4
Methods for Evaluating Potential Carcinogens and Anticarcinogens

Carcinogenic activity in rodents, following the oral administration of certain dyes, was first demonstrated in the early 1930s. Since then, numerous experimental studies have been conducted to identify carcinogens in the diets of humans. Such studies in the 1930s and 1940s were predominantly experimental and focused on food additives, especially colorants, contaminants, and carcinogens formed during food processing, cooking, and storage. Early experimental studies on the effects of malnutrition on carcinogenicity were also initiated during this period. Relatively few epidemiologic investigations were conducted until the midcentury. Although most investigations concentrated on cancer of the gastrointestinal tract and liver, it soon became clear that cancers at other sites could be induced by ingested chemicals. The oral route became widespread as a convenient method of administering any suspect carcinogen, irrespective of target organ, and a considerable database on chemicals tested for carcinogenicity was developed.

After World War II, results from experimental and epidemiologic studies reinforced the view that dietary patterns were significantly related to geographic variations in cancer incidence. However, in the absence of testable hypotheses and of well-conducted epidemiologic studies, the role of individual dietary components, including potential carcinogens, remained largely unclear for most organ sites, with few exceptions. Nonetheless, while most human studies concentrated on synthetic chemicals or dietary deficiency, the carcinogenic effect of natural carcinogens was not completely



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--> 4 Methods for Evaluating Potential Carcinogens and Anticarcinogens Carcinogenic activity in rodents, following the oral administration of certain dyes, was first demonstrated in the early 1930s. Since then, numerous experimental studies have been conducted to identify carcinogens in the diets of humans. Such studies in the 1930s and 1940s were predominantly experimental and focused on food additives, especially colorants, contaminants, and carcinogens formed during food processing, cooking, and storage. Early experimental studies on the effects of malnutrition on carcinogenicity were also initiated during this period. Relatively few epidemiologic investigations were conducted until the midcentury. Although most investigations concentrated on cancer of the gastrointestinal tract and liver, it soon became clear that cancers at other sites could be induced by ingested chemicals. The oral route became widespread as a convenient method of administering any suspect carcinogen, irrespective of target organ, and a considerable database on chemicals tested for carcinogenicity was developed. After World War II, results from experimental and epidemiologic studies reinforced the view that dietary patterns were significantly related to geographic variations in cancer incidence. However, in the absence of testable hypotheses and of well-conducted epidemiologic studies, the role of individual dietary components, including potential carcinogens, remained largely unclear for most organ sites, with few exceptions. Nonetheless, while most human studies concentrated on synthetic chemicals or dietary deficiency, the carcinogenic effect of natural carcinogens was not completely

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--> ignored. Thus, the senecio alkaloids, cycasin, and aflatoxin were all identified by the early 1960s. By 1970, the possible anticarcinogenic activity of vitamin A was being explored, as were the modifying effects of fruit, fiber, dairy products, and certain vegetables. In 1969, the International Union Against Cancer (UICC) convened a committee to address issues of cancer testing. The committee held a workshop that focused on the major testing methods and priorities for carcinogenicity testing. In proceedings from the workshop, the committee concluded, ''there is general agreement that both (a) the extent to which man is exposed to a substance, and (b) the degree of suspicion with which the substance is regarded, must be considered. In many specific cases (a) or (b) will be clearly dominant. Both natural and synthetic substances must be considered for testing. There is a tendency to consider first substances of the latter category; however, an increasing number of natural products with carcinogenic activity are being found and substances suspected to be in this category deserve more attention." (UICC, 1970). At about the same time, the National Research Council's Committee on Food Protection conducted a review of naturally occurring toxicants in foods, including carcinogens (NRC 1973), in response to growing public apprehension about the safety of the food supply. The committee's list comprised the major natural carcinogens and toxicants as we know them today, and emphasized that they should be further studied. Neither the UICC committee nor the National Research Council committee suggested that naturally occurring compounds posed any unique problems for testing, nor did they mention any qualitative differences between naturally occurring and synthetic carcinogens. Most cancers suspected to be diet-related are likely to have a multifactorial origin. The human diet is a complex mixture of nutrients and chemicals that are notoriously difficult to measure in observational studies and many of which might be plausible confounders of the effect under study. Although a single factor might be examined in animals through dietary manipulation, this is rarely possible in humans unless the suspected agent is identifiable, discrete,

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--> and present at high levels, such as a mycotoxin. In the past, traditional epidemiologic methods have been effective in identifying exposures to ingested carcinogens, e.g., aflatoxin and arsenic, in the diet at relatively high levels and in raising plausible hypotheses about individual foods and macro- or micronutrients. Modification of one component in a diet is usually associated with a change in others. An increase in calories from fat, for instance, usually reflects a reduced percentage of calories from other sources. However, in studying the role of dietary factors, the problem is even more complex because micro- and macronutrients might behave differently qualitatively and quantitatively between humans and the animals in which they are often studied. Further, experimental diets often compare extreme dietary variations, possibly at toxicologic or pharmacologic levels, leading to inappropriate conclusions in humans, in whom variations are usually within a more modest range. Accordingly, it is necessary to discuss first those limitations that arise from a lack of sensitivity or specificity inherent in the methods used for detecting trivial or minimal exposures and their effects in humans or animals. We must also discuss the issues involved in study of complex mixtures in the presence of multiple plausible confounders. When adequate human data are not available, it is often necessary to base opinions about human risk on results from experiments in animal models. Animal studies of suspected carcinogens are assumed, with some reservations, to provide qualitative predictions of human risk, especially where there is evidence of common mechanisms and endpoints. However, susceptibility to chemically induced carcinogenesis can show interspecies variability. This discordance results at least in part from differences, either hereditary or induced, among animal species in the steps involved in chemical carcinogenesis, particularly at the level of procarcinogen bioactivation and detoxification. Enzymes involved in bioactivation and detoxification of procarcinogens have now been identified and characterized in multiple animal species, including humans (Gonzalez and Gelboin 1994). There are many instances of interspecies

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--> differences in these enzymes, in terms both of catalytic specificity and of regulation (Wright and Stevens 1992). Hence, a given chemical can take divergent metabolic pathways, resulting in different health outcomes, depending on the species exposed. Furthermore, susceptibility to carcinogenesis can vary significantly within a species. In humans, much of this variability appears to reflect genetic heterogeneity. For example, there are several inherited variations in xenobiotic metabolizing enzymes and in DNA repair enzymes that have been associated with susceptibility to certain malignancies. Genetic predisposition to cancer can also be influenced by inherited mutations in tumor suppressor genes, as illustrated by the Li-Fraumeni syndrome, in which patients inherit mutations in one allele of the p53 gene, and in hereditary retinoblastoma, which involves the RB gene. Interestingly, inherited mutations in either of these tumor suppressor genes increases the susceptibility of individuals to certain radiation-induced tumors (Frebourg and Friend 1992). Inheritance of specific polymorphic alleles of the ras oncogene (Weston et al. 1991) and of the p53 gene (Weston et al. 1992) have been linked to lung cancer risk, but the significance of this association is not known. Recent identification on chromosome 17 of the BRCA1 gene that is associated with familial breast cancer (Miki et al. 1994) might provide a clue as to which genetic factors influence breast cancer risk. In addition, nongenetic factors such as diet and hormones might substantially influence susceptibility to cancer in both humans and inbred laboratory rodents. For example, differences in susceptibility to chemical carcinogenesis have been demonstrated between well-fed and calorie-deprived rodents of the same species, possibly because of calorie-induced differences in the catalytic activities of xenobiotic metabolizing and DNA repair enzymes. Individuals in different age groups might also differ in their susceptibility to chemical carcinogenesis. Biologic markers are being used to investigate individual susceptibility to various exogenous chemical agents. Cloning genes involved in the activation or detoxification of various xenobiotics and

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--> in the fidelity and efficiency of DNA repair, for example, will provide probes that may be used to identify and monitor interindividual variations. Currently used markers relate mainly to DNA-damaging (genotoxic) agents. However, because individuals might vary in their susceptibility to processes not directly involving DNA damage (nongenotoxic effects), markers specific for these changes are needed for routine use in molecular epidemiology studies. Despite the differences between humans and animals, epidemiologic and experimental models need to be considered as ways to evaluate the potential carcinogenicity of naturally occurring chemicals. For example, epidemiologic data have been crucial in developing the association between cigarette smoking and lung cancer. In addition, such studies have consistently demonstrated the relationship between the consumption of alcoholic beverages and cancer. Further experimental studies in diverse animal species have indicated that alcohol induces cancer by nongenotoxic mechanisms. In Chapter 4, the following questions are addressed: What methods are currently being used to identify and evaluate chemicals as potential carcinogens? Should the methods for testing naturally occurring potential carcinogens differ from those used for testing synthetic chemicals? Are existing methods adequate? How should naturally occurring compounds be prioritized for evaluation of carcinogenic potential? Methods For Evaluating Chemical Carcinogenesis Studies in Human Populations Epidemiology Epidemiology, a science based on population measurements, can

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--> be described as the study of the distribution and determinants of diseases in human populations and the application of the results to disease prevention or control. Epidemiologic approaches to determining cancer risks from chemical constituents of foods require the assessment of exposure (diet) and outcome (disease). Exposure data can be classified as (1) general diet, such as patterns of consumption of macro- and micronutrients, certain non-nutrient constituents, and caloric intake; and (2) the identification, isolation, and biological activity of individual suspected carcinogens and anticarcinogens in the diet. The complexity of the human diet makes it difficult to assess retrospectively. Dietary intake data are often based on the use of food diaries or recall of recent or past diet. These methods have qualitative and quantitative limitations. Over the past 2 decades, laboratory techniques have been developed that attempt to address some of the problems associated with epidemiologic studies of diet and cancer. Biologic markers of intake, either of certain nutrients or of individual chemicals found in foods, might provide a better assessment than has been possible before now of the role of diet in human cancer. Some biologic markers with potential use in epidemiologic studies have recently been reviewed (Riboli et al. 1987), and their use is discussed in more detail in the section on "Molecular Epidemiology." Generally, epidemiologic research follows one of four study designs: Ecologic Studies. These studies attempt to relate exposures to disease outcomes at a group level. Such studies suffer from several limitations: individual exposure data are not associated with individual outcome; investigators are unable to control for many potential confounders; and measures of exposure are crude. Because of these limitations, the primary value of such studies is in "hypothesis generation" (i.e., suggesting potentially important risk factors for study by methods based on individuals). On the other hand, such studies can often incorporate a broader range of exposures than can studies based on data from individuals. Thus, for weak risk factors,

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--> or for risks that occur only at extremes of exposure, this approach might be more useful in identifying or excluding etiologic factors than has traditionally been assumed (Prentice and Sheppard 1990). A common type of ecologic study in diet and cancer research has been international correlations of per capita food consumption with corresponding incidence or mortality rates from specific cancers (Armstrong and Doll 1975). Other studies have been carried out within national boundaries by the selection of distinctive subpopulations, such as ethnic groups (e.g., in Hawaii and South Africa), religious groups (e.g., Mormons and Seventh Day Adventists), or certain dietary cultures (e.g., vegetarians or abstainers from alcohol) (Lyon and Sorenson 1978, Kolonel et al. 1981). In such studies, the measure of exposure is often a very crude estimate of what individuals might actually be ingesting. Per capita food intakes, for example, use food production and import/export data to determine average exposures for individuals in the population. They do not account for food wastage or food fed to animals, nor for differences in intake by sex and age. Case-Control Studies. These studies are based on individuals rather than groups, and overcome many of the limitations just cited. In these studies, persons who have the outcome of interest, e.g., breast cancer, are identified, and suitable controls are obtained for comparison. Variables thought to be potential confounders in the relationship can be overcome by matching during control selection or by statistical adjustment at the time of data analysis. Other advantages of this design are that rare diseases (like most cancers) can be studied, results can be obtained rather quickly, and the research is relatively cost-effective. Disadvantages include the fact that exposure data are obtained retrospectively (dietary recall), and that differential misclassification between cases and controls (bias) can occur, despite great care in designing the study and in collecting the data. Examples of such studies are (1) a comparison of exposure to aflatoxins in foods relative to hepatitis B virus status between persons

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--> with liver cancer and controls (Qian et al. 1994); and (2) a study comparing consumption of salted fish by persons with nasopharyngeal cancer and controls (Ning et al. 1990). Such studies depend on dietary recall methods, primarily on diet histories, in which individuals recall their intake of specific foods at some specified time period in the past. These recall methods are subject to errors in memory. Such errors might be random (nondifferential) or selective (bias). Nondifferential error generally leads to reduced relative risks, so that a true positive finding might be missed. Bias, however, can lead to a false conclusion from the data. Sources of variation in food consumption data are discussed in Chapter 5. Although large sample sizes can help to reduce some of the effects of random misclassification, the effects of bias cannot be dealt with so readily. However, the findings from many case-control studies, such as those on the effects of fruits and vegetables on cancer risk, have been remarkably consistent, attesting to the strength of this approach (Steinmetz and Potter 1991). Nonetheless, there is evidence for biased recall in some case-control studies of breast cancer (Giovannucci et al. 1993) and of colorectal cancer (Wilkens et al. 1992). In some instances, biological specimens (usually serum) have been collected from cases and controls, in an effort to obtain more exact information. Unfortunately, effects of the disease itself on serum levels, variability in serum levels over time, and other factors limit the value of this approach. Newer biologic marker approaches that overcome some of these limitations are discussed below. Cohort Studies. These studies are generally preferred over case-control studies, because the potential for bias is less. In this design, healthy subjects are classified on exposures of interest prior to disease occurrence. The incidence of disease over time is then compared between the two groups. Since exposure data (e.g., diet histories) are obtained prospectively, recall bias is reduced, but the potential for substantial misclassification is nearly always present. However, prospectively assembled cohort studies are expensive,

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--> because very large samples are required, and the subjects must be followed for many years to accrue sufficient numbers of cases for meaningful statistical analysis. Such studies are not generally useful for very rare cancers. An alternative approach is to use pre-existing data sets. However, although this might be less costly, such data might not be ideal. An example of a cohort study in nutritional epidemiology research is a population of more than 100,000 U.S. nurses being monitored for breast, colon, and other cancers relative to antecedent dietary intakes (e.g., fat and red meat) (Willett et al. 1990, Willett 1994). Other diet-related cohorts in the U.S. include a population of 8,000 Japanese-American men in Hawaii (Heilbrun et al. 1984) and a sample of over 40,000 women in Iowa (Folsom et al. 1990). Cohort studies have often included biochemical measures, such as serum nutrient levels, since data collection occurs prior to the onset of disease. However, because of the lengthy period of follow-up, changes in dietary habits (e.g., fat intake) might occur in the participants, complicating the analyses. A multicenter, prospective cohort study designed to investigate the relationship of diet, nutritional status, various lifestyles and environmental factors, and the incidence of different forms of cancer is currently being conducted in Europe. The cohort of the European Prospective Investigation Into Cancer and Nutrition (EPIC) study, developed under the auspices of IARC (IARC 1993), will eventually total approximately 350,000 middle-aged men and women. Data on current diet are being collected by means of detailed dietary assessment. A standardized questionnaire is being used to obtain anthroprometric measurements, as well as information on physical activity, tobacco smoking, alcohol consumption, occupation, socio-economic status, reproductive history, contraception, use of hormone replacement therapy, previous illness, and current drug use. Blood samples are being collected that will be analyzed at a later date. Samples from subjects who develop cancer will be compared with appropriate disease-free control subjects.

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--> The range of analyses will depend on the type of cancer and availability of techniques. The EPIC study has several advantages, including the prospective approach, large sample size, and a wide range of dietary exposures. Short-term screening procedures for dietary modulators of cancer risk are also being developed. One problem that needed to be addressed was the necessity of collecting dietary samples from multiple countries in a comparable and standardized manner (Friedenreich et al. 1992). Intervention Studies. Intervention studies (randomized trials) are theoretically the most desirable of the basic epidemiologic approaches to research. Because they resemble experiments, their results are potentially the most convincing. In intervention studies, individuals are randomly allocated to an experimental or a control group. The experimental arm receives the intervention of interest, while the control arm does not. Because of the randomized design, the potential for bias is minimal, and any differences in outcome between the two groups can be attributed with some confidence to the intervention itself. Intervention studies that involve dietary manipulation are particularly difficult to perform successfully and to interpret. For example, if the intervention involves decreasing a macronutrient, such as fat, then to maintain weight, protein or carbohydrate must be increased, or energy expenditure decreased. Thus, a change in outcome could be attributable to any of the altered variables, not just to fat. Even an intervention that does not focus on macronutrients could have an effect on total caloric intake. For example, increasing vegetable intake (which adds considerable bulk to the diet) could result in decreased consumption of higher calorie foods, thereby leading to inadvertent weight loss. Even well-designed intervention trials can founder on such obstacles. Examples of intervention studies related to dietary exposures include a trial of ß-carotene supplements to lower risk of skin cancers (Greenberg et al. 1990); a trial of tocopherol and ß -carotene

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--> supplements to reduce the incidence of lung and other cancers among male smokers (Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group 1994); The Carotene and Retinol Efficacy Trial (CARET; Thornquist et al. 1993, Omenn et al. 1994); the Physicians Health Study (PHS; Hennekens et al.); trials of calcium supplements and precursors of colon cancer (Vargas and Alberts 1992); and a trial of low fat intake and breast and colon cancer (the recently begun Women's Health Initiative) (IOM 1993). Under ideal conditions, one would always choose to conduct intervention trials. However, use of trials is limited by several considerations, including the following: (1) excessively large sample size requirements unless very high-risk (and therefore nonrepresentative) populations are selected for the trial; (2) substantial logistical difficulties, such as maintaining compliance to dietary change over extended time periods; (3) the possibility in dietary interventions that the controls might also change their habits on their own initiative, thereby reducing differences between the two groups; (4) very high costs that must be justified; and (5) ethical considerations that often preclude the study (only interventions that are likely to be beneficial and almost certainly not harmful can be tested). Thus, intervention studies can only be justified when substantial supporting evidence from other studies already exists. Implementation of these four basic designs in epidemiologic research has been expanded in recent years by the incorporation of new discoveries in molecular genetics and advances in molecular biology techniques. This field has been referred to as molecular epidemiology and is discussed in detail below. Molecular Epidemiology Research on molecular mechanisms of carcinogenesis will likely provide additional methods for identifying human exposures to

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--> adding of cancer prevention agents to mutagenesis assay systems before or after treatment with carcinogens or mutagens; treating animals with agents before or after treatment with a carcinogen; or measuring the impact of the agent on the metabolism of the carcinogen or on enzyme systems that are induced by the carcinogen. It should be noted that the problems associated with extrapolating results from rodent carcinogenicity studies to humans are also inherent in the experiments designed to assess anticarcinogenicity. The use of a high-dose carcinogen, high-dose treatment with the agent under study, and short-term observation periods all limit the application of these results to humans. Studying the effect of anticarcinogenic agents on specific stages of cancer development has identified whether the agents modify genotoxic or nongenotoxic processes. For example, studies have evaluated the ability of cancer prevention agents to inhibit nongenotoxic effects such as cell proliferation, by applying these agents before or after treatment with the phorbol ester TPA following exposure to a genotoxic agent. A recent approach to assessing cancer prevention is the use of intermediate markers for tumor formation, such as aberrant crypts and hyperplasia. This approach permits the study of potential cancer prevention agents in humans. In selecting agents to be evaluated as anticarcinogens, the criteria shown in Table 4-1 for establishing testing priorities can be applied to both synthetic and naturally occurring agents. Summary And Conclusions To limit the human risk of cancer, it is necessary to evaluate the carcinogenic potential of chemicals, whether they are synthetic or naturally occurring. Current strategies for identifying and evaluating potential naturally occurring carcinogens and anticarcinogens can be grouped into epidemiologic studies and those using experimental animal and cell models. The methods to assess carcinogenicity

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--> have been presented in this chapter and the following conclusions derived. As stated in Chapter 3, there is no reason to assume that the mechanisms involved in the process of carcinogenesis differ between naturally occurring and synthetic carcinogens. Consequently, they can be evaluated by the same methods. Current methods to identify potential human carcinogens, whether naturally occurring or synthetic, have limitations. Existing tests should be modified and coupled with new methods developed that reflect current understanding of the mechanisms of chemical carcinogenesis. The value of traditional epidemiologic approaches to identifying dietary carcinogens would be expanded by incorporating into their research designs new biochemical, immunologic, and molecular assays based on human tissues and biologic fluids. Despite their limitations, experimental models serve as important screening tests to identify potential human carcinogens. However, there are concerns about extrapolating the results from these models to humans, both with respect to carcinogenic risks and to risks at levels of human exposure. With respect to risk extrapolating, data from screening tests should be used in combination with mechanistic and other available information to predict more reliably the potential human carcinogenicity of a given substance. This is true for both synthetic and naturally occurring compounds. References Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. 1994. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N. Engl. J. Med. 330:1029-1035. Armstrong, B. and R. Doll. 1975. Environmental factors and

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