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--> 5 Risk Comparisons Previous chapters of this report have discussed the ways in which dietary carcinogens are identified and documented the presence in the human diet of both naturally occurring and synthetic substances that may possess carcinogenic potential. In this chapter, we discuss the relative risks posed by natural and synthetic dietary carcinogens. Throughout this report, the term diet is used to refer to foods and beverages consumed intentionally and customarily in the U.S., not as a result of accident or deprivation. As in previous chapters, it is convenient to differentiate among constitutive, derived, acquired, pass-through, and added naturally occurring food chemicals. The definition of a carcinogen adopted in this report is that used by the International Agency for Research on Cancer, namely any agent capable of increasing the incidence of malignant neoplasia. Operationally, the committee treats as carcinogens those agents classified in certain IARC categories (i.e., 1, 2A, and 2B) and in the National Toxicology Program's (1994) Annual Report as known to be or reasonably anticipated to be carcinogenic. The level of risk associated with a carcinogenic agent depends on both the potency of the agent and on the level of exposure to that agent: Carcinogenic potency can be estimated using clinical and epidemiologic data on humans or toxicologic data derived from animal bioassays. Exposure to carcinogenic agents present in the diet depends on both food consumption patterns and the concentration of those agents in foods consumed. Food consumption data can be collected through the use of food diaries, or by using questionnaires
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--> designed to gauge the frequency with which specific foods are consumed or to identify by recall those foods recently consumed. Concentrations of carcinogenic agents in the food supply can be determined by analytic techniques, such as chemical analyses for pesticide residues present on foods. Inferences about dietary cancer risks are complicated by several factors. Diet is a complex mixture containing a large number of micro-and macroingredients. Components of the diet may interact with one another in a synergistic or antagonistic way. Some dietary components, such as aflatoxin, might increase cancer risks, whereas others, such as fruits and vegetables rich in antioxidants, might reduce cancer risk. Food-consumption patterns can be highly variable even among individuals in the same population subgroup. Food consumption varies depending on availability, ethnic customs, age, economics, and other factors. Chemical contaminants, extraneous matter, and pesticide residues can be present in food at variable concentrations. Food composition and products derived from preparation and processing of food are also variable. In addition to variability in dietary intakes, individuals may also vary with respect to their susceptibility to food components with carcinogenic potential. Each of these sources of dietary variability can effect individual exposures to food chemicals, as well any associated risks. Estimates of potential dietary cancer risks are subject to considerable uncertainty; for example, epidemiological studies have failed to provide unambiguous evidence of the effects of dietary fat on cancer risk. Estimates of potential cancer risks associated with low levels of individual food chemicals derived on the basis of laboratory results are highly uncertain. The application of animal cancer test data to humans requires extrapolation from the high doses used in laboratory studies to much lower doses corresponding to concentrations in the human diet, and extrapolation from animals to humans. The joint effects of ingestion of multiple agents in the form of complex dietary mixtures are also difficult to define. Consequently,
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--> in evaluating dietary cancer risks, it is important that both uncertainty and variability be recognized and, if possible, characterized. Recognizing that estimates of cancer risk are uncertain, this chapter focuses on the following questions: Does diet contribute to an appreciable proportion of human cancer? What are the relative contributions of naturally occurring and synthetic agents to dietary cancer risk? Are there significant interactions between either synthetic or naturally occurring carcinogens and anticarcinogens in the diet? To determine whether synthetic or natural chemicals classified as carcinogens pose the greater risk, it is necessary to know 1) the identity of the carcinogens present in the diet; 2) levels of ingestion of specific dietary carcinogens, both natural and synthetic; and, 3) the carcinogenic potency of these chemicals. Although this information might be used to evaluate the potential risks associated with individual food chemicals, it is more difficult to evaluate the overall risk posed by carcinogens present in the diet as a whole. The human diet is a complex mixture of food chemicals that interact in ways that are not generally well understood. Consequently, much of the discussion in this chapter of the comparative risks of naturally occurring and synthetic carcinogens present in the diet will focus on individual substances rather than mixtures. The levels of exposure to dietary carcinogens vary widely, depending on food-consumption patterns and dietary concentrations of carcinogenic substances. Because consumption patterns vary among individuals, it is important to consider the range of exposures within the population of interest, particularly those persons with high dietary intakes of naturally occurring or synthetic carcinogens. For purposes of risk comparison, a quantitative measure of the
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--> potency of naturally occurring and synthetic carcinogens is required. A widely used measure of carcinogenic potency is the TD50' defined as the level of exposure resulting in an excess lifetime cancer risk of 50% (Peto et al. 1984, Sawyer et al. 1984). The TD50 can be derived from either epidemiologic or toxicologic investigations. Because the TD50 is often derived from high-dose experimental data, it does not necessarily provide an appropriate basis for making inferences about cancer risks at low levels of exposure. To obtain a measure of carcinogenic potency that is closer to human exposure levels, the committee also used the TD01 as an index of carcinogenic potency. Because risk is a function of exposure and potency, the ratio of exposure to potency has been proposed as a means of comparing the relative risk of exposure to different carcinogens (Ames and Gold 1987). This chapter reviews existing data on the comparative potency of naturally occurring and synthetic carcinogens. Specifically, the committee compiled a database on the carcinogenic potencies of 37 natural and 70 synthetic carcinogens known to occur in the diet. These substances were identified as being carcinogenic in animals or humans by either the U.S. National Toxicology Program or the International Agency for Research on Cancer. All of these chemicals were classified by the NTP as known or reasonably anticipated to be carcinogens or by IARC as known (Group 1), probable (Group 2A), or possible (Group 2B) human carcinogens. Although the potency of naturally occurring dietary carcinogens as a group was on average greater than that of the synthetic carcinogens, the potencies of both types vary widely with considerable overlap. As discussed above, they are also subject to considerable uncertainty. Based on this limited number of chemicals, which might not represent the universe of naturally occurring and synthetic dietary carcinogens, it appears difficult to distinguish between the potencies of the two classes. The overall contribution of diet to the human cancer burden is also considered. Although tobacco and diet are thought to account
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--> for the large majority of human cancer, the contribution of the diet is less well understood than that of tobacco and is subject to far greater uncertainty as to the attributable risk fraction. Recent reviews of the causes of human cancer have suggested that synthetic carcinogens present in the diet might be responsible for a very small fraction of the human cancer burden (Ames et al. 1995, Higginson 1988), due in part to regulations that have limited the use of pesticides, including those with carcinogenic potential, and preclude the use of carcinogenic substances as direct food additives. In terms of risk from food substances, calories and fat may represent the most important naturally occurring dietary constituents. Food chemicals produced naturally by plants for self-defense have not been investigated to the same extent, and therefore the degree to which they contribute to human cancer is less clear. Monitoring Food Consumption Sources of Information Pesticides in the Diets of Infants and Children (NRC 1993a) addresses issues of food and water consumption in the U.S. population. Directed primarily at the pediatric population, the report discusses approaches to quantifying food and water consumption in the population at large, and the limitations of methods for food consumption monitoring. National food surveys are conducted by the U.S. Department of Agriculture (USDA) and the Department of Health and Human Services. The USDA's Human Nutrition Information Service (HNIS) conducts a comprehensive Nationwide Food Consumption (NFC) Survey about every ten years. In the interim, the service conducts Continuing Surveys of Food Intakes of Individuals (CSFII). Both the 1977-1978 and the 1987-1988 NFC Surveys were
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--> reviewed in Pesticides in the Diets of Infants and Children. However, the 1987-1988 survey was considered less reliable for estimating dietary exposures because of the low response rate (34%). Other limitations of the 1987-1988 USDA survey are discussed by the Government Accounting Office (1991). Although subject to serious limitations, the USDA surveys provide the only comprehensive data currently and publicly available on food consumption by people of all ages. Some surveys focus on segments of the U.S. population: for example, the 1985-1986 CSFII emphasized women 19-50 years old and their children ages 1-5, a sample of low-income women and their children, and in 1985 only, men ages 19-50 years. In the CSFII 1989, 1990, and 1991 surveys, data were collected on individuals of both sexes in all age classes, with response rates higher than those of the 1987-1988 NFC Survey (over 50%). The results of the 1989 and 1990 surveys are available commercially (Technical Assessment Systems 1995a,b) and on computer media from the National Technical Information Service. There is substantial uncertainty in such food consumption data due to a variety of factors, including recall bias, measurement error, and recording errors. The fact that the numbers of people surveyed are relatively small and response rates poor makes generalization to the U.S. population at large difficult. The optimal system for collecting and validating data on food consumption has yet to be developed. Ideally, complete and accurate records of the types and quantities of food consumed by the survey respondents could be used as a reference against which different surveys providing estimates of consumption could be compared. Because of the problems in measuring actual food intake, however, validation studies have in the past focused on the comparisons of results obtained from different surveys using different data collection methods. Another series of food consumption surveys that provides nationwide data is conducted by DHHS's National Center for Health Statistics (NCHS). Since 1960, the center has conducted seven
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--> health examination surveys of the U.S. population. The National Health and Nutrition Examination Surveys (NHANES), including the recently completed NHANES III, were designed to obtain representative information on the health and nutritional status for the U.S. population through health and medical histories, dietary interviews, direct physical examinations, and laboratory measurements. NFC and NHANES surveys deal primarily with nutritional considerations and are less useful for evaluating ingestion of naturally occurring chemicals and food additives. NHANES I (1971-1974) and NHANES II (1976-1980) sought data on medical conditions, especially nutrition-related disorders (obesity, growth retardation, anemia, diabetes, atherosclerotic cardiovascular diseases, hypertension, and deficiencies of vitamins or minerals). Both were directed at the civilian, noninstitutional population. (Excluded were the homeless, residents of hotels, rooming houses, dormitories, Native American reservations, military posts, prisons, hospitals, and residential treatment centers for drug addiction, alcoholism, and obesity.) Both surveys covered the 48 contiguous states, although Alaska and Hawaii were included in NHANES II. These surveys are discussed in detail in the NRC report Diet and Health (NRC 1989a). NHANES II data have been used to evaluate the proportion of the population at risk for deficiencies of vitamin A, vitamin C, folate, iron, zinc, and protein. The target population for NHANES III was the U.S. civilian, noninstitutional population aged 2 months or older. The survey design called for a stratified sample of counties, blocks, and persons randomly selected from households. National samples were drawn during 1988-1991 and 1991-1994. Eighty-one counties were selected from 26 states; from these, approximately 40,000 persons of all races were selected, and about 30,000 agreed to participate in the medical examination. Precise estimates of health characteristics were needed for relatively small population subgroups (children, older persons, black, and Mexican Americans), which were subject to oversampling.
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--> Some of the 30 topics investigated in NHANES III were high blood pressure, high blood cholesterol, obesity, passive smoking, lung disease, osteoporosis, HIV, hepatitis, helicobacter pylori, immunization status, diabetes, allergies, growth and development, blood lead, anemia, food sufficiency, and dietary intake, including fats, antioxidants, and nutritional blood measures. Results from NHANES III are being analyzed by NCHS and are not yet available. Although NHANES data are extensive and derive from a broad range of measurements, the data are of limited use in the study of chronic diseases, in part because of the sample size, response rates, and recall bias. NHANES provides only cross-sectional data on a periodic basis. Diet and Health provides an in-depth discussion of the limitations of NHANES data. A number of factors need to be considered when using food composition and consumption data in estimating dietary cancer risks. For example, food composition databases do not contain data on the concentration of many of the potential carcinogenic constituents found in foods (USDA 1992). Information on macronutrients and on certain micronutrients with carcinogenic or anticarcinogenic potential is available for a large variety of foods. However, data on many other microconstituents, naturally occurring and synthetic, are lacking. For example, little information is available on plant biocides, non-nutritive plant products with anticarcinogenic potential, or compounds generated by cooking. Furthermore, databases frequently do not take into consideration variability among food samples, population groups, and individuals, or consumption patterns that vary over time. Sources of Variation in Food Composition and Consumption Individuals vary in their dietary habits, people of different ages have different dietary requirements, and the concentration of food
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--> constituents can differ substantially. This section addresses some of the sources of variation in exposure to carcinogens in the diet. Dietary risk assessments should take into consideration that food samples can vary greatly in composition (see Chapter 2). For example, plants may produce natural chemicals for purposes of self-defense when they come in contact with certain pests (Harborne 1993). The concentrations of these substances in a particular food can vary considerably among samples, depending on the extent of the stress to the plant prior to harvesting. Factors such as storage, cooking, and pesticide application rates also have effects on food composition. This variability could result in substantial seasonal, geographic, and individual variation among food samples and, consequently, among human exposure levels. Similarly, cultivars of fruits and vegetables may differ in the content of naturally occurring constituents. For example, a cultivar of Idaho potatoes had to be taken off the market when it was found to contain toxic levels of the neurotoxin solanine (IFBC 1990). Dietary assessments should also allow for consumption patterns that may vary among population subgroups (defined in terms of sex, ethnicity, income, and other characteristics) (Kolonel et al. 1983, USDA 1987). Using data from the 1977-1978 USDA survey, Pesticides in the Diets of Infants and Children concluded that infants and children consume more calories relative to body weight than adults, eat far less-varied diets, and consume far greater amounts of milk in some form. Because of the lack of diversity of infant diets, infants can consume much greater quantities of certain foods than adults: the average 1-year-old consumes approximately 40-fold more apple juice relative to body weight than the average adult (Murdoch et al. 1992). Other population subgroups whose dietary habits differ from those of the general population include vegetarians and religious groups with special dietary restrictions. However, such groups may also exhibit nondietary differences from the general population, with respect to other factors such as socio-economic status and smoking habits (Lyon et al. 1980). Water is a major component of food (see Chapter 2) containing
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--> trace levels of a number of chemicals and should be considered in any analysis of dietary risk. This fact is particularly important when estimating the risks to children from dietary exposures. Pesticides in the Diets of Infants and Children considered three types of water in its analysis of dietary risks: water intrinsic to food, tap water added to food during preparation, and the direct consumption of tap water. The report indicates that dietary sources of water represented by fruits, liquids (especially fruit juices and milk), and vegetables are greater for infants than for older children or adults, and should be considered in estimating the risk from dietary exposure to potential human carcinogens. Such age-dependent differences in dietary patterns need to considered when evaluating lifetime cancer risks (Goddard et al. 1995). Dietary patterns can change markedly over time with changes in food preferences and the introduction of new foods. For example, artificial sweeteners were unknown until the discovery of saccharin in 1879 (cf. Arnold et al. 1983); however, since its approval for widespread use as an artificial sweetener, aspartame has become a common constituent of the diets of many Americans. In addition, fabricated and genetically engineered foods introduced in recent years have also afforded consumers with new dietary choices. Finally, food consumption data and survey methods need to be standardized to make them more useful in estimating exposures and determining risk. Currently, there is no simple, uniform method for conversion of a food, as consumed, to its components in terms of raw agricultural constituents. In addition, surveys should be coordinated among concerned organizations and carried out in a timely manner in order to identify trends in food and water consumption. Factors Affecting Susceptibility Individuals within a subgroup may vary with respect to their
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--> susceptibility to the toxic effects of those agents. Most carcinogens, whether naturally occurring or synthetic, will be metabolized in the body to a greater or lesser degree by different individuals. Some of these substances may be activated to their carcinogenic derivatives, while others are detoxified. Some of the enzymes involved in these reactions, such as certain of the cytochrome P450 mixed function oxidases, are not only inducible but also encoded by polymorphic genes (Idle et al. 1992). As a result, individuals vary in their susceptibility to carcinogens (Omenn et al. 1990). Prescription and over-the-counter drugs may affect specific constituents of food, such as cholesterol and fat. Several million people take cholesterol-lowering agents, and new drugs are being developed to block lipid absorption. Information on the use of pharmaceutical products that may affect dietary cancer risks is therefore of interest. Dietary Exposure to Potential Carcinogens and Anticarcinogens Despite a substantial degree of measurement error in assessing food intakes, as well as limitations in the current food composition and consumption databases, useful estimates of human exposure to some naturally occurring constituents of foods can often be derived. Estimating exposures to synthetic agents is more problematic. Residues of pesticides, chemicals added in processing, and carcinogens produced during cooking can be extremely variable in foods and are usually present in microquantities. In addition, exposure estimates based on dietary intakes (as opposed to serum or tissue measurements) do not account for the bioavailability of food constituents, which depends on many factors, such as other foods consumed at the same time, and the manner in which constituents are structurally bound in food. In the sections that follow, dietary exposure levels to naturally
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