendorf J, Bang J J. et al. No effect of riboflavine, retinol, and zinc on precancerous lesions of the oesophagus: a randomized double-blind intervention study in a high-risk population in China. Lancet. 1985;2:111. [PubMed: 2862315]
93.
Must A, Jacques P F, Dallal G E. et al. Long-term morbidity and mortality of overweight adolescents. A follow-up of the Harvard Growth Study of 1922 to 1935. N Engl J Med. 1992;327:1350. [PubMed: 1406836]
94.
Mahboubi E, Kmet J, Cook P J. et al. Oesophageal cancer studies in the Caspian Littoral of Iran: the Caspian cancer registry. Br J Cancer. 1973;28:197. [PMC free article: PMC2008981] [PubMed: 4743904]
95.
Wynder E L, Bross I J. A study of etiological factors in cancer of the esophagus. Cancer. 1961;14:389. [PubMed: 13786981]
96.
Tuyns A. Alcohol et cancer. Lyon, France: International Agency for Research on Cancer; 1978.
97.
Tuyns A J, Pequignot G, Abbatucci J S. Oesophageal cancer and alcohol consumption: importance of type of beverage. Int J Cancer. 1979;23:443. [PubMed: 437923]
98.
Keller A Z. The epidemiology of esophageal cancer in the west. Prev Med. 1980;9:607. [PubMed: 7433422]
99.
Schoenberg B, Bailar J C, Fraumeni J F. Certain mortality patterns of esophageal cancer in the United States 1930-1967. J Natl Cancer Inst. 1971;46:63. [PubMed: 5546194]
100.
Schottenfeld D. Epidemiology of cancer of the esophagus. Semin Oncol. 1984;11:92. [PubMed: 6729492]
101.
Pottern L M, Morris L E, Blot W J. et al. Esophageal cancer among black men in Washington, D.C. I. Alcohol, tobacco, and other risk factors. J Natl Cancer Inst. 1981;67:777. [PubMed: 6944547]
102.
Ziegler R G, Morris L E, Blot W J. et al. Esophageal cancer among black men in Washington DC. II. Role of nutrition. J Natl Cancer Inst. 1981;67:1199. [PubMed: 6947105]
103.
Brown L M, Swanson C A, Gridley G. et al. Dietary factors and the risk of squamous cell esophageal cancer among black and white men in the United States. Cancer Causes Control. 1998;9:467. [PubMed: 9934713]
104.
Blair A, Fraumeni J F Jr. Geographic patterns of prostate cancer in the United States. J Natl Cancer Inst. 1978;61:1379. [PubMed: 281545]
105.
Cook-Mozaffari P. The epidemiology of cancer of the oesophagus. Nutr Cancer. 1979;1:51.
106.
Jaskiewicz K, Marasas W F O, Lazarus C. et al. Association of esophageal cytological abnormalities with vitamin and lipotrope deficiencies in populations at risk for esophageal cancer. Anticancer Res. 1988;8:711. [PubMed: 3178161]
107.
Graham S, Marshall J, Haughey B. et al. Nutritional epidemiology of cancer of the esophagus. Am J Epidemiol. 1990;131:454. [PubMed: 2301355]
108.
Mettlin C, Graham S, Priore R. et al. Diet and cancer of the esophagus. Nutr Cancer. 1981;2:143. [PubMed: 7346779]
109.
Coordinating Group for Research on Etiology of Esophageal Cancer in North China. The epidemiology and etiology of esophageal cancer in North China. A preliminary report. Chin Med J (Peking, Engl Ed) 1975;1:167 .
110.
Hormozdiari H, Day N E, Aramesh B, Mahboubi E. Dietary factors and esophageal cancer in the Caspian littoral of Iran. Cancer Res. 1975;35:3493. [PubMed: 1242686]
111.
van Rensburg S J. Epidemiologic and dietary evidence for a specific nutritional predisposition to esophageal cancer. J Natl Cancer Inst. 1981;67:243. [PubMed: 6943364]
112.
Yang C S. Research on esophageal cancer in China: a review. Cancer Res. 1980;40:2633. [PubMed: 6992989]
113.
Cook-Mozaffari P J, Azordegan F, Day W E. et al. Oesophageal cancer studies in the Caspian littoral of Iran: results of a case-control study. Br J Cancer. 1979;39:293. [PMC free article: PMC2009866] [PubMed: 465299]
114.
Marasas W F O, van Rensburg S J, Mirocha C J. Incidence of Fusarium species and the mycotoxins, deoxynivalenol and zearalenone, in corn produced in esophageal cancer areas in Transkei. J Agric Food Chem. 1979;27:1108. [PubMed: 161914]
115.
de Jong U W, Breslow N, Hong J G E. et al. Aetiological factors in oesophageal cancer in Singapore Chinese. Int J Cancer. 1974;13:291. [PubMed: 4822104]
116.
Launoy G, Milan C, Day N E. et al. Oesophageal cancer in France: potential importance of hot alcoholic drinks. Int J Cancer. 1997;71:917. [PubMed: 9185689]
117.
Vaughan T L, Davis S, Kristal A, Thomas D B. Obesity, alcohol, and tobacco as risk factors for cancers of the esophagus and gastric cardia: adenocarcinoma versus squamous cell carcinoma. Cancer Epidemiol Biomarkers Prev. 1995;4:85. [PubMed: 7742727]
118.
Blot W J, Devesa S S, Kneller R W, Fraumeni J F Jr. Rising incidence of adenocarcinoma of the esophagus and gastric cardia. JAMA. 1991;265:1287. [PubMed: 1995976]
119.
Devesa S S, Blot W J, Fraumeni J F Jr. Changing patterns in the incidence of esophageal and gastric carcinoma in the United States. Cancer. 1998;83:2049. [PubMed: 9827707]
120.
Gammon M D, Schoenberg J B, Ahsan H. et al. Tobacco, alcohol, and socioeconomic status and adenocarcinomas of the esophagus and gastric cardia. J Natl Cancer Inst. 1997;89:1277. [PubMed: 9293918]
121.
Kabet G C, Ng S K, Wynder E L. Tobacco, alcohol intake, and diet in relation to adenocarcinoma of the esophagus and gastric cardia. Cancer Causes Control. 1993;4:123. [PubMed: 8481491]
122.
Ji B T, Chow W H, Yang G. et al. Body mass index and the risk of cancers of the gastric cardia and distal stomach in Shanghai, China. Cancer Epidemiol Biomarkers Prev. 1997;6:481. [PubMed: 9232333]
123.
Lagergren J, Bergstrom R, Nyren O. Association between body mass and adenocarcinoma of the esophagus and gastric cardia. Ann Intern Med. 1999;130:883. [PubMed: 10375336]
124.
Blot W J, McLaughlin J K. The changing epidemiology of esophageal cancer. Semin Oncol. 1999;26:2. [PubMed: 10566604]
125.
Chow W H, Blot W J, Vaughan T L. et al. Body mass index and risk of adenocarcinomas of the esophagus and gastric cardia. J Natl Cancer Inst. 1998;90:150. [PubMed: 9450576]
126.
Brown L M, Swanson C A, Gridley G. et al. Adenocarcinoma of the esophagus: role of obesity and diet. J Natl Cancer Inst. 1995;87:104. [PubMed: 7707381]
127.
Giovannucci E, Stampfer M J, Colditz G A. et al. Folate, methionine, and alcohol intake and risk of colorectal adenoma. J Natl Cancer Inst. 1993;85:875. [PubMed: 8492316]
128.
Correa P. The new era of cancer epidemiology. Cancer Epidemiol Biomarkers Prev. 1991;1:5. [PubMed: 1845169]
129.
Graham S, Schotz W, Martino P. Alimentary factors in the epidemiology of gastric cancer. Cancer. 1972;30:927. [PubMed: 5079436]
130.
Haenszel W. Variation in the incidence of and mortality from stomach cancer, with particular reference to the United States. J Natl Cancer Inst. 1958;21:213. [PubMed: 13576088]
131.
Haenszel W, Kurihara M, Segi M, Lee R K C. Stomach cancer among Japanese in Hawaii. J Natl Cancer Inst. 1972;49:969. [PubMed: 4678140]
132.
Higginson J. Etiological factors in gastro-intestinal cancer in man. J Natl Cancer Inst. 1966;37:527. [PubMed: 5923503]
133.
Hirayama T. A study of the epidemiology of stomach cancer, with special reference to the effect of diet factor. Bull Inst Publ Health. 1963;12:85.
134.
Paymaster J C, Sanghvi L D, Gangadharan P. Cancer in the gastrointestinal tract in Western India. Epidemiologic study. Cancer. 1968;21:279. [PubMed: 4952506]
135.
Risch H A, Jain M, Choi N W. et al. Dietary factors and the incidence of cancer of the stomach. Am J Epidemiol. 1985;122:947. [PubMed: 2998182]
136.
Terry P, Nyren O, Yuen J. Protective effect of fruits and vegetables on stomach cancer in a cohort of Swedish twins. Int J Cancer. 1998;76:35. [PubMed: 9533759]
137.
Kamiyama S, Ohshima H, Shimada A. et al. Urinary excretion of N-nitrosamino acids and nitrate by inhabitants in high- and low-risk areas for stomach cancer in northern Japan. IARC Sci Publ. 1987;84:497. [PubMed: 3679430]
138.
Lu S, Ohshima H, Fu H. et al. Urinary excretion of N-nitrosoamino acids and nitrate by inhabitants of high- and low-risk areas for esophageal cancer in northern China: endogenous formation of nitrosoproline and its inhibition by vitamin C. Cancer Res. 1986;46:1485. [PubMed: 3943105]
139.
Hirayama T. The epidemiology of cancer of the stomach in Japan, with special reference to the role of diet. Gann Monogr. 1968;3:15.
140.
Nomura A, Stemmermann G, Chyou P. et al. Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. N Engl J Med. 1991;325:1132. [PubMed: 1891021]
141.
Parsonnet J, Friedman G, Vandersteen D. et al. Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med. 1991;325:1127. [PubMed: 1891020]
142.
Williams M P, Pounder R E. Helicobacter pylori: from the benign to the malignant. Am J Gastroenterol. 1999;94:S11. [PubMed: 10565604]
143.
Fox J G, Dangler C A, Taylor N S. et al. High-salt diet induces gastric epithelial hyperplasia and parietal cell loss, and enhances Helicobacter pylori colonization in C57BL/6 mice. Cancer Res. 1999;59:4823. [PubMed: 10519391]
144.
Correa P, Cuello C, Fajardo L F. et al. Diet and gastric cancer: nutrition survey of a high-risk area. J Natl Cancer Inst. 1983;70:673. [PubMed: 6572755]
145.
Haenszel W, Kurihara M, Locke F B. et al. Stomach cancer in Japan. J Natl Cancer Inst. 1976;56:265. [PubMed: 1255759]
146.
Joosens J V, Geboers J. Dietary salt and risks to health. Am J Clin Nutr. 1987;45:1277. [PubMed: 3578117]
147.
Nagai M, Hashimoto T, Yanagawa H. et al. Relationship of diet to the incidence of esophageal and stomach cancer in Japan. Nutr Cancer. 1982;3:257. [PubMed: 6890672]
148.
Tuyns A J. Sodium chloride and cancer of the digestive tract. Nutr Cancer. 1983;4:198. [PubMed: 6844144]
149.
MacDonald W E, Anderson F H, Hashimoto S. Histological effect of certain pickles on the human gastric mucosa. Can Med Assoc J. 1967;96:1521. [PMC free article: PMC1923030] [PubMed: 6026337]
150.
Sato T, Fukuyama T, Susuki T, Takayanagi J. The relationship between gastric cancer mortality rate and salted food intake in several places in Japan. Bull Inst Publ Health. 1959;8:187.
151.
Sato T, Fukuyama T, Urata G, Suzuki T. Bleeding in the glandular stomach of mice by feeding highly salted foods and a comment on salted foods in Japan. Bull Inst Publ Health. 1959;8:10.
152.
Shirai T, Imaida K, Fukushima S. et al. Effects of NaCl, Tween 60 and a low dose of N-ethyl-N’-nitro-N-nitrosoguanidine on gastric carcinogenesis of rats given a single dose of N-methyl-N’-nitro-N-nitrosoguanidine. Carcinogenesis. 1982;12:1419. [PubMed: 7151255]
153.
Takahashi M, Kokubo T, Furukawa F. et al. Effect of high salt diet on rat gastric carcinogenesis induced by N-methyl-N’-nitro-N-nitrosoguanidine. Gann Monogr. 1983;74:28. [PubMed: 6840437]
154.
Chu E W, Malmgren R A. An inhibitory effect of vitamin A on the induction of tumors for forestomach and cervix in the Syrian hamster by carcinogenic polycyclic hydrocarbons. Cancer Res. 1965;25:884. [PubMed: 5891010]
155.
Rigdon R H, Neal J. Relationship of leukemia to lung and stomach tumors in mice fed benzo(a)pyrene. Proc Soc Exp Biol Med. 1969;130:146. [PubMed: 5762491]
156.
Howard J W, Fazio T. Review of polycyclic aromatic hydrocarbons in foods. Analytical methodology and reported findings of polycyclic aromatic hydrocarbons in foods. J Assoc Off Anal Chem. 1980;63:1077. [PubMed: 6997260]
157.
Lijinsky W, Shubik P. Benzo(a)pyrene and other polynuclear hydrocarbons in charcoal-broiled meat. Science. 1964;145:53. [PubMed: 14162692]
158.
Lo M -T, Sandi E. Polycyclic aromatic hydrocarbons (polynuclears) in foods. Residue Rev. 1978;69:35. [PubMed: 356148]
159.
Fritz W. Zum Losungsverhalten der Polyaromaten beim Kochen von Kaffee-Ersatzstoffen und Bohnenkaffee. Dtsh Lebensm Rundsch. 1969;65:83.
160.
Choi N W, Entwistle D W, Michaluk W, Nelson N. Gastric cancer in Icelanders in Manitoba. Isr J Med Sci. 1971;7:1500. [PubMed: 5144593]
161.
Dungal N. The special problem of stomach cancer in Iceland. With particular reference to dietary factors. JAMA. 1961;176:789. [PubMed: 13888467]
162.
Soos K. The occurrence of carcinogenic polycyclic hydrocarbons in foodstuffs in Hungary. Arch Toxicol Suppl. 1980;4:446. [PubMed: 6933959]
163.
Voitalovich E A, Deekoon P P, Deemarsky L U, Shabad L M. Comparative study of malignant tumor frequency in Tookoom District of the Latvian SSR. Vopr Onkol. 1957;3:351. [PubMed: 13468339]
164.
Montes G, Cuello C, Gordillo G. et al. Mutagenic activity of gastric juice. Cancer Lett. 1979;7:307. [PubMed: 389416]
165.
Schlag P, Bockler R, Ulrich H. et al. Are nitrite and N-nitroso compounds in gastric juices risk factors for carcinoma of the operated stomach? Lancet. 1980;1:727. [PubMed: 6103154]
166.
Van Loon A J, Botterweck A A, Goldbohm R A. et al. Intake of nitrate and nitrite and the risk of gastric cancer: a prospective cohort study. Br J Cancer. 1998;78:129. [PMC free article: PMC2062934] [PubMed: 9662263]
167.
Hawksworth G, Hill M J, Gordillo G, Cuello C. Possible relationship between nitrates, nitrosamines and gastric cancer in southwest Colombia, in N-nitroso compounds in the environment. IARC Sci Publ. 1975;9:229.
168.
Ruddell W S J, Bone E S, Hill M J, Walters C L. Pathogenesis of gastric cancer in pernicious anaemia. Lancet. 1978;1:521. [PubMed: 76069]
169.
Weisburger J H, Marquardt H, Hirota N. et al. Induction of cancer of the glandular stomach in rats by extract of nitrite-treated fish. J Natl Cancer Inst. 1980;64:163. [PubMed: 6928041]
170.
Piacek-Llanes B, Tannenbaum S R. Formation of an activated N-nitroso compound in nitrite-treated fava beans (Vicia faba) Carcinogenesis. 1982;3:1379. [PubMed: 7151253]
171.
Langhans P, Heger R A, Hoberstein J, Bunte H. Operation-sequel carcinoma. An experimental study. Hepato-Gastroenterology. 1981;28:34. [PubMed: 7216138]
172.
Beasley R P, Lin C C, Hwan L Y, Chien C S. Hepatocellular carcinoma and hepatitis B virus: a prospective study of 22,707 men in Taiwan. Lancet. 1981;2:1129. [PubMed: 6118576]
173.
Anthony P P. Cancer of the liver: pathogenesis and recent aetiological factors. Trans R Soc Trop Med Hyg. 1977;71:466. [PubMed: 204084]
174.
Linsell C A, Peers F G. Aflatoxin and liver cell cancer. Trans R Soc Trop Med Hyg. 1977;71:471. [PubMed: 343308]
175.
Wogan G N. Dietary factors and special epidemiological situations of liver cancer in Thailand and Africa. Cancer Res. 1975;35:3499. [PubMed: 1104156]
176.
World Health Organization. Environmental Health Criteria 11. Mycotoxins. Geneva, Switzerland: WHO; 1979.
177.
Austin H, Delzell E, Grufferman S. et al. A case control study of hepatocellular carcinoma and the hepatitis B virus, cigarette smoking, and alcohol consumption. Cancer Res. 1986;46:962. [PubMed: 3000590]
178.
Purtilo D T, Gottlieb L S. Cirrhosis and hepatoma occurring at Boston City Hospital (1917-1968) Cancer. 1973;32:458. [PubMed: 4353016]
179.
Yu M C, Mack T, Hanisch R. et al. Hepatitis, alcohol consumption, cigarette smoking, and hepatocellular carcinoma in Los Angeles. Cancer Res. 1983;43:6077. [PubMed: 6315225]
180.
American Cancer Society. Nutrition and cancer: cause and prevention. American Cancer Society Special Report. New York, NY: ACS; 1984.
181.
Wynder E L. An epidemiological evaluation of the causes of cancer of the pancreas. Cancer Res. 1975;35:2228. [PubMed: 1149034]
182.
Longnecker DS, Morgan RGH. Diet and cancer of the pancreas: epidemiological and experimental evidence. In: Reddy BS, Cohen LA, editors. Diet, nutrition, and cancer: a critical evaluation. Vol 1: Macronutrients and cancer. Boca Raton, FL: CRC; 1986. p. 11.
183.
Solomon TE. Regulation of exocrine pancreatic cell proliferation and enzyme synthesis. In: Johnson LR, editor. Physiology of the gastrointestinal tract, Vol 2. New York: Raven; 1981. p. 873.
184.
Nevalainen T J, Janigan D T. Degeneration of mouse pancreatic acinar cells during fasting. Virchows Arch B Cell Pathol. 1974;15:107. [PubMed: 4211904]
185.
Roebuck B D, Yager J D Jr, Longnecker D S. Dietary modulation of azaserine-induced pancreatic carcinogenesis in the rat. Cancer Res. 1981;41:888. [PubMed: 7459874]
186.
Mack TM. Pancreas. In: Schottenfeld D, Fraumeni Jr EF, editors. Cancer epidemiology and prevention. Philadelphia, PA: W.B. Saunders; 1982. p. 638.
187.
MacMahon B. Risk factors for cancer of the pancreas. Cancer. 1982;50:2676. [PubMed: 7139561]
188.
Soler M, Chatenoud L, La Vecchia C. et al. Diet, alcohol, coffee and pancreatic cancer: final results from an Italian study. Eur J Cancer Prev. 1998;7:455. [PubMed: 9926293]
189.
Longnecker D S, Roebuck B D, Yager J D Jr. et al. Pancreatic carcinoma in azaserine-treated rats: induction, classification, and dietary modulation of incidence. Cancer. 1981;47:1562. [PubMed: 6974040]
190.
Pour P M, Runge R G, Birt D. et al. Current knowledge of pancreatic carcinogenesis in the hamster and its relevance to the human disease. Cancer. 1981;47:1573. [PubMed: 6456057]
191.
Silverman D T, Swanson C A, Gridley G. et al. Dietary and nutritional factors and pancreatic cancer: a case-control study based on direct interviews. J Natl Cancer Inst. 1998;90:1710. [PubMed: 9827525]
192.
McGuinness E E, Hopwood D, Wormsley K G. Further studies of the effects of raw soya flour on the rat pancreas. Scand J Gastroenterol. 1982;17:273. [PubMed: 6890232]
193.
McGuinness E E, Morgan R G H, Levison D A. et al. The effects of long-term feeding of soya flour on the rat pancreas. Scand J Gastroenterol. 1980;15:497. [PubMed: 7192012]
194.
McGuinness E E, Morgan R G H, Levison D A. et al. Interaction of azaserine and raw soya flour on the rat pancreas. Scand J Gastroenterol. 1981;16:49. [PubMed: 7195064]
195.
Morgan R G H, Levinson D A, Hopwood D. et al. Potentiation of the action of azaserine on the rat pancreas by raw soya bean flour. Cancer Lett. 1977;3:87. [PubMed: 560908]
196.
Gullo L, Pezzilli R, Morselli-Labate A M. Coffee and cancer of the pancreas: an Italian multicenter study. The Italian Pancreatic Cancer Study Group. Pancreas. 1995;11:223. [PubMed: 8577674]
197.
Harnack L J, Anderson K E, Zheng W. et al. Smoking, alcohol, coffee, and tea intake and incidence of cancer of the exocrine pancreas: the Iowa Women’s Health Study. Cancer Epidemiol Biomarkers Prev. 1997;6:1081. [PubMed: 9419407]
198.
Nishi M, Ohba S, Hirata K, Miyake H. Dose-response relationship between coffee and the risk of pancreas cancer. Jpn J Clin Oncol. 1996;26:42. [PubMed: 8551666]
199.
Partanen T, Hemminki K, Vainio H, Kauppinen T. Coffee consumption not associated with risk of pancreas cancer in Finland. Prev Med. 1995;24:213. [PubMed: 7597024]
200.
Denda A, Inui S, Sunagawa M. et al. Enhancing effect of partial pancreatectomy and ethionine-induced pancreatic regeneration on the tumorigenesis of azaserine in rats. Gann Monogr. 1978;69:633. [PubMed: 729961]
201.
McGuinness E E, Hopwood D, Wormsley K G. Potentiation of pancreatic carcinogenesis in the rat by DL-ethionine-induced pancreatitis. Scand J Gastroenterol. 1983;18:189. [PubMed: 6687017]
202.
Pour P M, Reber H A, Stepan K. Modification of pancreatic carcinogenesis in the hamster model. XII. Dose-related effect of ethanol. J Natl Cancer Inst. 1983;71:1085. [PubMed: 6316010]
203.
Tweedie J H, Reber H A, Pour P M, Pounder D M. Protective effect of ethanol on the development of pancreatic cancer. Surg Forum. 1981;32:222.
204.
Waterhouse J, Muir CS, Shanmugaratnam K, Powell J. Incidence in five continents. IARC Sci Publ 1982;4:No.42.
205.
Jensen O M, Maclennan R, Wahrendorf J. Diet, bowel function, fecal characteristics and large bowel cancer in Denmark and Finland. Nutr Cancer. 1982;4:5. [PubMed: 7155918]
206.
Ward J M, Anjo T, Ohannesian L. et al. Inactivity of fecapentaene-12 as a rodent carcinogen or tumor initiator and guidelines for its use in biological studies. Cancer Lett. 1988;42:49. [PubMed: 3141039]
207.
Haenszel W. Cancer mortality among the foreign-born in the United States. J Natl Cancer Inst. 1961;26:37. [PubMed: 13710420]
208.
Jensen OM. The epidemiology of large bowel cancer. In: Reddy BS, Cohen LA, editors. Diet, nutrition, and cancer: a critical evaluation. Vol 1: Macronutrients and cancer. Boca Raton, FL: CRC; 1986. p. 27.
209.
McMichael A J, McCall M G, Hartshome J M, Woodlings T L. Patterns of intestinal cancer in European migrants to Australia: the role of dietary change. Int J Cancer. 1980;25:431. [PubMed: 7372370]
210.
Kurihara M, Aoki K, Tominaga S. Cancer mortality statistics in the world. Nagoya: University of Nagoya Press; 1984.
211.
Hirayama T. Association between alcohol consumption and cancer of the sigmoid colon: observations from a Japanese cohort study. Lancet. 1989;2:725. [PubMed: 2570969]
212.
Lipkin M, Reddy B, Newmark H, Lamprecht S A. Dietary factors in human colorectal cancer. Annu Rev Nutr. 1999;19:545. [PubMed: 10448536]
213.
Miller A B, Howe G R, Jain M. et al. Food items and food groups as risk factors in a case-control study of diet and colo-rectal cancer. Int J Cancer. 1983;32:155. [PubMed: 6307893]
214.
Reddy BS. Diet and colon cancer: evidence from human and animal model studies. In: Reddy BS, Cohen LA, editors. Diet, nutrition, and cancer: a critical evaluation. Vol 1: Macronutrients and cancer. Boca Raton, FL: CRC; 1986. p. 47.
215.
Le Marchand L, Wilkins L R, Mi M P. Obesity in youth and middle age and risk of colorectal cancer in men. Cancer Causes Control. 1992;3:349. [PubMed: 1617122]
216.
West D W, Slattery M L, Robison L M. et al. Dietary intake and colon cancer: sex and anatomic site-specific associations. Am J Epidemiol. 1989;130:883. [PubMed: 2554725]
217.
Brownson R C, Zahm S H, Chang J C, Blair A. Occupational risk of colon cancer. An analysis by anatomic subsite. Am J Epidemiol. 1989;130:675. [PubMed: 2773916]
218.
Fredriksson M, Bengtsson N O, Hardell L, Axelson O. Colon cancer, physical activity, and occupational exposures. A case-control study. Cancer. 1989;63:1838. [PubMed: 2702592]
219.
Garabrant D H, Peters J M, Mack T M, Bernstein L. Job activity and colon cancer risk. Am J Epidemiol. 1984;119:1005. [PubMed: 6731427]
220.
Gerhardsson M, Norell S E, Kiviranta H. et al. Sedentary jobs and colon cancer risk. Am J Epidemiol. 1986;123:775. [PubMed: 3962961]
221.
Paffenbarger R S Jr, Hyde R T, Wing A L. Physical activity and incidence of cancer in diverse populations: a preliminary report. Am J Clin Nutr. 1987;45:312. [PubMed: 3799521]
222.
Peters R K, Garabrant D H, Yu M C, Mack T. A case-control study of occupational and dietary factors in colorectal cancer in young men by subsite. Cancer Res. 1989;49:5459. [PubMed: 2766308]
223.
Vena J E, Graham S, Zielezny M. et al. Lifetime occupational exercise and colon cancer. Am J Epidemiol. 1985;122:357. [PubMed: 4025286]
224.
Vena J E, Graham S, Zielezny M. et al. Occupational exercise and risk of cancer. Am J Clin Nutr. 1987;45:318. [PubMed: 3799522]
225.
Fraser G, Pearce N. Occupational physical activity and risk of cancer of the colon and rectum in New Zealand males. Cancer Causes Control. 1993;4:45. [PubMed: 8431530]
226.
Albanes D, Blair A, Taylor P R. Physical activity and risk of cancer in the NHANES I population. Am J Public Health. 1989;79:744. [PMC free article: PMC1349635] [PubMed: 2729471]
227.
Ballard-Barbash R, Schatzkin A, Albanes D. et al. Physical activity and risk of large bowel cancer in the Framingham Study. Cancer Res. 1990;50:3610. [PubMed: 2340509]
228.
Gerhardsson M, Floderus B, Norell S E. Physical activity and colon cancer risk. Int J Epidemiol. 1988;17:743. [PubMed: 3272134]
229.
Gerhardsson de Verdier M, Steineck G, Hagman U. et al. Physical activity and colon cancer: a case-referent study in Stockholm. Int J Cancer. 1990;46:985. [PubMed: 2249904]
230.
Kato I, Tominaga S, Matsuura A. et al. A comparative case-control study of colorectal cancer and adenoma. Jpn J Cancer Res. 1990;81:1101. [PubMed: 2125036]
231.
Lee I M, Paffenbarger R S, Hsieh C C. Physical activity and risk of developing colorectal cancer among college alumni. J Natl Cancer Inst. 1991;83:1324. [PubMed: 1886158]
232.
Polednak A P. College athletics, body size, and cancer mortality. Cancer. 1976;38:382. [PubMed: 947530]
233.
Slattery M L, Schumacher M C, Smith K R. et al. Physical activity, diet, and risk of colon cancer in Utah. Am J Epidemiol. 1988;128:989. [PubMed: 3189298]
234.
Wu A H, Paganini-Hill A, Ross R K, Henderson B E. Alcohol, physical activity and other risk factors for colorectal cancer: a prospective study. Br J Cancer. 1987;55:687. [PMC free article: PMC2002031] [PubMed: 3620314]
235.
Martinez M E, Giovannucci E, Spiegelman D. et al. Leisure-time physical activity, body size, and colon cancer in women. Nurses’ Health Study Research Group. J Natl Cancer Inst. 1997;89:948. [PubMed: 9214674]
236.
Martinez M E, Heddens D, Earnest D L. et al. Physical activity, body mass index, and prostaglandin E2 levels in rectal mucosa. J Natl Cancer Inst. 1999;91:950. [PubMed: 10359547]
237.
Le Marchand L, Wilkens L R, Kolonel L N. et al. Associations of sedentary lifestyle, obesity, smoking alcohol use, and diabetes with the risk of colorectal cancer. Cancer Res. 1997;57:4787. [PubMed: 9354440]
238.
Bostick R M, Potter J D, Kushi L H. et al. Sugar, meat, and fat intake, and non-dietary risk factors for colon cancer incidence in Iowa women (United States) Cancer Causes Control. 1994;5:38. [PubMed: 8123778]
239.
Garland C, Shekelle R B, Barrett-Connor E. et al. Dietary vitamin D and calcium and risk of colorectal cancer: a 19-year prospective study in men. Lancet. 1985;1:307. [PubMed: 2857364]
240.
Graham S, Marshall J, Haughey B. et al. Dietary epidemiology of cancer of the colon in western New York. Am J Epidemiol. 1988;128:490. [PubMed: 2843038]
241.
Klatsky A L, Armstrong M A, Friedman G D, Hiatt R A. The relations of alcoholic beverage use to colon and rectal cancer. Am J Epidemiol. 1988;128:1007. [PubMed: 3189277]
242.
Lee I M, Paffenbarger R S. Quetelet’s index and risk of colon cancer in college alumni. J Natl Cancer Inst. 1992;84:1326. [PubMed: 1495102]
243.
Lew E A, Garfinkel L. Variations in mortality by weight among 750,000 men and women. J Chronic Dis. 1979;32:563. [PubMed: 468958]
244.
Phillips R L, Snowden D A. Dietary relationships with fatal colorectal cancer among Seventh-Day Adventists. J Natl Cancer Inst. 1985;74:307. [PubMed: 3856044]
245.
Giovannucci E, Ascherio A, Rimm E B. et al. Physical activity, obesity and risk for colon cancer and adenoma in men. Ann Intern Med. 1995;122:327. [PubMed: 7847643]
246.
Little J, Logan R F A, Hawtin P G. et al. Colorectal adenomas and energy intake, body size and physical activity: a case-control study of subjects participating in the Nottingham faecal occult blood screening programme. Br J Cancer. 1993;67:172. [PMC free article: PMC1968212] [PubMed: 8427777]
247.
Neugut A I, Garbowski G C, Lee W C. et al. Dietary risk factors for the incidence and recurrence of colorectal adenomatous polyps. A case-control study. Ann Intern Med. 1993;118:91. [PubMed: 8416323]
248.
Albanes D, Jones D Y, Schatzkin A. et al. Adult stature and risk of cancer. Cancer Res. 1988;48:1658. [PubMed: 3345534]
249.
Albanes D, Taylor P R. International differences in body height and weight and their relationship to cancer incidence. Nutr Cancer. 1990;14:69. [PubMed: 2367236]
250.
Chute C G, Willett W C, Colditz G A. et al. A prospective study of body mass, height, and smoking on the risk of colorectal cancer in women. Cancer Causes Control. 1991;2:117. [PubMed: 1873436]
251.
Clinton S K, Imrey P B, Mangian H J. et al. The combined effects of dietary fat, protein, and energy intake on azoxymethane-induced intestinal and renal carcinogenesis. Cancer Res. 1992;52:857–865. [PubMed: 1737347]
252.
Klurfeld D M, Weber M M, Kritchevsky D. Inhibition of chemically induced mammary and colon tumor promotion by caloric restriction in rats fed increased dietary fat. Cancer Res. 1987;47:2759–2762. [PubMed: 3567901]
253.
Kumar S P, Roy S J, Todumo K, Reddy B S. Effect of different levels of calorie restriction on azoxymethane-indcuced colon carcinogenesis in male F344 rats. Cancer Res. 1990;50:5761. [PubMed: 2393850]
254.
Reddy B S, Wang C -X, Maruyama H. Effect of restricted caloric intake on azoxymethane-induced colon tumor incidence in male F344 rats. Cancer Res. 1987;47:1226. [PubMed: 3815332]
255.
Colditz G A, Cannuscio C C, Frazier A L. Physical activity and reduced risk of colon cancer: implications for prevention. Cancer Causes Control. 1997;8:649. [PubMed: 9242482]
256.
Ma J, Pollak M N, Giovannucci E. et al. Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-1 and IGF-binding protein-3. J Natl Cancer Inst. 1999;91:620. [PubMed: 10203281]
257.
Rose D P, Boyar A P, Wynder E L. International comparisons of mortality rates for cancer of the breast, ovary, prostate, and colon, and per capita food consumption. Cancer. 1986;58:2363. [PubMed: 3768832]
258.
Rosenberg L, Metzger L S, Palmer J R. Alcohol consumption and risk of breast cancer: a review of the epidemiologic evidence. Epidemiol Rev. 1993;15:133. [PubMed: 8405196]
259.
Bristol J B, Emmett P M, Heaton K W, Williamson R C. Sugar, fat, and the risk of colorectal cancer. Br Med J (clin Res Ed) 1985;291:1467. [PMC free article: PMC1418069] [PubMed: 2998541]
260.
Giovannucci E, Rimm E B, Stampfer M J. et al. Intake of fat, meat and fiber in relation to risk of colon cancer in men. Cancer Res. 1994;54:2390. [PubMed: 8162586]
261.
Jain M, Cook G M, Davis F G. et al. A case-control study of diet and colo-rectal cancer. Int J Cancer. 1980;26:757. [PubMed: 7216545]
262.
Kune G A, Kune S. The nutritional causes of colorectal cancer: an introduction to the Melbourne study. Nutr Cancer. 1987;9:1. [PubMed: 3808967]
263.
Kune S, Kune G A, Watson L F. Case-control study of alcoholic beverages as etiologic factors: the Melbourne colorectal cancer study. Nutr Cancer. 1987;9:43. [PubMed: 3808969]
264.
Kune S, Kune G A, Watson L F. Case-control study of dietary etiological factors: the Melbourne Colorectal Cancer Study. Nutr Cancer. 1987;9:21. [PubMed: 3027675]
265.
Lyon J L, Mahoney A W, West D W. et al. Energy intake: its relationship to colon cancer risk. J Natl Cancer Inst. 1987;78:853. [PubMed: 3033383]
266.
Peters R K, Pike M C, Garabrandt D, Mack T M. Diet and colon cancer in Los Angeles County, California. Cancer Causes Control. 1992;3:457. [PubMed: 1525327]
267.
Potter J D, McMichael A J. Diet and cancer of the colon and rectum: a case-control study. J Natl Cancer Inst. 1986;76:557. [PubMed: 3007842]
268.
Sandler R S, Lyles C M, Peipins L A. et al. Diet and the risk of colorectal adenomas: macronutrients, cholesterol and fiber. J Natl Cancer Inst. 1993;85:875. [PubMed: 8388061]
269.
Willett W C, Hunter D J, Stampfer M J. et al. Dietary fat and fiber in relation to risk of breast cancer: an eight year follow-up. JAMA. 1992;268:2037. [PubMed: 1328696]
270.
Benito E, Cabeza E, Moreno V. et al. Diet and colorectal adenomas: a case-control study in Majorca. Int J Cancer. 1993;55:213. [PubMed: 8370618]
271.
Macquart-Moulin G, Riboli E, Cornee J. et al. Colorectal polyps and diet: a case-control study in Marseilles. Int J Cancer. 1987;40:179. [PubMed: 3038756]
272.
McGee D, Reed D, Stemmermann G. et al. The relationship of dietary fat and cholesterol to mortality in 10 years: the Honolulu Heart Program. Int J Epidemiol. 1985;14:97. [PubMed: 3988448]
273.
Meyer F, White E. Alcohol and nutrients in relation to colon cancer in middle-aged adults. Am J Epidemiol. 1993;138:225. [PubMed: 8395140]
274.
Stemmermann G N, Nomura A M Y, Heilbrun K L. Dietary fat and the risk of colorectal cancer. Cancer Res. 1984;44:4633. [PubMed: 6467218]
275.
Tuyns A J, Haelterman M, Kaaks R. Colorectal cancer and the intake of nutrients: oligosaccharides are a risk factor, fats are not: a case-control study in Belgium. Nutr Cancer. 1987;10:181. [PubMed: 2829139]
276.
Willett W C, Stampfer M J, Colditz G A. et al. Relation of meat, fat, and fiber intake to the risk of colon cancer in a prospective study among women. N Engl J Med. 1990;323:1664. [PubMed: 2172820]
277.
Bjelke E. Epidemiologic studies of cancer of the stomach, colon, and rectum, with special emphasis on the role of diet. Scand J Gastroenterol Suppl. 1974;31:1. [PubMed: 4532803]
278.
Goldbohm R A, van den Brandt P A, van’t Veer P. et al. A prospective cohort study on the relation between meat consumption and the risk of colon cancer. Cancer Res. 1994;54:718. [PubMed: 8306333]
279.
Phillips R L, Snowdon D A. Association of meat and coffee use with cancers of the large bowel, breast, and prostate among Seventh-Day Adventists: preliminary results. Cancer Res. 1983;43(5 Suppl):2403s. [PubMed: 6831464]
280.
Kritchevsky D, Klurfeld DM. Fat and cancer. In: Alfin-Slater RB, Kritchevsky D, editors. Human nutrition: a comprehensive treatise. Vol 7: Cancer and nutrition. New York, NY: Plenum; 1991. p. 51.
281.
Newberne P M, Nauss K M. Dietary fat and colon cancer: variable results in animal models. Prog Clin Biol Res. 1986;222:311. [PubMed: 3538042]
282.
Clinton S K, Bostwick D G, Olson L M. et al. Effects of ammonium acetate and sodium cholate on N-methyl-N-nitrosoquanidine-induced colon carcinogenesis on rats. Cancer Res. 1988;48:3035. [PubMed: 3365693]
283.
Kato I, Akhmedkhanov A, Koenig K. et al. Prospective study of diet and female colorectal cancer: the New York University Women’s Health Study. Nutr Cancer. 1997;28:276. [PubMed: 9343837]
284.
Topping D C, Visek W J. Nitrogen intake and tumorigenesis in rats injected with 1,2-dimethylhydrazine. J Nutr. 1976;106:1583. [PubMed: 10359]
285.
Visek WJ, Clinton SK. Dietary protein and cancer. In: Alfin-Slater RB, Kritchevsky D, editors. Human nutrition: a comprehensive treatise. Vol 7: Cancer and nutrition. New York, NY: Plenum; 1991. p. 103.
286.
Clinton S K, Destree R, Anderson D B. et al. 1,2-dimethylhydrazine-induced colon cancer in rats fed beef or vegetable protein. Nutr Reports Int. 1979;20:335.
287.
Cooper A J L. Biochemistry of sulfur-containing amino acids. Ann Rev Biochem. 1983;52:187. [PubMed: 6351723]
288.
Feinberg A P, Vogelstein B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature. 1983;301:89. [PubMed: 6185846]
289.
Goelz S E, Vogelstein B, Hamilton S R, Feinberg A P. Hypomethylation of DNA from benign and malignant human colon neoplasms. Science. 1985;228:187. [PubMed: 2579435]
290.
Hoffman R M. Altered methionine metabolism, DNA methylation and oncogene expression in carcinogenesis. A review and synthesis. Biochim Biophys Acta. 1984;738:49. [PubMed: 6204687]
291.
Holliday R. The inheritance of epigenetic defects. Science. 1987;238:163. [PubMed: 3310230]
292.
Makos M, Nelkin B D, Lerman M I. et al. Distinct hypermethylation patterns occur at altered chromosome loci in human lung and colon cancer. Proc Natl Acad Sci USA. 1992;89:1929. [PMC free article: PMC48567] [PubMed: 1347428]
293.
Cramer D W, Welch W R, Hutchinson G B. et al. Dietary animal fat in relation to ovarian cancer risk. Obstet Gynecol. 1984;63:833. [PubMed: 6728366]
294.
Davies M J, Bowey E A, Adlercreutz H. et al. Effects of soy or rye supplementation of high-fat diets on colon tumour development on azoxymethane-treated rats. Carcinogenesis. 1999;20:927. [PubMed: 10357769]
295.
Thiagarajan D G, Bennink M R, Bourquin L D, Kavas F A. Prevention of precancerous colonic lesions in rats by soy flakes, soy flour, genestein, and calcium. Am J Clin Nutr. 1998;68:1394S. [PubMed: 9848506]
296.
Burkitt DP, Trowell HC. Refined carbohydrate foods and disease: some implications of dietary fibre. London: Academic; 1975.
297.
Trowell H. Definition of dietary fiber and hypotheses that it is a protective factor in certain diseases. Am J Clin Nutr. 1976;29:417. [PubMed: 773166]
298.
Malhotra S L. Dietary factors in a study of colon cancer from cancer registry, with special reference to the role of saliva, milk and fermented milk products and vegetable fibre. Med Hypotheses. 1977;3:122. [PubMed: 578288]
299.
Reddy B S, Hedges A R, Laakso K, Wynder E L. Metabolic epidemiology of large bowel cancer: fecal bulk and constituents of high-risk North American and low-risk Finnish population. Cancer. 1978;42:2832. [PubMed: 728877]
300.
Trock B, Ianza E, Greenwald P. Dietary fiber, vegetables, and colon cancer: critical review and meta-analysis of the epidemiologic evidence. J Natl Cancer Inst. 1990;82:650. [PubMed: 2157027]
301.
Bingham S A, Williams D R R, Cummings J H. Dietary fiber consumption in Britain: new estimates and their relation to large bowel cancer mortality. Br J Cancer. 1985;52:399. [PMC free article: PMC1977192] [PubMed: 2994706]
302.
Liu K, Stamler J, Moss D. et al. Dietary cholesterol, fat, and fibre, and colon-cancer mortality. An analysis of international data. Lancet. 1979;2:782. [PubMed: 90870]
303.
Lyon J L, Sorenson A W. Colon cancer in a low-risk population. Am J Clin Nutr. 1978;31:s227. [PubMed: 707378]
304.
Dales L G, Friedman G D, Ury H K. et al. A case-control study of relationships of diet and other traits to colorectal cancer in American blacks. Am J Epidemiol. 1979;109:132. [PubMed: 425952]
305.
Hu J, Liu Y, Yu Y, Zhao T. et al. Diet and cancer of the colon and rectum: a case-control study in China. Int J Epidemiol. 1991;20:362. [PubMed: 1917235]
306.
Iscovich J M, L’Abbe K A, Castelleto R. et al. Colon cancer in Argentina. II. Risk from fibre, fat and nutrients. Int J Cancer. 1992;51:858. [PubMed: 1322375]
307.
Slattery M L, Caan B J, Potter J D. et al. Dietary energy sources and colon cancer risk. Am J Epidemiol. 1997;145:199. [PubMed: 9012592]
308.
Heilbrun L K, Nomura A, Hankin J H, Stemmermann G. Diet and colorectal cancer with special reference to fiber intake. Int J Cancer. 1989;44:1. [PubMed: 2545631]
309.
Fuchs C S, Giovannucci E L, Colditz G A. et al. Dietary fiber and the risk of colorectal cancer and adenoma in women. N Engl J Med. 1999;340:169. [PubMed: 9895396]
310.
Jansen M C, Bueno-de-Mesquita H B, Buzina R. et al. Dietary fiber and plant foods in relation to colorectal cancer mortality: the Seven Countries Study. Int J Cancer. 1999;81:174. [PubMed: 10188715]
311.
Giovannucci E, Stampfer M J, Colditz G. et al. Relationship of diet to risk of colorectal adenoma in men. J Natl Cancer Inst. 1992;84:91. [PubMed: 1310511]
312.
Little J, Logan R F A, Hawtin P G. et al. Colorectal adenomas and diet: a case-control study of subjects participating in the Nottingham faecal occult blood screening programme. Br J Cancer. 1993;67:177. [PMC free article: PMC1968225] [PubMed: 8381298]
313.
Macquart-Moulin G, Riboli E, Cornee J. et al. Case-control study on colorectal cancer and diet in Marseilles. Int J Cancer. 1986;38:183. [PubMed: 3015806]
314.
Neugut A I, Lee W C, Garbowski G C. et al. Obesity and colorectal adenomatous polyps. J Natl Cancer Inst. 1991;83:359. [PubMed: 1995919]
315.
Sandler R S, Lyles C M, McAuliff C. et al. Cigarette smoking, alcohol, and the risk of colorectal adenomas. Gastroenterology. 1993;104:1445. [PubMed: 8482454]
316.
Bidoli E, Franceschi S, Talamini R. et al. Food consumption and cancer of the colon and rectum in north-eastern Italy. Int J Cancer. 1992;50:223. [PubMed: 1730516]
317.
Phillips R. Role of life-style and dietary habits in risk of cancer among Seventh-Day Adventists. Cancer Res. 1975;35:3513. [PubMed: 1192416]
318.
Pickle L W, Greene M H, Ziegler R G. et al. Colorectal cancer in rural Nebraska. Cancer Res. 1984;44:363. [PubMed: 6690049]
319.
Bjelke E. Dietary factors and the epidemiology of cancer of the stomach and large bowel. Aktuel Ernaehrungs Med Klin Prax. 1978;2(Suppl):10.
320.
Graham S, Dayal H, Swanson M. et al. Diet in the epidemiology of cancer of the colon and rectum. J Natl Cancer Inst. 1978;61:709. [PubMed: 278848]
321.
Manousos O, Day N E, Trichopoulos D. et al. Diet and colorectal cancer: a case-control study in Greece. Int J Cancer. 1983;32:1. [PubMed: 6862688]
322.
Modan B, Barell V, Lubin F. et al. Low-fiber intake as an etiologic factor in cancer of the colon. J Natl Cancer Inst. 1975;55:15. [PubMed: 1159808]
323.
Macrae F. Wheat bran fiber and development of adenomatous polyps: evidence from randomized, controlled clinical trials. Am J Med. 1999;106:38S. [PubMed: 10089114]
324.
Jacobs L R. Dietary fiber and cancer. J Nutr. 1987;117:1319. [PubMed: 3039088]
325.
Jacobs L R. Relationship between dietary fiber and cancer: metabolic, physiologic and cellular mechanisms. Proc Soc Exp Biol Med. 1986;183:299. [PubMed: 3025886]
326.
Kritchevsky D, Klurfeld DM. Dietary fiber and cancer. In: Alfin-Slater RB, Kritchevsky D, editors. Human nutrition: a comprehensive treatise. Vol 7: Cancer and nutrition. New York, NY: Plenum; 1991. p. 211.
327.
Jenab M, Thompson L U. The influence of phytic acid in wheat bran on early biomarkers of colon carcinogenesis. Carcinogenesis. 1998;19:1087. [PubMed: 9667748]
328.
Clinton S K, Visek W J. Wheat bran and the induction of intestinal benzo(a)pyrene-hydroxylase by dietary benzo(a)pyrene. J Nutr. 1989;119:395. [PubMed: 2537889]
329.
Kune G A, Vitetta L. Alcohol consumption and the etiology of colorectal cancer: a review of the scientific evidence from 1957 to 1991. Nutr Cancer. 1992;18:97. [PubMed: 1437657]
330.
Carstensen J M, Bygren L O, Hatschek T. Cancer incidence among Swedish brewery workers. Int J Cancer. 1990;45:393. [PubMed: 2407667]
331.
Dean G, MacLennan R, McLoughlin H, Shelley E. Causes of death of blue collar workers at a Dublin brewery 1954-73. Br J Cancer. 1979;40:581. [PMC free article: PMC2010066] [PubMed: 497108]
332.
Pollack E S, Nomura A M Y, Heilbrun L K. et al. Prospective study of alcohol consumption and cancer. N Engl J Med. 1984;310:617. [PubMed: 6694673]
333.
Stemmermann G N, Nomura A M Y, Chyou P H, Yoshizawa C. Prospective study of alcohol intake and large bowel cancer. Digest Dis Sci. 1990;35:1414. [PubMed: 2226103]
334.
Williams R R, Horm J W. Association of cancer sites with tobacco and alcohol consumption and socioeconomic status of patients: interview study from the Third National Cancer Survey. J Natl Cancer Inst. 1977;58:525. [PubMed: 557114]
335.
Freudenheim J L, Graham S, Marshall J R. et al. Lifetime alcohol intake and risk of rectal cancer in western New York. Nutr Cancer. 1990;13:101. [PubMed: 2300490]
336.
Kabat C C, Howson C P, Wynder E L. Beer consumption and rectal cancer. Int J Epidemiol. 1986;15:494. [PubMed: 3818156]
337.
Kune G A, Kune S, Read A. et al. Colorectal polyps, diet, alcohol, and family history of colorectal cancer: a case-control study. Nutr Cancer. 1991;16:25. [PubMed: 1656394]
338.
Cope G F, Wyatt J I, Pinder I F. et al. Alcohol consumption in patients with colorectal adenomatous polyps. Gut. 1991;32:70. [PMC free article: PMC1379217] [PubMed: 1991640]
339.
Kikendall J W, Bowen P E, Burgess M B. et al. Cigarettes and alcohol as independent risk factors for colonic adenomas. Gastroenterology. 1989;97:660. [PubMed: 2753326]
340.
Kono S, Ikedu N, Yanai F. et al. Alcoholic beverages and adenomatous polyps of the sigmoid colon: a study of male self-defence officials in Japan. Int J Epidemiol. 1990;9:848. [PubMed: 2084011]
341.
Giovannucci E, Ascherio A, Rimm E B. et al. Intake of alcohol, folate amd methionine and risk of colon cancer in men. J Natl Cancer Inst. 1995;87:265. [PubMed: 7707417]
342.
Finkelstein J D, Cello J P, Kyle W E. Ethanol-induced changes in methionine metabolism in rat livers. Biochem Biophys Res Commun. 1974;61:525. [PubMed: 4455233]
343.
Bruce W. Recent hypotheses for the origin of colon cancer. Cancer Res. 1987;47:4237. [PubMed: 3300962]
344.
Corpet C E, Stamp D, Medline A. et al. Promotion of colonic microadenoma growth in mice and rats fed cooked sugar or cooked casein and fat. Cancer Res. 1990;50:6955. [PubMed: 2208161]
345.
Sinha R, Rothman N. Exposure assessment of heterocyclic amines (HCAs) in epidemiologic studies. Mutat Res. 1997;376:195. [PubMed: 9202756]
346.
Sinha R, Rothman N. Role of well-done, grilled red meat, heterocyclic amines (HCAs) in the etiology of human cancer. Cancer Lett. 1999;143:189. [PubMed: 10503902]
347.
Sinha R, Chow W H, Kulldorff M. et al. Well-done, grilled red meat increases the risk of colorectal adenomas. Cancer Res. 1999;59:4320. [PubMed: 10485479]
348.
Ehrich M, Aswell J E, Van Tassell R L, Wilkins T D. Mutagens in the feces of 3 South African populations at different levels of risk for colon cancer. Mutat Res. 1979;64:231. [PubMed: 384227]
349.
Mower H F, Ichinotsubo D, Wang L W. et al. Fecal mutagens in two Japanese populations with different colon cancer risks. Cancer Res. 1982;42:1164. [PubMed: 7059973]
350.
Kuhnlein H, Kuhnlein U, Bell P A. The effect of short-term dietary modification on human fecal mutagenic activity. Mutat Res. 1983;113:1. [PubMed: 6828040]
351.
Buell P. Changing incidence of breast cancer in Japanese-American women. J Natl Cancer Inst. 1973;51:1479. [PubMed: 4762931]
352.
Rohan T E I, Bain C J. Diet in the etiology of breast cancer. Epidemiol Rev. 1987;9:120. [PubMed: 3315714]
353.
Gray G E, Pike M C, Henderson B E. Breast cancer incidence and mortality rates in different countries in relation to known risk factors and dietary practices. Br J Cancer. 1979;39:1. [PMC free article: PMC2009807] [PubMed: 758926]
354.
Goodwin P J, Boyd N F. Critical appraisal of the evidence that dietary fat intake is related to breast cancer risk in humans. J Natl Cancer Inst. 1987;79:473. [PubMed: 3476790]
355.
Miller AB. Nutrition and the epidemiology of breast cancer. In: Reddy BS, Cohen LA, editors. Diet nutrition, and cancer: a critical evaluation. Vol 1: Macronutrients and cancer. Boca Raton, FL: CRC; 1986.
356.
Mills P K, Beeson W L, Phillips R L, Fraser G E. Dietary habits and breast cancer incidence among Seventh-Day Adventists. Cancer. 1989;64:582. [PubMed: 2743252]
357.
Graham S, Marshall J, Mettlin C. et al. Diet in the epidemiology of breast cancer. Am J Epidemiol. 1982;116:68. [PubMed: 7102657]
358.
Hirohata T, Nomura A M, Hankin J H. et al. An epidemiologic study on the association between diet and breast cancer. J Natl Cancer Inst. 1987;78:595. [PubMed: 3104644]
359.
Hirohata T, Shigematsu T, Nomura A M. et al. Occurrence of breast cancer in relation to diet and reproductive history: a case-control study in Fukuoka, Japan. Natl Cancer Inst Monogr. 1985;69:187. [PubMed: 3834330]
360.
Hislop T G, Coldman A J, Elwood J M. et al. Childhood and recent eating patterns and risk of breast cancer. Cancer Detect Prev. 1986;9:47. [PubMed: 3731194]
361.
Lubin J H, Burns P E, Blot W J. et al. Dietary factors and breast cancer risk. Int J Cancer. 1981;28:685. [PubMed: 7333703]
362.
Miller A B, Kelly A, Choi N W. et al. A study of diet and breast cancer. Am J Epidemiol. 1978;107:499. [PubMed: 665664]
363.
Talamini R, LaVecchia C, Decarli A. et al. Social factors, diet and breast cancer in Northern Italian population. Br J Cancer. 1984;49:723. [PMC free article: PMC1976841] [PubMed: 6547346]
364.
Toniolo P, Riboli E, Protta F. et al. Calorie-providing nutrients and risk of breast cancer. JNCI. 1989;81:278. [PubMed: 2913325]
365.
Gillette C A, Zhu Z, Westerlind K C. et al. Energy availability and mammary carcinogenesis: effects of calorie restriction and exercise. Carcinogenesis. 1997;18:1183. [PubMed: 9214601]
366.
Huang Z, Hankinson S E, Colditz G A. et al. Dual effects of weight and weight gain on breast cancer risk. JAMA. 1997;278:1407. [PubMed: 9355998]
367.
Le Marchand L, Kolonnel, Earle M E. et al. Body size at different periods of life and breast cancer risk. Am J Epidemiol. 1988;128:137. [PubMed: 3381822]
368.
London S J, Colditz G A, Stampfer M J. Prospective study of relative weight, height and risk of breast cancer. JAMA. 1989;262:2853. [PubMed: 2810620]
369.
Lubin F, Ruder AM, Wax Y, Lemarchand L. Overweight and changes in weight throughout adult life in breast cancer etiology: a case-control study. Am J Epidemiol 1988;128:137:152.
370.
Ziegler R G, Hoover R N, Nomura A M. et al. Relative weight, weight change, height, and breast cancer risk in Asian-American women. J Natl Cancer Inst. 1996;88:650. [PubMed: 8627641]
371.
Rockhill B, Willett W C, Hunter D J. et al. A prospective study of recreational physical activity and breast cancer risk. Arch Intern Med. 1999;159:2290. [PubMed: 10547168]
372.
Carroll K K, Hopkins G J. Dietary polyunsaturated fat versus saturated fat in relation to mammary carcinogenesis. Lipids. 1979;14:155. [PubMed: 106196]
373.
Prentice R L, Kakar F, Hursting S. et al. Aspects of the rationale for the Women’s Health Trial. J Natl Cancer Inst. 1988;80:802. [PubMed: 3292773]
374.
Boyd N F, Martin L J, Noffel M M. et al. A meta-analysis of studies of dietary fat and breast cancer risk. Br J Cancer. 1993;68:627. [PMC free article: PMC1968413] [PubMed: 8353053]
375.
Holmes M D, Hunter D J, Colditz G A. et al. Association of dietary intake of fat and fatty acids with risk of breast cancer. JAMA. 1999;281:914. [PubMed: 10078488]
376.
Clinton S K, Alster J M, Imrey P B. et al. The combined effects of dietary protein and fat intake during the promotion phase of 7, 12-dimethylbenz[a)anthracene-induced breast cancer in rats. J Nutr. 1988;118:1577. [PubMed: 3145333]
377.
Prentice R L, Pepe M, Self S G. Dietary fat and breast cancer: a quantitative assessment of the epidemiological literature and a discussion of methodological issues. Cancer Res. 1989;49:3147. [PubMed: 2655892]
378.
Schatzkin A, Greenwald P, Byer D, Clifford C. The dietary fat-breast cancer hypothesis is alive. JAMA. 1989;261:3284. [PubMed: 2654436]
379.
Garland M, Hunter D J, Colditz G A. et al. Alcohol consumption in relation to breast cancer risk in a cohort of United States women 25-42 years of age. Cancer Epidemiol Biomarkers Prev. 1999;8:1017. [PubMed: 10566558]
380.
Henderson I C. What can a woman do about her risk of dying of breast cancer? Curr Probl Cancer. 1990;14:163. [PubMed: 2167816]
381.
Longnecker M P, Berlin J A, Orza M J, Chlmers T C. A metaanalysis of alcohol consumption in relation to risk of breast cancer. JAMA. 1988;260:652. [PubMed: 3392790]
382.
Mezzetti M, La Vecchia C, Decarli A. et al. Population attributable risk for breast cancer: diet, nutrition, and physical exercise. J Natl Cancer Inst. 1998;90:389. [PubMed: 9498489]
383.
Smith-Warner S A, Spiegelman D, Yaun S S. et al. Alcohol and breast cancer in women: a pooled analysis of cohort studies. JAMA. 1998;279:535. [PubMed: 9480365]
384.
Dorgan J F, Sowell A, Swanson C A. et al. Relationships of serum carotenoids, retinol, alpha-tocopherol, and selenium with breast cancer risk: results from a prospective study in Columbia, Missouri. Cancer Causes Control. 1998;9:89. [PubMed: 9486468]
385.
Zhang S, Hunter D J, Forman M R. et al. Dietary carotenoids and vitamins A, C, and E and risk of breast cancer. J Natl Cancer Inst. 1999;91:547. [PubMed: 10088626]
386.
Chiarodo A. National Cancer Institute roundtable on prostate cancer: future research directions. Cancer Res. 1991;51:2498. [PubMed: 2015610]
387.
Clinton S K, Giovannucci E. Diet, nutrition, and prostate cancer. Annu Rev Nutr. 1998;18:413. [PubMed: 9706231]
388.
Pienta K J, Espar P S. Risk factors for prostate cancer. Ann Intern Med. 1993;118:793. [PubMed: 8470854]
389.
Ross R K, Shimizu H, Paganini-Hill A. et al. Case-control studies of prostate cancer in blacks and whites in Southern California. J Natl Cancer Inst. 1987;78:869. [PubMed: 3471995]
390.
Kolonel L N, Yoshizawa C N, Hankin J H. Diet and prostatic cancer: a case-study control in Hawaii. Am J Epidemiol. 1988;127:999. [PubMed: 3358418]
391.
Nilsen T I, Vatten L J. Anthropometry and prostate cancer risk: a prospective study of 22,248 Norwegian men. Cancer Causes Control. 1999;10:269. [PubMed: 10482485]
392.
Snowdon D A, Phillips R L, Choi W. Diet, obesity and risk of fatal prostate cancer. Am J Epidemiol. 1984;120:244. [PubMed: 6465122]
393.
Talamini R, LaVecchia C, Decarli A. et al. Nutrition, social factors and prostatic cancer in Northern Italian population. Br J Cancer. 1986;53:817. [PMC free article: PMC2001412] [PubMed: 3718835]
394.
Mukherjee P, Sotnikov A V, Mangian H J. et al. Energy intake and prostate tumor growth, angiogenesis, and vascular endothelial growth factor expression. J Natl Cancer Inst. 1999;91:512. [PubMed: 10088621]
395.
Clinton S K, Mulloy A L, Li S P. et al. Dietary fat and protein intake differ in modulation of prostate tumor growth, prolactin secretion and metabolism, and prostate gland prolactin binding capacity in rats. J Nutr. 1997;127:225. [PubMed: 9039822]
396.
Chan J M, Stampfer M J, Giovannucci E. et al. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science. 1998;279:563. [PubMed: 9438850]
397.
Lee M M, Wang R T, Hsing A W. et al. Case-control study of diet and prostate cancer in China. Cancer Causes Control. 1998;9:545. [PubMed: 10189039]
398.
Howe G R, Miller A B, Jain M. Total energy intake: implications for epidemiologic analyses. Am J Epidemiol. 1986;124:157. [PubMed: 3013002]
399.
Severson R K, Nomura A M Y, Grove J S, Stemmermann G N. A prospective analysis of physical activity and cancer. Am J Epidemiol. 1989;130:522. [PubMed: 2763997]
400.
Gann P H, Hennekens C H, Sacks F M. et al. A prospective study of plasma fatty acids and risk of prostate cancer. J Natl Cancer Inst. 1994;86:281. [PubMed: 8158682]
401.
Giovannucci E, Rimm E B, Colditz G A. et al. A prospective study of dietary fat and risk of prostate cancer. J Natl Cancer Inst. 1993;85:1571. [PubMed: 8105097]
402.
Le Marchand L, Kolonel L N, Wilkins L R. et al. Animal fat consumption and prostate cancer: a prospective study in Hawaii. Epidemiology. 1994;5:276. [PubMed: 8038241]
403.
Clinton S K, Palmer S S, Spriggs C E, Visek W J. The growth of Dunning transplantable prostate adenocarcinomas in rats fed diets varying in fat content. J Nutr. 1988;118:1577. [PubMed: 3392600]
404.
Wang Y, Corr J G, Thaler H T. et al. Decreased growth of established human prostate LNCaP tumors in nude mice fed a low-fat diet. J Natl Cancer Inst. 1995;87:1456. [PubMed: 7545759]
405.
Rose D P, Cohen L A. Effects of dietary menhaden oil and retinyl acetate on the growth of DU 145 human prostatic adenocarcinoma cells transplanted into athymic nude mice. Carcinogenesis. 1988;9:603. [PubMed: 3356068]
406.
Rose D P, Connoly J M. Effects of fatty acids and eicosanoid synthesis inhibitors on the growth of two human prostate cancer cell lines. Prostate. 1991;18:243. [PubMed: 2020620]
407.
Heinonen O P, Albanes D, Virtamo J. et al. Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial. J Natl Cancer Inst. 1998;90:440. [PubMed: 9521168]
408.
Giovannucci E L, Ascherio A, Rimm E B. et al. Intake of carotenoids and retinol in relationship to risk of prostate cancer. J Natl Cancer Inst. 1995;87:1767. [PubMed: 7473833]
409.
Clinton S K. Lycopene: chemistry, biology, and implications for human health and disease. Nutr Rev. 1998;56:35. [PubMed: 9529899]
410.
Giovannucci E. Tomatoes, tomato-based products, lycopene, and cancer: review of the epidemiologic literature. J Natl Cancer Inst. 1999;91:317. [PubMed: 10050865]
411.
Clinton S K, Emenhiser C, Schwartz S J. et al. Cis-trans lycopene isomers, carotenoids, and retinol in the human prostate. Cancer Epidemiol Biomarkers Prev. 1996;5:823. [PubMed: 8896894]
412.
Gann P H, Ma J, Giovannucci E. et al. Lower prostate cancer risk in men with elevated plasma lycopene levels: results of a prospective analysis. Cancer Res. 1999;59:1225. [PubMed: 10096552]
413.
Corder E H, Guess H A, Hulka B S. et al. Vitmain D and prostate cancer: a predignostic study with stored sera. Cancer Epidemiol Biomarkers Prev. 1993;2:467–472. [PubMed: 8220092]
414.
Giovannucci E, Rimm E B, Wolk A. et al. Calcium and fructose intake in relation to risk of prostate cancer. Cancer Res. 1998;58:442. [PubMed: 9458087]
415.
Clark L C, Combs G F, Turnbull B W. et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled tiral. Nutritional Prevention of Cancer Study Group. JAMA. 1996;276:1957. [PubMed: 8971064]
416.
Yoshizawa K, Willett W C, Morris S J. et al. Study of prediagnostic selenium level in toenails and the risk of advanced prostate cancer. J Natl Cancer Inst. 1998;90:1219. [PubMed: 9719083]
417.
Goodman M T, Hankin J H, Wilkens L R. et al. Diet, body size, physical activity, and the risk of endometrial cancer. Cancer Res. 1997;57:5077. [PubMed: 9371506]
418.
Terry P, Baron J A, Weiderpass E. et al. Lifestyle and endometrial cancer risk: a cohort study from the Swedish Twin Registry. Int J Cancer. 1999;82:38. [PubMed: 10360818]
419.
National Cancer Institute. Diet, nutrition, and cancer prevention: a guide to food choices. NIH Pub. No. 87-28-78. Washington, DC: National Institutes of Health, Public Health Service, U.S. Dept. Health and Human Services, U.S. Government Printing Office; 1987.
420.
La Vecchia C, Decarli A, Negri E. et al. Dietary factors and the risk of epithelial ovarian cancer. J Natl Cancer Inst. 1987;79:663. [PubMed: 3116309]
421.
Risch H A, Jain M, Marrett L D, Howe G R. Dietary fat intake and risk of epithelial ovarian cancer. J Natl Cancer Inst. 1994;86:1409. [PubMed: 8072035]
422.
Kushi L H, Mink P J, Folsom A R. et al. Prospective study of diet and ovarian cancer. Am J Epidemiol. 1999;149:21. [PubMed: 9883790]
423.
Clinton SK, Michaud D, Giovannucci E. Nutrition and bladder cancer. In: Heber D, Blackburn GL, Go VLW, editors. Nutritional oncology. San Diego, CA: Academic Press; 1997. p. 463.
424.
Bruemmer B, White E, Vaughan T L, Cheney C L. Nutrient intake in relation to bladder cancer among middle-aged men and women. Am J Epidemiol. 1996;144:485. [PubMed: 8781464]
425.
Michaud D S, Spiegelman D, Clinton S K. et al. Fruit and vegetable intake and incidence of bladder cancer in a male prospective cohort. J Natl Cancer Inst. 1999;91:605. [PubMed: 10203279]
426.
Michaud D S, Spiegelman D, Clinton S K. et al. Fluid intake and the risk of bladder cancer in men. N Engl J Med. 1999;340:1390. [PubMed: 10228189]
427.
Price J M, Biava C G, Oser B L. et al. Bladder tumors in rats fed cyclohexamine or high doses of a mixture of cyclamate and saccharin. Science. 1970;167:1131. [PubMed: 5411626]
428.
National Academy of Sciences, National Research Council. Evaluation of cyclamate for carcinogenicity. Report of Committee on the Evaluation of Cyclamate for Carcinogenicity, Commission of Life Sciences. Washington, DC: National Academy Press; 1985.
429.
Donato F, Boffetta P, Fazioli R. et al. Bladder cancer, tobacco smoking, coffee and alcohol drinking in Brescia, northern Italy. Eur J Epidemiol. 1997;13:795. [PubMed: 9384269]
430.
Snowdon D A, Phillips R L. Coffee consumption and risk of fatal cancers. Am J Public Health. 1984;74:820. [PMC free article: PMC1651954] [PubMed: 6742274]
431.
Jacobsen B K, Bjelke E, Kvale G, Heuch I. Coffee drinking, mortality and cancer incidence: results from a Norweigan prospective study. J Natl Cancer Inst. 1986;76:823. [PubMed: 3457969]
432.
Jensen O M, Wahrendorf J, Knudsen J B, Sorenson B L. The Copenhagen casecontrol study of bladder cancer. II. The effect of coffee and other beverages. Int J Cancer. 1986;37:651. [PubMed: 3699928]
433.
Willett W C. Goals for nutrition in the year 2000. Ca Cancer J Clin. 1999;49:331. [PubMed: 11198950]
434.
Hunter D J, Willett W C. Diet, body size, and breast cancer. Epidemiol Rev. 1993;15:110. [PubMed: 8405195]
435.
Micozzi M S. Nutrition, body size, and breast cancer. Yearbook Phys Anthropol. 1985;28:175.
436.
Hawrylewicz E J, Huang H H, Kissane J Q, Drab E A. Enhancement of 7, 12-dimethylbenz(a)anthracene (DMBA) mammary tumorigenesis by high protein in rats. Nutr Reports Int. 1982;26:793.
437.
Freudenheim J L, Graham S, Marshall J R. et al. Folate intake and carcinogenesis of the colon and rectum. Int J Epidemiol. 1991;20:368. [PubMed: 1917236]
438.
McMichael AJ. Serum cholesterol and human cancer. In: Alfin-Slater RB, Kritchevsky D, editors. Human nutrition: a comprehensive treatise. Vol 7: Cancer and nutrition. New York, NY: Plenum; 1991. p. 141.
439.
Nomura A M, Stemmermann G N, Heilbrun L K. et al. Serum vitamin levels and the risk of cancer of specific sites to men of Japanese ancestry in Hawaii. Cancer Res. 1985;45:2369. [PubMed: 3986777]
440.
Lipkin M. Calcium modulation of intermediate biomarkers in the gastrointestinal tract. In: Lipkin M, Kelloff G, Newmark H, editors. Calcium, vitamin D and cancer. Boca Raton, FL: CRC; 1991.
441.
Caderni G, Stuart E W, Bruce W R. Dietary factors affecting the proliferation of epithelial cells in the mouse colon. Nutr Cancer. 1988;11:147. [PubMed: 3405868]
442.
Clark L C. The epidemiology of selenium and cancer. Fed Proc. 1985;44:2584. [PubMed: 3996614]
443.
National Academy of Sciences. Toward Healthful Diets. Washington, DC: National Academy Press; 1978.
444.
World Health Organization. Diet, Nutrition and the Prevention of Chronic Diseases. Technical Report Series, No. 797. Geneva, Switzerland: WHO; 1990. [PubMed: 2124402]
445.
American Cancer Society guidelines on diet, nutrition, and cancer. The Work Study Group on Diet, Nutrition, and Cancer. CA Cancer J Clin. 1991;41:334. [PubMed: 1933533]
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Bookshelf ID: NBK20914

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