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2 Approach to the Study This report suggests useful directions for research into the relationship between diet, nutrition, and cancer. From the beginning of its study, the committee was cognizant of the widely held belief among scientists that research is most vigorous when it is the product of individual choices by investigators, rather than the result of a preconceived strategy. However, when research has an important and defined practical objective, the committee believes that there is justification for concentrating a part of the overall research effort on questions that are recognized to be central to further progress toward that objective. In approaching its task, the committee adopted the strategy described in the following paragraphs. The assessment of the literature in the committee's first report (National Research Council, 1982) served as the primary guide to the identification of needed research. As indicated in that earlier report, the evidence associating some dietary constituents to carcinogenesis was judged to be sufficiently convincing to allow the committee not only to formulate conclusions about their carcinogenic or inhibitory effects but also to propose interim dietary guidelines toward reducing the risk of certain cancers. Among these dietary components are total dietary fat; certain fruits, vegetables, and whole grain cereals; cured, pickled, and smoked foods; and alcoholic beverages. No firm conclusions could be reached on other dietary constituents. The committee recognized, however, that by working solely from its first report, it would be identifying only those gaps in knowledge that were implied by the already published literature. To gain assurance that it was not overlooking as yet unpublished work on new avenues of research that might have an important bearing on the relationship between diet and cancer, and to obtain insights from other researchers in the field, the committee constituted an informal panel of more than 100 distinguished scientists knowledgeable about cancer, nutrition, and related areas. These panelists were asked to contribute their sugges- tions for research. In addition, approximately one-third of the nearly 70 investigators who responded by sending suggestions were invited to meet with the committee at a miniconference devoted to exploring ideas for fruitful research. The resulting long lists of suggestions were consolidated and combined with the suggestions generated by the com- mittee. Priority items were then selected. This report contains both general and specific recommendations, reflecting the relative state of knowledge in each area. Unlike the committeets first report, which was suitable for the general scienti- fic community, this report is directed primarily to investigators in the field and to institutions that support them. 5
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6 DIET, NUTRITION, AND CANCER: DIRECTIONS FOR RESEARCH In the chapters that follow, the committee makes three kinds of recommendations for future research. One set of recommendations derives directly from gaps in the current state of knowledge about the effects of specific dietary components. Where conclusions are uncer- tain, simply because information is incomplete, recommendations are directed toward supplying missing data. Where the uncertainty stems from the imprecision of the data, there are recommendations for meth- odological improvement. Where several causal factors seem to be operating, there are recommendations that their interactions be studied. Such recommendations only highlight what would be obvious to an experienced investigator. A second set of recommendations arises from the fact that there are multiple etiological factors in carcinogenesis, including combi- nations of dietary components, complex steps in cancer progression, and a multiplicity of cancer types. This complexity has led the committee to make recommendations for long-term, multifaceted studies that are necessarily large and therefore unavoidably expensive. Such studies are likely to be most informative when they can be conducted under especially favorable circumstances. For example, high risk human populations may be studied under circumstances that permit simulta- neous study of multiple risk factors. Information from such studies could be supplemented with laboratory data derived from a suitable animal model. A third kind of recommendation calls attention to the need for behavioral and social studies. This stems from the finding in the com- mittee's first report that most common cancers appear to be influenced by diet--suggesting that, to a certain extent, individuals may be able to influence their chances of getting cancer. However, knowledge that a certain exposure strongly influences cancer is apparently not sufficient to convince people to modify their behavior. For example, it is clear that simply demonstrating a causal connection between smok- ing and lung cancer has not eliminated the smoking habit. Therefore, the committee has addressed the need for social and behavioral research to supplement research in the area of physiology, pathology, cytology, nutrition, and biochemistry. This report deals primarily with research on diet, nutrition, and cancer. The committee made no attempt to discuss other environmental or genetic factors that are known to be associated with cancer. How- ever, Chapter 3 briefly addresses the relationship between research on the basic mechanisms of carcinogenesis and our overall understanding of the ways that diet affects cancer. Although it is the committee's judgment that research on diet and carcinogenesis can progress without waiting for further discoveries in basic mechanisms, it is aware of the need to press forward simultaneously with fundamental investigations, particularly taking advantage of new opportunities afforded by recent advances in cellular and molecular biology. Such fundamental research is likely to improve not only our understanding of the impact of diet
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Approach to the Study 7 and nutrition on carcinogenesis but also our ability to address~nany aspects of the prevention and treatment of cancer. Chapters 4 and 5 discuss methodological shortcomings regarded by the committee as major hurdles in the comparison and interpretation of data from both epidemiological and laboratory studies. Research to refine methodology as well as to reexamine certain methodological issues is recommended. The next three chapters deal with specific dietary components. Macroconstituents (i.e., total caloric intake, fats, protein, carbo- hydrates, dietary fiber, and alcohol) are discussed in Chapter 6. As noted in the first report, it often is difficult to separate the effects of fat, protein, and carbohydrates. This is particularly evident in studies to determine the effect of changing the total caloric intake--which nay be accomplished by changes in the levels of any or all of the three macronutrients. Compared to information that has been provided by a multitude of studies on fats, less is known about proteins and there are relatively few data on the effects of different types of carbohydrates. Therefore, there is a need to identify more clearly the effects of protein and carbohydrates, espe- cially the individual components of dietary fiber. In its first report, the committee concluded that the evidence relating fats and certain alcoholic beverages to cancer is sufficiently convincing to justify certain interim dietary guidelines; however, further research i s needed to expand the data base for both of these dietary compo- nents. It is also necessary to identify the effects of the indi- vidual components of fat as well as the mechanisms by which a high fat diet appears to increase the incidence of certain cancers. Chapter 7 focuses on several microconstituents, i.e., vitamins, minerals, and nonnutritive constituents, and on foods rich in these substances that have been either identified in laboratory experiments as inhibitors of carc~nogenes~s or associated in epidemiological studies with a lower risk of cancer. We need to refine our knowledge about the effects of these components, to identify the active consti- tuents in fruits and vegetables, and to elucidate their mechanisms of action. Chapter 8 takes up two major subjects on which the committee did not reach firm conclusions in its first report: (1) mutagens in foods and (2) substances in foods that are naturally present (e.g., myco- tox~ns), that are intentionally added (e.g., additives), or that accidentally enter the food supply (e.g., pesticide residues). The contribution of such substances to overall cancer risk cannot be fully assessed for several reasons, including insufficient knowledge about the exposure of humans, the absence of carcinogenicity test data on the vast majority of these compounds, and our inability to estimate relia- bly the risk from exposure, even to those chemicals that are known to be carcinogenic. The committee emphasizes the need to obtain infor- mation that will enable us to understand the relevance of dietary
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8 DIET, NUTRITION, AND CANCER: DIRECTIONS FOR RESEARCH mutagens to human health and to determine the level of risk posed by mutagens, additives, and contaminants. Although the committee makes no attempt in this report to focus separately on research on methods to assess risk, this theme--the need to quantify the level of risk--is encountered time and again, espe- cially in discussing the applicability of results from laboratory studies to human health. Clearly, there is a need to develop better methods for assessing the risk to humans arising from the presence of initiators and modifiers of carcinogenesis in the diet. Chapter 9 examines how knowledge about diet and cancer can be applied in the development of public health programs aimed at modify- ing behavior to reduce cancer incidence. The committee believes that studies of the factors that motivate change in consumer behavior will be necessary if knowledge on diet and cancer is to yield benefit to public health. The first report of this committee contains extensive lists of references. Since this second report draws heavily on the same litera- ture, the citations herein are limited to studies not previously described.