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Cancer Causes and Control, 1997, 8, pp. 575-590 Plant foods and colon cancer: an assessment of specific foods and their related nutrients (United States) Martha L. Slattery, John D. Potter, Ashley Coates, Khe-Ni Ma, T. Dennis Berry, Debra M. Duncan, and Bette J. Caan (Received 8 October 1996; accepted in revised form 18 December 1996) Plant foods have been associated inversely with colon cancer. Since a major focus of this study was to identify components of plant foods which may account for their association with colon cancer, nutrients which are commonly found in plant foods also were evaluated. A population-based case-control study was conducted in Northern California, Utah, and the 'Twin Cities' area of Minnesota (United States). Complete data were available from interviewer-administered questionnaires on 1,993 cases and 2,410 controls. Higher intakes of vegetables (for highest relative to lowest quintile of intake) were associated inversely with colon cancer risle the odds ratio (OR) was 0.7 for both men (95 percent [CI] confidence interval ~ 0.5-0.9) and women (CI ~ 0.5-1.0). Associations were stronger among those with proximal tumors. Total fruit intake was not associated with colon cancer risk although, among men, higher levels of whole grain intake were associated with a decreased risk (OR -- 0.6, CI =~ 0.4-0.9 for older men); high intakes of refined grains were associated with an increased risk (OK = 1.5, CI = 1.1-2.1). Dietary fiber intake was associated with a decreased risk of colon cancem OR = 0.5 (CI = 0.3-0.9) for older men; OR = 0.7 (CI -- 0.4-1.2) for older women; OR. = 0.6 (CI -- 0.4-1.0) for men with proximal tumors; OR. = 0.5 (CI = 0.3-0.9) for women with proximal tumors. Other nutrients, for which plant foods were the major contributor - such as vitamin B6, thiamin, and niacin (women only) - also were associated inversely with colon cancer. Neither p-carotene nor vitamin C was protective for colon cancer. Adjustment of plant foods for nutrients found in plant foods or for supplement use did not appreciably alter the observed associations between plant foods and colon cancer. Cancer Causes and Control 1997, 8, 575-590 Key ~vords: [~-carotene, colon cancer, dietary fiber, folate, fruits, thiamin, United States, vegetables, vitamin C, vitamin B6, whole grains. Introduction Plant foods have been hypothesized to reduce risk of cancer by the variety of bioactive compounds they contain, including polyphenolics, allium compounds, lignans and phytoestrogens, trace minerals, antioxidants, and dietary fiber.1~ Of the many dietary factors evaluated for their relationship with colon cancer, vegetables, plant Dr Slattery, Ms Ma, and Mr Berry are with the Department of Oncological Sciences, University of Utah, Salt Lake City, Utah, USA. Dr Potter is with the Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. Drs Coates, Duncan, and Caan are with :be Division of Research, Kaiser Permanente Medical Care Program, Oakland, California, USA. Address correspondence to Dr Slattery, Department of Oncological Sciences, University of Utah, 546 Chipeta gray, Suite 1100, Salt Lake City, Utah, USA. This study was funded by grant ROI CA4899g from the US National Institutes of Health. Case identification and verification was supported by the Utah Cancer Registry, the Northern California Cancer Registry, the Sacramento Tumor Registry, and Cancer Surveillance Program Region 3 in California, and the Minnesota Cancer Surveillance System. 1997 Rapid Science Publishers Cancer Causes and Control. Vol 8. 1997 375

I 114.1_ Slattery et al foods rich in many phytochemicals, nutrients, and fiber are some of the most consistently identified environ- mental factors associated with a decreased risk of colon cancer.~'~ Consumption of fruits and whole grains also have been associated with decreasing risk of colon cancer, although the associations are less consistent than those observed for vegetable intake.('t* The purpose of this study was to evaluate the associa- tions between specific plant foods and colon cancer. To do this, we evaluated specific foods as well as their meas- urable constituents; analyses were necessarily limited to nutrients available in standard dietary databases. A major goal of the study was to determine if measurable constituents of p/ant foods explained the associations with colon cancer observed for plant foods. We assessed asso- ciations in the context of gender-, age-, and site-specific associations as well as those with and without a family history of colorectal cancer in order to obtain a better understanding o£ subgroups within the population who may be more or less affected by plant foods and their contributing nutrients. Materials and methods Study population Study participants were from the Kaiser Permanente Medical Care Program (KPMCP) of Northern California, an eight-county area in Utah (Davis, Salt Lake, Utah, Weber, Wasatch, Toode, Morgan, and Summit Counties) and the metropolitan 'Twin Cities' (Minneapolis, St. Paul) area (Anoka, Carver, Dakota, Hennepin, Ramsey; Scott, and Washington counties) in Minnesota (Unked States). Eligibility criteria for case subjects included diagnosis with first primary colon cancer (ICD-O-2" codes 18.0, 18.2-18.9) between 1 October 1991 and 30 September 1994, between 30 and 79 years of age at time of diagnosis, and mentally competent to complete the interview. Those with cancer in the rectosigmoid junction or rectum (defined as the first 15 cm from the anal verge) and those with known familial adenomatous polyposis, ulcerative colitis, or Crohn's disease, as indicated on the pathology report, were not eligible. Abstractors visited each report- ing hospital or pathology laboratory on a monthly basis to identify cases. Using this rapid=reporting system, the majority of case subjects were interviewed within three months of diagnosis. Of those invited to participate in the study, 76 percent cooperated, representing 64.5 percent of all eligible cases. Methods used to ascertah controls have been reported?" Briefly; control subjects from the K.PMCP were identified from membership lists; subjects under age 65 from Utah were identified from random-digit-dialing and lists of individuals with a current Utah driver's license or state 576 Cancer Causes and Control. Vol 8. 1997 ID; control subjects aged 65 and older in Utah were identified from Health Care Financing Administration lists (Social Security); controls subjects in Minnesota were identified from lists of individuals with a Minnesota driver's license or state ID. Controls were matched to cases by five-year age groups and gender. Of all controls asked to participate, 64 percent cooperated. Reasons for nonpar- ticipation have been previously outlined.)J The main reason for nonparticipation by controls was our inability to locate them (n = 752). Of these, 663 were controls selected from driver's license lists in Minnesota where new license holders were added on a regular basis but names of people who had moved or had died were not removed. Thus, of all digible controls, a total of 53.2 percent participated in the interview if unable-to-locate controls from Minnesota are included in the denominator;, if controls who we are unable to locate and verify residency were excluded from the denominator, the total is 63.9 percent. A total of 2,083 eligible cases and 2,476 digible controls were interviewed. Of these, 90 cases and 66 controls were excluded from the analysis because: (i) they were missing data on a key variable; (ii) data were considered to be of poor quality by the interviewer;, or (Hi) they reported Crohn's disease or ulcerative colitis at the time of inter- view. A tdtal of 1,993 cases and 2,410 controls are included in the analyses presented. The racial composition of study participants was: 4.2 percent Black, not Hispanic; 4.4 percent Hispanic; and 91.4 percent White, not Hispanic. Data were collected by trained and certified interviewers using laptop computers. After a week of formal training provided by study staff, interviewers were required to complete 10 taped interviews which were evaluated for interviewer behavior, reading of questions, adequate prob- ing, correct use of the referent year, and ability to obtain responses from subjects as outlined in the two-volume interviewer manual developed for the study. The referent period that study participants were asked to recall was the year two years prior to the date of diagnosis for cases or date of selection for controls. The interview took approximately two hours to complete. Quality con- trol methods used in the study have been described elsewhere?4 Briefly, all interviews were audio-taped and interviews were selected randomly for review for com- pleteness, consistency, interviewer behavior, probing behavior, use of the referent period correctly; and other interviewing behaviors as outlined in the interviewer manual. Dietary intake Dietary intake data were ascertained using a ,computerized adaptation of the CARDIA diet history,ts-t7 This ques- tionnaire has been compared for relative validity and reliability of past-month dietary-consumption patterns. With dais questionnaire, participants were asked to recall foods eaten, the frequency with which they were eaten,

foods eaten as additions to other foods, and use of fats in the preparation of foods. Three-dimensional food models were used to help participants estimate their usual serving size; cue cards were used to help participants consistently identify foods within broad categories. Foods eaten away from home were ascertained and those prepared with fat were assigned the fat most commonly used at a medium- priced restaurant. Where it was possible that many types of food within a category would be eaten, such as types of cereal, participants were asked to report the three items mostly commonly eaten. Seasonal consumption was obtained for fresh and canned fruits, and for four vege- tables (corn on the cob, tomatoes, summer and winter squash). Nutrient values for specific foods were calculated using the Nutrition Coordinating Center (NCC) nutrient database.'* Food classification NCC food codes from the diet history were categorized into food groups using standard serving sizes. Food codes for fruits included 15 separate canned, cooked, and frozen fruits, 23 separate fresh fruits, and eight separate types of dried fruits. Fruit juice was categorized as orange and grapefruit juice (two food codes) and other fruit juice (apple juice or cider, sweetened and low-calorie cranberry juice, grape juice, grapefruit juice, papaya juice, pineapple juice, prune juice, and nectars) (these items were later combined since no difference in association was noted for these two categories). Standard serving sizes for fruits were: one-half cup of canned fruit; one piece of most fresh fruits except for grapefruit (where one-half piece was considered a standard serving); one-half cup of berries, cherries, or grapes; one-quarter cup of dried fruit; and six ounces of fruit juice. Vegetables were derived from over 55 individual food items which included: raw and cooked vegetables; salsa; salads; potatoes which were baked, mashed, or eaten as a salad; cruciferous vegetables (cabbage, brussels sprouts, rutabagas, turnips, broccoli, cauliflower, parsnips, oriental vegetables, and mixed vegetables containing cruciferous vegetables); onions; legumes; and vegetable juice (two food codes for mixed vegetable and tomato juice). Vege- tables prepared with high amounts of fat, such as fried potatoes, were excluded from these food groupings because the 'five-a-day' guidelines do not include these vegetablesJ' Standard serving sizes for vegetables were one-half of vegetables, except for raw broccoli and cauliflower where one cup was considered a standard serving, one-quarter cup of salsa, and six ounces of juice. Fruits and vegetables, such as apples, apricots, oranges, grapefruits, tangerines, bananas, berries, tomatoes, salad greens, and dark yellow vegetables such as carrots and winter squash also were evaluated using standard serving sizes to denote level of consumption. These food items Plant foods and colon cancer were of interest either because of dietary constituents that they contain but that were not complete in the nutrient database, (i.e., lycopene in tomatoes) or because of the frequency with which they are eaten in the population. Foods included as part of whole grains included whole wheat and high fiber breads, bran muffins, whole grain cereals, brown rice, kasha, and high fiber crackers (29 food codes). Refined grains were categorized by 40 food codes which included white bread, French bread, rolls, biscuits, bagels, pancakes and waffles, corubread, muffins other than bran muffins, pasta, white rice, non-whole grain cereals and crackers, and pretzels. Standard serving sizes for grains were: two slices of bread; one biscuit, bagel, piece of cornbread, or muffin; one-half cup pasta, rice, or cooked cereals; one cup of dry cereals; and three crackers. The nuts and seeds group included nuts, seeds, and butters made from nuts and seeds. Standard serving sizes were one-quarter cup of nuts and seeds and two table- spoons of butters. Some plant foods included in mixed dishes (such as vegetables in stews and mixed dishes) were not included in these food groupings. Other data Other data used were age at the time of diagnosis or selection, body mass index (BMI) (wt/hti for men and w~/ht*~ for women) reported for the referent period, pres- ence or absence of one or more first-degree relatives with colorectal cancer, use of aspirin and/or nonsteroidal anti- inflammatory drugs (NSAIDs) on a regular basis defined as three times a week for at least one month, and long-term vigorous leisure-time physical activity.2~a°'1 The BMI of weight/height*~ was used for women because it has been shown to be more independent of height than weight/ heightz among women." Information on tumor site was obtained from local tumor registries and was classified as proximal (cecum through transverse colon) or distal (splenic flexure, descending, and sigmoid colon). Statistical methods The percentage of the total study population intake of each nutrient contributed by plant foods was calculated. We assessed nutrients for which plant foods contributed over 50 percent of the nutrient in the diet. Because plant foods are the major contributors of these nutrients, an association observed with these nutrients could explain possible biological mechanisms whereby plant foods are associated with colon cancer risk. Because we are studying plant foods, we have not included nutrients from supple- ments; however, analyses conducted among nonusers of supplements and users of supplements showed similar patterns to those presented here. Adjustment for supple- ment use did not alter our findings. C~ncer Ca~se~ ~d Control. Vol 8. 1997 577

M.L. $1~ttery e~ al The goal of the statistical analysis in this study was to provide a point- and interval estimate of risk for plant foods and their contributing nutrients. Thus, odds ratios (OR) and 95 percent confidence intervals (CI) were calculated from unconditional logistic regression models which included the following adjustment variables: age at selection; BMI; total energy intake and dietary calcium (all treated as continuous variables); family history of colorectal cancer (yes/no); long-term vigorous physical activity (four exposure levels);.and use of aspirin and/or NSAIDs (yes/no) treated as categorical variables. BMI and physical activity were associated with colon cancer in these data and also were associated with plant food consumption; thus, they were used as adjustment factors in these analyses. Total energy intake was used as an adjustment variable rather than dietary fat, since, in these data, dietary fat was not associated with risk of colon cancer-although total energy intake increased risk of colon cancerY To adjust adequately for total energy intake, it was necessary also to adjust for dietary calcium. Adjustment for other factors - such as cigarette smoking, alcohol consumption, and vitamin/mineral supplement use- did not alter our observations and are not included in the final models. Similarly, adjustment for center (Utah, Minnesota, or KPMCP) did not change the results, as might be expected since case/control status was not associated with the center. For broad categories of plant foods, such as fruit, vege- tables, and grains, foods were categorized based upon the quintile distribution of servings in the gender-specific control population. When looking at specific fruits and vegetables, such as tomatoes, categories were derived which represented meaningful eating patterns in this population. Nutrients were categorized into quintiles based upon the distribution of the control population for men and women separately. Data on folic acid and B vitamins were analyzed using density measures (amount/I,000 kcal) since dietary recommendations are based on caloric intake. For other nutrients, we assessed the absolute amount of nutrients to determine if the amount consumed was associated with colon cancer risk. Age-specific analyses were performed using the median age in the controls, 67 years, as the cut-point. Linear trend associations were assessed from logistic regression modds using the food or nutrient of interest as a continuous variable. Interaction was assessed by the overall improved fit of the logistic model with categorized interaction terms in the model compared with those models without inter- action te~s.z~ Results The mean number of servings of fruits and vegetables consumed by both men and women were approximately two servings of fruits and three and one-half servings of vegetables per day (Table 1). Men consumed slightly more nuts and seeds, whole grain, and refined grain products than women. We evaluated intake of soy products, such as tofu, but because of the rarity with which these plant foods were eaten, we were unable to evaluate associations in a meaningful manner (96 percent of men and 98 percent of women never ate soy products). Increasing intake of vegetables was associated inversely with colon cancer. Associations were strongest for older men, younger women, and those with proximal tumors (Table 2). High levels of whole grain consumption also were associated with decreased risk of colon cancer among men, with the strongest associations being for men who were older at diagnosis (OR = 0.6, CI - 0.4-0.9) or had distal tumors (OR = 0.7, CI = 0.5-1.0). Refined grains slightly increased risk of colon cancer among men. Nut and seed intakes were not associated with colon cancer risk. Among both men and women, higher levels of intake of canned fruit were associated directly with risk of proxi- mal tumors (Table 3). High intake of fresh fruit was assodated with a slight nonsignificant reduction in risk among women; among men, high intake of dried fruit was associated with a 30 percent reduction of risk of distal colon tumors. High levels of fruit juice were associated with a slight increased risk of colon cancer;, we could not identify any specific type of fruit juice which explained this association. Further assessment of types of fresh fruit (data not shown in table) showed a very modest non- significant reduction in risk associated with eating three or more apples/week relative to none (OR = 0.9 [CI = 0.7-1.1] for men and OR = 0.8 [CI = 0.7-1.1] for women). Among women, we also observed the following associa- tions: three or more citrus fruits/week relative to none was associated with decreased risk (OR = 0.8, CI = 0.6- 1.0) and eating apricots on a weekly basis relative to none was associated with decreased risk of proximal tumors (OR = 0.6, CI = 0.4-0.8). Specific vegetables which were associated inversely with colon cancer were: dark yellow vegetables, tomatoes, and salad greens (Table 4). Some differences by gender and tumor site were observed, with dark yellow vegetables being protective only in men, and tomatoes and salad greens being more inversely associated with proximal tumors. However, in all categories of vegetable consump- tion, levels of intake were generally low, with the upper group being four to five standard servings (a total of two to two and one-half cups of vegetables) per week. Plant foods contributed over 50 percent of several nutrients, including vegetable protein, dietary fiber, ~= carotene, vitamin C, folic acid, vitamin B6, thiamin, niacin, copper, and iron in the diets of the study population (Table 5); these dietary, constituents were chosen for further 578 Cancer Causes and Control. Vol 8. 1997

Plant, foods and colon cancer Table 1. Mean and standard deviation of plant foods and related nutrients in the US multicenter study population Men Women Cases Controls Cases Controls (n- 1,099) (n=~ 1,290) (n= 894) (n= 1,120) Mean (SD) Mean (SO) Mean (SO) Mean (SD) Foods (standard servings per day) Fruits 2.0 (1.8) 2.0 (1.7) 2.0 (1.5) 2.0 (1.6) Canned 0.4 (0.6) 0.4 (0.6) 0.4 (0.6) 0.4 (0.6) Fresh 1.5 (1.5) 1.5 (1.3) 1.5 (1.2) 1.5 (1.2) Dried 0.1 (0.4) 0.1 (0.3) 0.1 (0.3) 0.1 (0.6) Vegetables 3.4 (2.7) 3.7" (2.9) 3.6 (2.7) 3.7 (2.9) Legumes 0.2 (0.3) 0.2 (0.3) 0.1 (0.2) 0.1 (0.3) Juice Fruit 0.9 (1.0) 0.8 (1.1) 0.8 (0.9) 0,8 (0.9) Vegetable 0.1 (0.3) 0.1 (0.3) 0.1 (0.2) 0.1 (0.3) Grains Whole 1.4 (1.1) 1.6 (1.3) 1.2 (0.8) 1.2 (0.9) Refined 2.6 (1.6) 2.4 (1.6) 2.0 (1.3) 1.9 (1.3) Nuts and seeds 0.5 (0.8) 0.5 (0.7) 0.3 (0.5) 0.3 (0.4) Nutrients (Intake per day) Total energy (kcal) 2,752 (1,218) 2,651 (1,197) 2,066 (913) 1,991 (858) Vegetable protein(g) 33.2 (16.1) 33.1 (15.6) 26.8 (12.3) 26.6 (12.4) Fiber (g) Dietary fiber 26.5 (12.7) 27.0 (12.6) 22.8 (10.4) 22.9 (10.2) Soluble fiber 8.9 (4.3) 9.1 (4.4) 7.7 (3.5) 7.7 (3.5) Insoluble fiber 17.3 (8.5) 17.5 (8.2) 14.8 (6.9) 14.8 (6.7) Pectin 3.4 (2.2) 3.5 (2.2) 3.1 (1.7) 3.1 (1.6) Vitamins ~-c~rotene (mcg) 5,950 (6,808) 6,001 (5,036) 6,173 (5,106) 5,998 (5,042) Vitamin C (mg) 170 (115) 172 (109) 167 (98) 167 (95) Folic acid (mcg) 421 (208) 422 (201) 347 (156) 352 (159) Pantothenic acid (rag) 6.5 (2.9) 6.5 (2.9) 5.2 (2.3) 5.2 (2.3) Vitamin B~ (mg) 2.5 (1.1) 2.5 (1.1) 2.0 (0.8) 2.0 (0.8) Thiamin (mg) 2.2 (1.0) 2.2 (0.9) 1.7 (0.8) 1.7 (0.7) Riboflavin (rag) 2.7 (1.3) 2.7 (1.3) 2.1 (0.9) 2.1 (0.9) Niacin (mg) 28.5 (12.4) 27.8 . (12.5) 21.5 (8.9) 21.2 (8.7) Minerals Potassium (rag) 4,225 (1,782) 4,243 (1,767) 3,546 (1,439) 3,548 (1,385) Selenium (mcg) 155 (65) 152 (68) 120 (49) 118 (49) Magnesium (rag) 446 (191) 448 (185) 356 (145) 355 (141) Copper (mg) 2.0 (0.9) 2.0 (0.9) 1.6 (0.7) 1.6 (0.7) Iron (mg) 18.9 (8.2) 18.7 (8.3) 14.9 (6.5) 14.6 (6.4) Zinc (mg) 15.2 (6.9) 15.0 (7.1) 11.5 (5.3) 11.3 (5.0) SD = standard deviation. analyses. Whole grains were a major contributor of sde- nium in the diet of the study population as indicated by the database; however, vegetables were not. This may indicate the difficul .ty of capturing accurate selenium values, which are regionally variable, using standard nutrient databases. Total amounts of dietary, soluble and insoluble fiber, • ~nd pectin were associated inversely with colon cancer (Table 6). The strongest associations were observed for those diagnosed at an older age and those with proximal tumors. The association between total dietary fiber and colon cancer was as good an indicator of risk as either subtype of fiber, and, in many instances, the associations were stronger with dietary fiber than its component sub- types. The amount of dietary fiber per 1,000 kcal also was associated with colon cancer (data not shown in table) with associations being slightly stronger for men diag- nosed at a younger age (OR = 0.7, CI = 0.5-1.1) and for Cancer Cause~ and Contz'o|. Vo| ~. 1997 579

Table 2. Association between plant foods and colon cancer risk in the US multicenter study population Standard All subjects < 67 years 67+ years Distal Proximal servings/day OR= (Cl) OR: (CI) ORa (CI) OR= (CI) ORa (CI) Men (no. cases/controls) Fruits:b ~ 0.7 0.7-1.3 1.4-1.9 2.0-2.9 • 2.9 P trend Vegetables: < 1.5 1.6-2.5 2.6-3.4 3.5-5.2 • 5.2 P trend Whole grains: < 0.5 0.6-1.0 1.1-1.6 1.7-2.3 • 2.3 P trend Refined grains: < 1.1 1.2-1.8 1.8-2.6 2.7-3.4 > 3.4 P trend Nuts and seeds: None 0.1 -O,5 0.6-1.0 • 1.0 P trend Women (no. cases/controls) Fruits:b ~; 0,9 1.0-1.4 1.5-2.0 2.1-3.0 • 3.0 P trend Vegetables: < 1.7 1.8-2.6 2.7-3.7 3.8-5.2 • 5.2 P trend Whole grains: < 0.5 0.6-0.9 1.0-1.3 1.4-1.9 • 1.9 P trend 1.099/1,290 542/645 557/645 542/I .290 526/1.290 1.0 -- 1.0 -- 1.0 -- 1.0 -- 1.0 -- 1.1 (0.8-1.4) 1.1 (0.8-1.6) 1.0 (0.7-1.5) 1.1 (0.8-1.5) 1.1 (0.8-1.6) 1.1 (0.9-1.5) 1.1 (0.6-1.6) 1.1 (0.8-1.7) 1.0 (0.7-1.4) 1.3 (0.9-1.8) 1.1 (0.8-1.4) 1.2 (0.6-1.8) 1.0 (0.7-1.5) 0.9 (0.7-1.3) 1.4 (1.0-1.9) 1.1 (0.8-1.4) 1.2 (0.8-1.7) 0.9 (0.6-1.4) 1.1 (0.8-1.5) 1.1 (0.8L1.6) 0.74 0.56 0.24 0.58 0.98 1.0 -- 1.0 -- 1.0 -- 1.0 -- 1.0 -- 1,1 (0,9-1.4) 1..4 (0,9-2,0) 0.9 (0.6-1.3) 1,0 (0,7-1.3) 1,2 (0,9-1,6) 1.0 (0.8-1.3) 1.0 (0.7-1.5) 1.0 (0.7-1.4) 0.9 (0.7-1.3) 1.0 (0.7-1.4) 0.9 (0.7-1.2) 1.0 (0.7-1.4) 0.9 (0.6-1.3) 1.0 (0.7-1.3) 0.9 (0.6-1.3) 0.7 (0.5-0,9) 0.9 (0.6-1.3) 0.6 (0.4-0.9) 0.8 (0.6-1.2) 0.6 (0.4-0.8) < 0.01 0.06 0.02 0.10 < 0.01 1.o -- 1.o -- 1.o -- 1.o -- 1.o -- 0.9 (0.7-1.1) 0.9 (0.6-1.3) 0.8 (0.6-1.1) 0.9 (0.7-1.3) 0.8 (0.6-1.1) 1.1 (0.8-1,4) 1.3 (0.9-1.8) 0.S (0.6-1.2) 0.9 (0.7-1.3) 1.2 (0.9-1.6) 0.9 (0.7-1.2) 1.0 (0.7-1.4) 0.S (0.6-1.1) 0.9 (0.7-1.3) 0.9 (0.7-1.3) 0.8 (0.6-1.0) 0.9 (0.6-1.4) 0.6 (0.4-0.9) 0.7 (0.5-1.0) 0.S (0.6-1.2) 0.02 0.26 0.02 0.04 0.14 1.0 i 1.0 -- 1.0 -- 1.0 i 1.0 1.4 (1,1-1.9) 1.8 (1.2-2.7) 1,2 (0.9-1.8) 1.5 (1,0-2.1) 1.5 (1,1-2.1) 1.5 (1,1-1.9) 1,8 (1.2-2.7) 1.2 (0.9-1.8) 1.6 (1.1-2.3) 1.4 (1.0-2.0) 1.2 (0.9-1.6) 1.4 (0.9-2.2) 1,2 (0.8-1.7) 1.4 (1.0-2.1) 1.1 (0,6-1.6) 1.5 (1.1-2.1) 1.8 (1.2-2.7) 1.4 (0.9-2.2) 1,8 (1.2-2.6) 1.5 (1,0-2.1) 0.30 0.32 0.62 0,22 0.52 1.0 -- 1.0 -- 1.0 ~ 1.0 ~ 1.0 1,1 (0.8-1.2) 0,9. (0.6-1.2) 1,1 (0.8-1.4) 1.0 (0.7-1.3) 1.0 (0.7-1.3) 1.0 (0.8-1,3) 1.1 (0.7-1.6) 1.0 (0.7-1.4) 1.1 (0.6-1.5) 1,0 (0.7-1.4) 1.1 (0.8-1.4) 1.0 (0.6-1.4) 1.2 (0.8-1.8) 1.2 (0.6-1.7) 1.0 (0.7-1.4) 0.98 0.74 0.82 0.96 0.88 894/1,120 4491543 4451577 429/1,120 44611,120 1.0 -- 1.0 -- 1.0 ~ 1.0 ~ 1.0 1.2 (0.9-1.5) 1.0 (0.6-1.4) 1.6 (1.0-2.4) 1.2 (0.8-1.7) 1.1 (0.6-1.6) 1.0 (0.7-1.3) 0.S (0.6-1.3) 1.2 (0.8-1.8) 1.0 (0.7-1.5) 0.9 (0.6-1.3) 1.0 (0.7-1.3) 0.7 (0.5-1.1) 1.5 (1.0-2.3) 1.0 (0.6-1.4) 1.0 (0.7-1.5) 1.0 (0.7-1.4) 0.8 (0.5-1.2) 1.4 (0.9-2.1) 1.1 (0.7-1.6) 1.0 (0.7-1.5) 0.54 0.34 0.84 0.76 0.64 1.0 -- 1.0 ~ 1.0 -- 1.0 -- 1.0 0.9 (0.7-1.1) 0.7 (0.4-1.1) 1.0 (0.7-1.5) 0.9 (0.6-1.3) 0.8 (0.6-1.2) 0.9 (0.7-1.2) 0.7 (0.4-1.0) 1.2 (0.8-1.7) 0.9 (0.6-1.3) 0.9 (0.6-1.2) 0.7 (0.5-1.0) 0.7 (0.4-1.0) 0.S (0.5-1.1) 0.7 (0.5-1.0) 0.7 (0.5-1.0) 0.7 (0.5-1.0) 0.6 (0.4-0.9) 0.8 (0.6-1.3) 0.8 (0.6-1.2) 0.6 (0.4-0.9) 0.04 0.24 0.04 0.42 0.02 1.0 -- 1.0 -- 1.0 -- 1.0 -- 1.0 -- 1.4 (1.1-1.9) 1.5 (1.0-2.2) 1.3 (0.8-2.0) 1.4 (1.0-2.0) 1.4 (1.0-2.0) 1.3 (1.0-1.8) 1.3 (0.9-1.9) 1.3 (0.9-2.0) 1.4 (1.0-2.0) 1.3 (0.9-1.9) 1.4 (1.0-1.9) 1.4 (0.9-2.2) 1.4 (0.9-2.1) 1.6 (1.1-2.3) 1.2 (0.8-1.7) 1.0 (0.6-1.4) 1.1 (0.7-1.7) 1.0 (0.s-1.5) 1.2 (0.8-1.8) 0.9 (0.6-1.3). 0.56 0.92 0.42 0.56 0.18 580 Cancer Cause~ and Con~ro|. Vol 8. t997

Plans foods and colon cancer Table 2. Continued Standard All subjects < 67 years 67+ years Distal Proximal servings/day ORa (CI) ORa (Cl) ORa (CI) ORa (CI) ORa (CI) Refined grains: ~ 0.9 1.0 -- 1.0 -- 1.0 -- 1.0 ~ 1.0 -- 1.0-1.4 1.2 (0.9-1.6) 1.1 (0.7-1.8) 1,2 (0,8-1.8) 1.4 (0.9-2.0) 1.1 (0,7-1.5) 1.5-1.9 1.0 (0.7-1.4) 0.9 (0.6-1.4) 1.2 (0.8-1,8) 1.0 (0.7-1.5) 1.0 (0,7-1.5) 2.0-2.7 1.2 (0.9-1.6) 1.0 (0.6-1.6) 1.4 (0.9-2.2) 1.2 (0.8-1.7) 1.2 (0,8-1.7) > 2.7 1.1 (0.8-1.6) 1.1 (0.6-1.6) 1.3 (0.8-2.1) 1.0 (0.7-1.6) 1.2 (0,7-1.8) P trend 0.62 0.48 0.94 0.74 0.74 Nuts and seeds: None 1.0 -- 1.0 -- 1.0 -- 1.0 ~ 1.0 -- 0.1-0.2 1.2 (0.9-1,5) 1.4 (1.0-2.0) 1.1 (0.8-1.5) 0.9 (0.7-1.3) 1.5 (1,1-2.1) 0.3-0.5 1.0 (0.8-1.3) 1.2 (0.8-1.7) 0.9 (0.6-1.3) 0.8 (0.6-1.1) 1.3 (0,9-1.8) > 0.5 1.0 (0.8-1.5) 1.3 (0.9-1.9) 0.8 (0.5-1.2) 0.9 (0.7-1.3) 1.2 (0.8-1.7) P trend 0.52 0.48 0.94 0.74 0.74 OR = odds ratio; CI = 95% confidence interval. Model adjusted for age, body mass index (wtJht2 for men, wt/htl's for women), physical activity, use of aspirin/NSAID, presence or absence of a first-degree relative with colorectal cancer, total energy intake and calcium. Cut points based on quintile distribution in controls. Standard servings were equivalent to one-half cup of canned fruit, 1 medium piece of fresh fruit, one-quarter cup of dried fruit, one-half cup serving of vegetables, 2 slices of bread, 1 muffin, 1 biscuit, one-half cup pasta or rice, and one-quarter cup of nuts and seeds or 2 tbsp of peanut butter. Fruit and vegetable categories do. not include juice. distal tumors (OR = 0.6, CI = 0.4-0.9) than the compara- ble values for absolute amount of fiber consumed; for women, the associations when using density measures (OR = 0.6, CI = 0.4-1.3 for proximal tumors) were similar to those shown in Table 6. Dietary starch (data not shown in table) was not associated statistically significandy with colon Cance~ Associations between colon cancer and intake of other nutrients contributed by plant foods showed the follow- ing (Table 7): an inverse association for vegetable protein ~expressed as grams/I,000 kcal) among women, and an inverse association for high intake of vitamin B6 and thiamin, p-carotene was associated with an increased risk among women with proximal tumors. Dietary potassium, magnesium, selenium, iron, copper, and zinc were not associated consistently significantly with altered risk of colon cancer in either men or women (data not shown). We assessed the associations of plant foods with colon cancer after adjusting for types of fiber, vegetable protein, vitamins, and minera~ls found in plant foods. Results for aJl subjects are shown in Table 8. For the most part, there vcere few differences observed between colon cancer risk and plant foods with various types of adjustment. Adjustment for dietary fiber slightly decreased the risk associated with vegetables (OR = 0.7 when adjusted, and 0.8 when not adjusted) while adjustment of vegetables for vitamins actually increased the protective association (OR = 0.6 when adjusted for vitamins). \V4"e assessed the interaction between having a family history of a first-degree relative with colorectal cancer and intake of plant foods. In general, associations were as expected on an additive scale; plant foods were protective for those with a family history of colorectal cancer as well as for those without a family history of colorectal cancer. We did observe, however, that low levels of vegetable intake increased risk among those with a family history of colorectal cancer beyond that expected from the combined risk of family history of colorectal cancer and low vegetable intake on either the additive or multiplicative scales (Table 9). Among older women and those with distal tumors, there was significant improved fit of the model which included an interaction term for family history and vegetable consumption (P = 0.04 for both modds). Younger men who consumed a diet high in refined grains and who had a family history' of colo- rectal cancer had more than a sevenfold increase ~ risk compared with men who only ate a diet high in refined grains without a family history of colorectal (OR = 1.5) or who had a family history of colorectal cancer but ate low levels of refined grains (OR = 1.5). We observed no interaction between family history of colorectal cancer and consumption of other plant foods or nutrients commonly found in plant foods. Discussion Results from this study corroborate the findings of many other studies that increasing levels of vegetable intake are associated with a decreased risk of colon cancer, especially, for proximal tumors)"1° The associations between risk of colon cancer and whole grains and fruit intake are less consistent in the literature and in this population. We observed that whole grains appeared protective for men, especially those who were diagnosed at a younger age Cancer Causes and Control. Vol 8. 1997 581

M.L Slattet~ ~ ~1 Table 3. Colon cancer risk associated with various types of fruits in the US multicenter study population No. (cases/controls) = Men Women All subjects Distal Proximal All subjects Distal Proximal ORa (Cl) ORa (CI) ORa (Cl) ORa (CI) OR= (Cl) OR" (CI) (I ,099/1,290) (542/1,290) (52611,290) (894/1,120) (42911 ,I 20) (44611 ,I 20) Canned~ None 1.0 ~ t.0 m 1.0 ~ 1.0 ~ 1.0 ~ 1.0 m 0,1-0,6 1,0 (0,7-1.3) 0,8 (0,5-1,1) 1,3 (0,9-1,5) 1,1 (0,8-1,5) 1,1 (0,8-1,7) 1,0 (0,6-1,5) 0,7-1.8 0,9 (0,7-1.2) 0,8 (0,6-1,0) 1,2 (0,9-1,6) 1,1 (0,8-1,4) 0,9 (0,7-1,3) 1,2 (0,8-1,6) 1,9-4,2 1,0 (0,8-1,3) 0,8 (0,6-1,0) 1,4 (1,0-1.9) 1,0 (0,8-1,4) 0,9 (0,6-1,2) 1,1 (0,8-1,6) > 4,2 1,2 (0,9-1,5) 0,8 (0,6.1,1) 1,6 (1,3-2,4) 1,2 (0,9-1,6) 1,0 (0,7-1,4) 1,4 (1,0-1.9) P trend 0,90 0,14 0,16 0,44 0,50 0,30 Fresh <3.8 1.0 -- 1.0 ~ 1.0 -- 1.0 -- 1.0 -- 1.0 -- 3.9-7.0 1.2 (0.9-1.5) 1.1 (0.8-1.5) 1.4 (1.0-1.9) 0.9 (0.7-1.3) 0.8 (0.6-1.2) 1.0 (0.7-1.5) 7.1-10.3 1.1 (0.8-1.4) 1.0 (0.7-1.36) 1.3 (0.9-1.8) 0.8 (0.6-1.1) 0.9 (0.6-1.2) 0.8 (0.6-1.2) 10.4-15.2 1.1 (0.5-1.4) 1.0 (0.7-1.37) 1.2 (0.9-1,7) 1.0 (0.7-1.3) 1.0 (0.7-1.4) 1.0 (0.7-1.4) > 15.2 1.0 (0.8-1.3) 1.1 (0.8-1.45) 1.0 (0.7-1,5) 0.8 (0.6-1.1) 0.8 (0.6-1.2) 0.8 (0.6-1.2) P trend 0.98 0.46 0.86 0.78 0.72 0.48 Dried None 1.0 ~ 1.0 ~ 1.0 ~ 1.0 ~ 1.0 ~ 1.0 ~ 0.1-0.2 1.0 (0.6-1.8) 0.6 (0.3-1.4) 1.4 (0.8-2.7) 0.9 (0.6.1.4) 0.7 (0.4-1.4) 0.9 (0.5-1,6) 0.3-1,2 0.8 (0.7-1.0) 0.8 (0.6-1.1) 0.9 (0.6-1.2) 1.2 (0.9-1.6) 1.1 (0.8-1,S) 1.2 (0.9-1.7) > 1,2 0,7 .(0,6-0,9) 0,6 (0,5-0,9) 0,8 (0,6-1,0) 1,3 (1,0-1,6) 1,3 (1,0-1,8) 1.3 (0,9-1,7) P trend 0.10 0,02 0,96 0,54 0,96 0,44 Juice ~o.8 1.o -- 1.o -- 1.o -- 1,o -- 1.o -- 1.o -- 0.9-3.0 1,1 (0.8-1~4) 1.0 (0.7-1.4) 1.1 (0,8-1.5) 1.3 (0,9-1.7) 1.7 (0.2-2.5) 1.0 (0.7-1.5) 3.3-5.6 1.~. (1.1-1.9) 1.3 (0.9ol.7) 1.7 (1.2-2.4) 1.2 (0.9-1.6) 1.4 (0.9-2.0) 1.2 (0.8-1.7) 5.7-9.2 1,2 (0.9-1.5) 1.0 (0.7-1.3) 1.4 (1.0-2.00) 1.5 (1,1-1.9) 1.8 (1.2-2.6) 1.3 (0.9-1.8) > 9.2 1.2 (0,9-1.6) 1.1 (0.8-1.6) 1.3 (0.9-1.8) 1.3 (1.0-1.7) 1.5 (1.0-2.2) 1.2 (0.5-1.7) P trend 0.82 0.70 0.90 0.72 0.62 0.82 OR = odds ratio and CI = 95% confidence interval. Adjusted for age, body mass index (wtJht~ for men, wt/htl"s for women), lifetime vigorous leisure-time activity, presence or absence of a first-degree relative with colorectal cancer, use of aspirin/NSAIDs, dietary calcium, and energy intake. Standard servings of fruits/week based on the quintile distribution in the controls and were equivalent to one-half cup of canned fruit, 1 piece of fresh fruit, one-quarter cup of dried fruit, and 6 oz. of juice. and for those with distal tumors. We observed no asso- ciation with total fruit intake, although cerr~dn types of fruit, such as high consumption of dried fruit by men, were associated inversely with colon cancer. Plant foods are the custodians of numerous dietary constituents, including vitamins, minerals, fiber, and other potentially antic~rcinogerdc factors. The anticarcinogenic properties of vegetables could be attributed, at least in part, to fiber, vitamin, or mineral content, or to other bioactive compounds. Dithiolthiones, glucosinolates, indoles, isothiocyanates and thiocyanates, flavonoids, and phenols found in plant foods, are potentially anficarcino- genic.7 However, these bioactive compounds are unavailable in standard nutrient databases, leaving assess- ment of foods which contain these compounds as a surrogate for their intake. Evaluation of specific fruits and vegetables indicated food-specific associations with colon cancer. Apricots, carrots, and tomatoes were associated inversely with colon cancer, sugge.sting that carotenoids such as lycopene may be protective for colon cancer. Cruciferous vegetables have been associated with colon cancer in some studies and, in this study, showed ordy a slight inverse association. These vegetables contain indoles and glucosinolates which have demonstrated chemoprevendve potential from studies in animals and call systems,zs Whether observed site-specific associations for various fruit and vegetable groups suggest that specific bioacdve components of fruits and vegetables have unique properties and mechanisms which alter risk of colon cancer or whether this is chance variation remains to be elucidated. The finding that canned fruit and iuice were associated with a slight increased risk of colon cancer in both genders suggests a possible role for sugar in colon caa'cinogenesis

Plant foods and colon cancer Table 4. Colon cancer risk associated with various types of vegetables in the US multicenter study population standard servings/ week No, (cases/controls) = Men Women All subjects Distal Proximal All subjects 01stal Proximal OR" (Cl) OR= (Cl) OR" (Cl) OR" (Cl) OR" (Cl) OR= (Cl) (1,09911,290) (542/1,290) (526/1,290) (894/1,1 20) (429/1,120) (44611,120) "~egumes2 None 1.0 -- 1.0 ~ 1.0 ~ 1.0 w 1.0 ~ 1.0 -- 0.I-1.0 1,1 (0.9-1.4) 1.2 (0.9-1.5) 1.2 (0.9-1.6) 1.0 (0,6-1.3) 1.0 (0.7-1.3) 1.1 (0.8-1.4) > 1.0 1,1 (0.9-1.4) 1.1 (0.8-1.4) 1.2 (0.9-1.7) 0.9 (0,7-1.1) 1.0 (0.7-1.3) 0.8 (0.6-1.1) P trend 0,72 0.78 0.76 0.04 0.14 0.14 Dark yellow None 1.0 -- 1.0 -- 1.0 -- 1.0 -- 1.0 -- 1.0 -- 0.1-1.5 0.9 (0.6-1.1) 0.8 (0.6-1.0) 1.0 (0.7-1.4) 1.0 (0.8-1.4) 1.2 (0.8-1.8) 0.9 (0.6-1.3) 1.6-4.0 0.9 (0.7-1.2) 0.8 (0.6-1.2) 1.0 (0.7-1.4) 1.0 (0.7-1.3) 1.1 (0.7-1.7) 0.9 (0.6-1.3) • 4.0 0,7 (0.6-1.0) 0.7 (0.5-1.0) 0.8 (0.5-1.1) 0.9 (0.6-1.3) 1.1 (0.7-1.7) 0.8 (0.5-1.2) P trend 0.14 0.28 0.34 0.28 0.96 0.18 Tomatoes None 1.0 ~ 1.0 ~ 1.0 ~ 1.0 ~ 1.0 ~ 1.0 ~ 0.1-2.0 0.9 (0.7-~1.1) 0.8 (0.6-1.1) 0.9(0.8-1.2) 1.0 (0.8-1.3) 1.2 (0.8-1.7) 0.9 (0.6-1.2) 2.1-4.0 0.9 (0.7-1.1) 1.0 (0.7-1.4) 0.8 (0.6-1.1) 0.8 (0.6-1.1) 1,0 (0.6-1.5) 0.7 (0.5-1.0) • 4.0 0.6 (0.4-0.8) 0.7 (0.5-1.1) 0.4 (0.3-0.7) 0.9 (0.6-1.3) 1,2 (0.8-1.9) 0.8 (0.5-1.2) P trend 0.06 0.72 < 0.01 0.20 0,12 0.06 Cruciferous None 1.0 -- 1.0 -- 1.0 -- 1.0 -- 1.0 -- 1.0 ~ 0.1-1.0 1.0 (0.8-1,4) 0.9 (0.6-1.3) 1.2 (0.6-1.7) 1.0 (0.7-1,5) 1.1 (0,7-1.8) 0.9 (0.6-1.4) 1.1-3.0 1.1 (0.9-1,5) 1.0 (0.7-1.4) 1.3 (0.9-1.8) 1.0 (0.7-1.4) 0.9 (0.6-1.5) 1.0 (0.7-1.5) 3.1-5.5 0.9 (0.7-1,2) 0.9 (0.6-1.2) 0.9 (0.6-1.4) 1.0 (0.7-1.4) 0.9 (0.6-1.4) 1.0 (0.7-1.6) • 5.5 0.8 (0.6-1.1) 0.8 (0.6-1.2) 0.8 (0.5-1.1) 1.0 (0.7-1.8) 1.2 (0.7-13) 0.9 (0.6-1.4) P trend 0.08 0.14 0.24 0.68 0.54 0.96 Salad greens < 1.0 1.0 -- 1.0 -- 1.0 ~ 1.0 ~ 1.0 ~ 1.0 ~ 1.1-2.0 1.0 (0.8-1.3) 1,0 (0.7-1.4) 1.0 (0.7-1.4) 1.2 (0.8-1.6) 1.1 (0.7-1.7) 1.2 (0.8-1.7) 2.1-3.0 1.0 (0.7-1.3) 1,0 (0.7-1.5) 0.9 (0.6-1.3) 0.8 (0.6-1.1) 0.9 (0.6-1.3) 0.8 (0.5-1.2) 3.1-5.0 0.8 (0.6-1.0) 0.8 (0.6-1.1) 0.8 (0.6-1.1) 1.0 (0.7-1.3) 1.0 (0.7-1.4) 1.0 (0.7-1.4) > 5,0 0.8 (0.6-1.1) 0.9 (0.7-1.3) 0.7 (0.5-0.9) 0.7 (0.5-1.0) 0.7 (0.5-1.0) 0.7 (0.5-1.0) P trend 0.02 0.22 0.34 0.04 0.04 0.22 Vegetable juice None 1.0 ~ 1.0 ~ 1.0 ~ 1.0 -- 1.0 ~ 1.0 ~ 0.1-1.0 1.0 (0.8-1.2) 0.9 (0.6-1.2) 1.1 (0.8-1.5) 0.9 (0.7-1.2) 0.8 (0.6-1,2) 1.0 (0.7-1.4) > 1.0 1.2 (0.9-1.5) 1.1 (0.9-1.5) 1.3 (1.0-1.7) 1.2 (0.9-1.5) 1.2 (0.9-1,6) 1.2 (0.9-1.6) ~ trend 0.80 0.80 0.98 0.94 0.60 0.62 OR = odds ratio and CI = 95% confidence interval. Adjusted for age, body mass index (wt/ht~ for men, wt/ht1"5 for women), lifetime vigorous leisure-time activity, presence or absence of a first-degree relative with colorectal cancer, use of aspirin/NSAIDs, dietary calcium, and energy intake. Legumes include bean soup, split peas, lentils and other dry beans; dark yellow vegetables include carrots, winter squash, yams: tomatoes include fresh, canned or cooked tomatoes; cruciferous includes cabbage, Brussels sprouts, broccoli, parsnips, rUtabagas, turnips, and cauliflower; salad greens include all types of lettuce, raw spinach, and salad greens. Standard servings per week were based on one-half cup of servings of legumes, dark yellow vegetables, tomatoes, cruciferous vegetables, 1 cu~ of salad greens, and 6 oz. of vegetable juice. rs Causes ~d Control. VoI 8. 1997 583

Table 5. Percent of nutrients in the diet contributed by plant products in the US multicenter study population Men Fruits Vegetables Whole Nuts Refined Total Fruits Vegetables grains grains (%)" (%) (%) (%) (%) (%) (%)" (%) Worglel~ Whole grains (%) Nuts (%) Refined grains (%) Total (%) Energy 9.7 5.7 7.6 Vdgetable protein 8.1 16.6 20.5 Fiber (g) Dietary fiber 18.7 23.1 20.1 Soluble fiber 22.6 23.7 14.3 Insoluble fiber 17.0 22.8 23.3 Pectin 39.5 30.9 1.4 Vitamins J~-carotene 11.2 " 56.1 0.1 Vitamin C 51.2 25.2 3.0 Vitamin E 11.3 9.7 8.4 Folio acid 16.8 21.2 20.3 Pantothenic acid 9.9 13.8 8.0 Vitamin Be 18.0 15.2 15.0 Thiamin 9.7 10.1 18.8 Riboflavin 6.0 6.6 13.2 Niacin 4.9 8.2 16.6 Minerals Potassium 7.3 1.3 13.9 Selenium 18.6 15.9 5.4 Magnesium 10.2 11.9 15,0 Copper 12.0 17.2 11.6 Iron 5.6 12.1 21.9 Zinc 2,6 8.1 12.9 3,6 12,5 39.1 12.9 7.0 8.0 2.9 12.3 43.1 9.5 26.9 81.6 10,2 19.6 20.9 7.3 25.2 83.2 4,5 11.6 78.0 22,4 26.3 19,3 3.2 10.6 81.8 2.5 13.9 77.0 27.0 26.8 13.3 1.7 12.4 81,2 4.9 10.6 78.6 20.5 25.9 22.7 3.5 9.8 82.4 6.1 0.7 78.6 44.2 35.1 1.2 3.9 0.6 85.0 0.1 0,4 67,8 12.2 61.8 0.1 < 0.1 0.3 74.4 0.1 2.2 81.6 54,6 27.7 3.0 < 0.1 1.7 87.0 13.4 5.0 47.8 14.5 12.4 8.8 10.0 4.9 50.6 3.5 13.0 74.8 19.4 25.8 18.1 2.6 11.4 77,3 3.3 8.0 43.0 12.7 16.8 8.1 2.4 7.6 47.6 2.3 8.5 59.0 22,4 18.8 13.1 1.7 7.6 63.6 2.9 22.4 63.9 12.3 12.5 18.5 2.1 21.1 66.5 1.1 13.4 40.3 7.9 8,8 12.6 0.8 12.6 42.7 5.3 17.9 52.9 6.5 10.4 16.1 4.4 17.1 54.5 1.3 21.3 45.1 6.0 4.8 15.0 0.9 20.8 47.5 2.6 3.9 46.4 21.9 18.9 5.1 1.9 3.6 51.4 6.8 7.6 51.5 12.9 14.3 15.0 5.0 7.2 54.4 8.1 8.9 57.8 15.4 20.4 11.6 5.8 7.8 61.0 2.5 19.9 62.0 7.3 14.6 21.8 1.9 19.4 65.0 4.2 7.8 35.6 3.6 9.5 13.2 3.2 7.8 37.3 Percent of total nutrient intake,

Plant foods and colon cancer Table 6. Association between colon cancer and fiber in the US multicentar study population All subjects < 67 years 67+ years Distal Proximal OR= (CI) OR= (CI) OR" (CI) OR" (CI) OR" (CI) Men (no. cases/controls) 1,099/1.290 542/645 557/645 542/1,290 526/1,290 Dietary fiber (g) < 17.2 1.0 w 1.0 ~ 1.0 w 1.0 Q 1.0 -- 17.3-22.3 0.9 (0.7-1.2) 0.9 (0.6-1.4) 0.8 (0.6-1.2) 0.8 (0.6.1.1) 1.0 (0.8-1.4) 22.4-27.5 0.9 (0.7-1,1) 0.9 (0.6-1.4) 0.8 (0.6-1.2) 0.8 (0.6-1.1) 0.9 (0.7-1.3) 27.6-34.5 0,9 (0,7-1.2) 0.9 (0.6-1.4) 0,9 (0.6-1,4) 0,9 (0.6-1.2) 1.0 (0.7-1,4) > 34.5 0,7 (0.5-1.0) 0.9 (0.6-1.5) 0.5 (0.3-0.9) 0.8 (0.5-1.3) 0.6 (0.4-1.0) P trend 0.16 0.34 0.10 0.56 0.10 Soluble fiber(g) <5.6 1.0 ~ 1.0 -- 1.0 ~ 1.0 ~ 1.0 -- 5.7-7.4 1.0 (0.8-1.3) 1.0 (0.7-1.5) 1.0 (0.7-1.4) 1.0 (0.7-1,4) 1.0 (0,7-1.4) 7.5-9.1 1,0 (0.7-1.3) 1.0 (0.7-1.5) 0.9 (0.6-1.3) 0.8 (0.6-1,2) 1.0 (0.7-1.4) 9.2-11.7 0,8 (0.6-1.1) 0.9 (0.6-1.4) 0.7 (0.5-1.1) 0.8 (0.6-1.1) 0.9 (0.7-1.3) > 11.7 0,8 (0.6-1.1) 1.0 (0.6-1.6) 0.6 (0.3-0.9) 0.9 (0.6-1.4) 0.6 (0.4-1.0) P trend 0.08 0.32 0.02 0.38 0.10 Insoluble fiber(g) < 11.0 1.0 w 1.0 Q 1.0 -- 1.0 w 1.0 w 11.1-14.4 0.9 (0.7-1.2) 1.0 (0.7-1.5) 0:8 (0.5-1.1) 0.8 (0.5-1.1) 1.0 (0.7-1.4) 14.5-17.8 0.8 (0.6-1.1) 0.9 (0.6.1.3) 0.8 (0.6-1.2) 0.8 (0.6-1.1) 0.9 (0.6-1.2) 17.9-22.5 1.0 (0.7-1.3) 1.0 (0.7-1.5) 0.9 (0.6-1.3) 1,0 (0.7-1.4) 0.9 (0.7-1.3) > 22.5 0.7 (0.5-1.0) 0.8 (0.5-1.3) 0.6 (0.4-0.9) 0.8 (0.5-1.2) 0.6 (0.4-1.0) P trend 0.16 0.34 0.14 0.66 0.08 Pectin (g) ~1.9 1.0 -- 1.0 ~ 1.0 -- 1.0 ~ 1.0 ~ 2.0-2.7 0.9 (0.7-1,.1) 0.7 (0.5-1.0) 1.0 (0.7-1.4) 0.8 (0.6-1.1) 0.9 (0.6-1.2) 2.8-3.5 0.9 (0.7-1.2) 0.9 (0.6-1.3) 0.9 (0.6-1.3) 0.9 (0.6-1.2) 1.0 (0.7-1.4) 3.6-4.7 0.8 (0.6-1.0) 0.7 (0.5-1.0) 0.9 (0.6-1.3) 0.7 (0.5-1.0) 0.8 (0.6-1.1) > 4.7 0.7 (0.5-0.9) 0.7 (0.5-1.1) 0.6 (0.5-0.9) 0.8 (0.6-1.2) 0.5 (0.4-0.8) P trend 0.02 0.36 0.02 0.20 0.02 Women (no. cases/controls) 89411120 4491543 446/577 429/1.120 446/1.120 Dietary fiber (g) ~ 14.5 1.0 ~ 1.0 -- 1.0 ~ 1.0 ~ 1.0 -- 14.6-18.9 1.1 (0.9-1.5) 1.3 (0.8-1.9) 1.1 (0.7-1.6) 1.2 (0.8-1.8) 1.1 (0.8-1.6) 19.0-23.3 0.8 (0.6-1.1) 0.9 (0.5-1.3) 0.8 (0.5-1.2) 1.0 (0.7-1.5) 0.7 (0.5-1.0) 23.4-30.3 0.9 (0.7-1.3) 1.0 (0.6-1,6) 0.9 (0.6-1.4) 1.1 (0.8-1.7) 0.8 (0.6-1.2) • 30.3 0.8 (0.5-1.1) 0.9 (0.5-1,5) 0.7 (0.4-1.2) 1.2 (0.8-1.9) 0.5 (0,3-0.9) P trend 0.12 0.42 0.18 0.62 0.02 Soluble fiber(g) ~4.8 1.0 -- 1.0 ~ 1.0 ~ 1.0 ~ 1.0 w 4.9-6.4 1.1 (0.8-1.4) 1.0 (0.7-1.6) 1.3 (0.6.1.8) 1.1 (0.7-1.5) 1.1 (0.8-1.6) 6.5-7.8 0.8 (0.6.1.1) 0,7 (0.4-1.0) 1.0 (0.7-1.6) 0.8 (0.6-1.2) 0.8 (0.5-1.2) 7.9-10.1, 0.9 (0.6.1.2) 0,8 (0.5-1.3) 1.0 (0.6.1.5) 1.0 (0.7-1.5) 0.8 (0.6-1.2) • 10.1 0.7 (0.5-1.1) 0,7 (0.4-1.2) 0.8 (0.6.1.4) 0.9 (0.6-1.4) 0,6 (0.4-1.0) P trend 0.06 0,10 0.40 0.60 0,02 Insoluble fiber (g) ~; 9.5 1.0 -- 1.0 -- 1.0 ~ 1.0 ~ 1.0 -- 9.6-12.2 1.0 (0.7-1.3) 1.1 (0.7-1.6) 0.9 (0.6-1.3) 1.0 (0.7-1.5) 0.9 (0.7-1.3) 12.3-15.0 0.8 (0.6-1.0) 0.7 (0.5-1.1) 0.8 (0.6-1.3) 0.9 (0.6-1.3) 0.7 (0.5-1.0) 15.1-19.8 0.8 (0.6.1.1) 1.0 (0.6-1.6) 0.7 (0.5-1.1) 1.0 (0.7-1.5) 0.7 (0.5-1.1) • 19.8 0.7 (0.5-0.9) 0.7 (0.4-1.1) 0.6 (0.4-1.1) 1.0 (0.6-1.6) 0.5 (0.3-0.7) P trend 0.02 0.18 0.08 0.98 < 0.01 Pectin (g) ~;1.8 1.0 ~ 1.0 -- 1.0 ~ 1,0 Q 1.0 -- 1.9-2,4 0.8 (0.6.1.1) 1.0 (0.6-1.4) 0.7 (0.5-1.0) 0.9 (0.6-1.3) 0.8 (0.5-1.1) 2.5-3.2 0.9 (0.7-1.2) 0.9 (0.6-1.3) 0.9 (0,6-1.4) 0.9 (0.6-1.2) 0.9 (0.7-1.3) 3.2-4,2 0.7 (0.5-1.0) 0.7 (0.5-1.1) 0.8 (0,5-1.1) 0.8 (0.6-1.2) 0.7 (0.5-I.0) > 4.2 0.8 (0.6-1.1) 0.8 (0.5-1.3) 0.8 (0,5-1.3) 1.0 (0.6-1.4) 0.7 (0.5-1.1) P trend 0.10 0.18 0.38 0.68 0.08 OR = odds ratio; CI = 95% confidence interval. Model adjusted for age. body mass index (wt/ht~ for men, wt/ht1"s for women). lifetime vigorous leisure time physical activity, use of aspirin/NSAIDs, presence or absence of a first-degree relative with colorectai cancer, total energy intake, arid calcium. Czacer C=uses a~d Control. Vol 8. 1997 585

Table 7. Associations between colon cancer and nutrients found in the US multicenter study population No. (cases/controls) = Men Women All subjects Distal Proximal All subjects Distal Proximal OR" (Cl) OR" (Cl) OR= (Cl) OR= (el) OR= (Cl) OR" (Cl) (I ,096/1,290) (542/1,290) (526/1,290) (894/1,120) 142911,120) (446/1 ,I 20) Vegetable proteinb Low 1.0 m 1.0 m 1.0 -- 1.0 m 1.0 -- 1.0 -- 2 1.2 (0.9-1.5 1.1 (0.8-1.5) 1.3 (1.0-1.8) 0.8 (0.6-1.1) 0.9 (0.6-1.3) 0.8 (0.6-1.2) 3 1.0 (0.8-1.3) 0.9 (0.6-1.2) 1.2 (0.6-1.7) 0.9 (0.7-1.2) 0.S (0.5-1.1) 1.0 (0.7-1.4) 4 1.0 (0.8-1.4) 1.1 (0.7-1.5) 1.0 (0.7-1.5) 0.7 (0.5-1.0) 0.7 (0.4-1.0) 0.8 (0.5-1.2) High 0.9 (0.7-1.3) 0.9 (0.6-1.4) 1.0 (0.7-1.6) 0.7 (0.5-1.0) 0.7 (0.5-1.2) 0.7 (0.4-1.2) P trend 0.46 0.56 0.64 0.04 0.08 0.20 Vitamins ~-carotene Low 1.0 ~ 1.0 ~ 1.0 -- 1.0 ~ 1.0 ~ 1.0 -- 2 1.1 (0.8-1.4) 1.0 (0.7-1.4) 1.3 (0.9-1.7) 1.0 (0.7-1.3) 0.8 (0.5-1.1) 1.2 (0.6-1.7) 3 0.9 (0.7-1.1) 0.7 (0.5-1.0) 1.1 (0.7-1.5) 1.2 (0.9-1.6) 1.0 (0.7-1.4) 1.5 (1.0-2.1) 4 1.2 (0.9-1.6) 1.2 (0.8-1.6) 1.3 (0.9-1.8) 1.1 (0.8-1.5) 0.9 (0.6-1.3) 1.4 (0.9-2.1) High 1.1 (0.6-1.5) 1.2 (0.8-1.7) 1.2 (0.8-1.7) 1.3 (0.9-1.8) 1.1 (0.7-1.7) 1.7 (1.1-2.8) P trend 0.40 0.36 0.44 0.16 0.64 0.03 Vitamin C Low 1.0 -- 1.0 -- 1.0 -- 1.0 -- 1.0 ~ 1.0 -- 2 0.9 (0.7-1.2) 0.8 (0.6-1.1) 1.0 (0.7-1.4) 1.1 (0.8-1.5) 1.3 (0.9-1.9) 1.0 (0.7-1.4) 3 1.1 (0.8-1.4) 1.0 (0.7-1.4) 1.1 (0.8-1.6) 1.1 (0.8-1.4) ~.2 (0.8-1.8) 1.0 (0.7-1.4) 4 1.0 (0.6-1.3) 0.9 (0.6-1.3) 1.0 (0.8-1.6) 1.2 (0.9-1.6) 1.2 (0.8-1.7) 1.3 (0.9-1.8) High 0.9 (0.6-1.2) 0.9 (0.6-1.3) 0.8 (0.6-1.3) 1.0 (0.7-1,4) 0.9 (0.6-1.5) 1.1 (0.7-1,8) P trend 0.64 0.76 0.78 0.90 0.68 0.30 Folic acid Low 1.0 m 1.0 -- 1.0 -- 1.0 -- 1.0 m 1.0 -- 2 1.3 (1.0-1.7) 1.4 (1.0-1.9) 1.3 (0.9-1.8) 0.9 (0.7-1.2) 0.7 (0.5-1.0) 1.2 (0.8-1.7) 3 1.1 (0.6-1,4) 1.0 (0.7-1.5) 1.0 (0.7-1,5) 1.0 (0.7-1.4) 0.8 (0.6-1.2) 1.3 (0.9-1.9) 4 0.9 (0.7-1.2) 0.8 (0.7-1.3) 1.0 (0.7-1.4) 0.9 (0.6-1.1) 0.7 (0.5-1.0) 1.0 (0.7-1.6) High 1.2 (0.8-1.6) 1.2 (0.8-1.7) 1.2 (0.8-1.9) 0.9 (0.6-1.3) 0.7 (0.4-1.0) 1.2 (0.8-1.9) P trend 0.70 0.58 0.88 0.38 0.10 0.56 Vitamin Bs Low 1.0 ~ 1.0 -- 1.0 ~ 1.0 ~ 1.0 ~ 1.0 -- 2 0.9 (0.7-1.2) 1.0 (0.7-1.4) 0.8 (0.6-1,1) 0.7 (0.5-0.9) 0.6 (0.4-0.8) 0.7 (0.5-1.0) 3 0.9 (0.7-1.1) 0.9 (0.7-1.2) 0.8 (0.6-1.1) 0.7 (0.5-0.9) 0.6 (0.5-0.9) 0.7 (0.5-1.0) 4 0.8 (0.6-1.0) 0.9 (0.7-1.3) 0.7 (0.5-0.9) 0.7 (0.6-1.0) 0.6 (0.4-0.9) 0.8 (0.6-1.2) High 0.7 (0.6-1.0) 0.7 (0.5-0.9) 0.8 (0.6-1.1) 0.6 (0.5-0.8) 0.6 (0.4-0.8) 0.6 (0.4-0.9) P trend < 0.01 0.02 0.10 < 0.01 < 0.01 0.08 Thiamin Low 1.0 -- 1.0 -- 1.0 -- 1.0 -- 1.0 -- 1.0 ~ 2 0.8 (0.6-1.0) 0.8 (0.6-1.1) 0.7 (0.5-1.0) 0.9 (0.7-1.2) 0.8 (0.6-1.1) 1.0 (0.7-1.4) 3 0.8 (0.6-1.1) 0.8 (0.6-1.1) 0.9 (0.6-1.2) 0.8 (0.6-1.1) 0.6 (0.4-0.8) 1.1 (0.8-1.5) 4 0.7 (0.6-0.9) 0.7 (0.5-1.0) 0.7 (0.6-1.0) 0.9 (0.7-1.2) 0.8 (0.6-1.2) 1.0 (0.7-1.5) High 0.7 (0.5-0.9) 0.6 (0.4-0.9) 0.8 (0.6-1.2) 0.7 (0.5-0.9) 0.6 (0.4-0.9) 0.7 (0.5-1.0) P trend < 0.01 < 0.01 0.26 0.02 0.03 0.18 Niacin Low 1.0 ~ 1.0 ~ 1.0 ~ 1.0 ~ 1.0 ~ 1.0 ~ 2 1.1 (0.6-1.4) 1.0 (0.8-1.4) 1.0 (0.8-1.4) 0.8 (0.6-1.0) 0.9 (0.6-1.3) 0.6 (0.4-0.9) 3 0.9 (0.7-1.2) 0.9 (0.7-1.3) 0.8 (0.6-1.2) 0.9 (0.7-1.2) 1.0 (0.7-1.4) 0.8 (0.6-1.2) 4 1.0 (0.8-1.4) 1.2 (0.8-1.6) 0.9 (0.6-1.3) 0.9 (0.7-1.2). 0.8 (0.5-1.1) 1.0 (0.7-1.4) High 1.0 (0.7-1.3) 1.0 (0.7-1.4) 0.9 (0.7-1.3) 0.8 (0.6-1.0) 0.8 (0.5-1.1) 0.7 (0.5-1.1) P trend 0.72 0.86 0.46 0.22 0.18 0.54 OR = Odds ratio; CI = confidence interval. Model adjusted for age, body mass index (wt/ht2 for men, wt/ht~'s for women), lifetime vigorous leisure time physical activity, use of aspirin/NSAIDS, presence or absence of a first-degree relative with colorectal cancer, total energy intake, and calcium. The cut points for men are as follows: Vegetable protein (g/1,000 Kcal): 9.99, 11.9, 13.4, 15.3; ~-carotene (mcg): 2,538, 3,884, 5,483, 8,475; Vitamin C (mg): 92.4, 128.2, 169.7, 240.4; Folic acid (mcg/1,000 Kcal): 120, 140, 170, 210; B6 (mg/1,000 Kcal): 0.75, 0.87, 1.01, 1.18; Thiamin (mg/1,000 Kcal): 0.69, 0.77, 0.85, 0.96; Niacin (mg/1,000 Kcal): 8.67, 9.87, 11.0, 12.6. For women: Vegetable protein (g/1,000 Kcal): 10.9, 12.5, 14.1, 15.8; I~carotene (mcg): 25.78, 3884, 5609, 8369; Vitamin C (mg): 90.9, 130.2, 168.8, 230.6, Folic acid (mcg/1,000 Kcal): 130, 160, 190, 230; B6 (mg/t,000 Kcal): 0.82, 0.96, 1.08, 1.28; Thiamin (mg/1,000 Kcal): 0.71, 0.79, 0.87, 0.99; Niacin (rag/1,000 Kcal): 8.9, 9.9, 11.2, 12.8. 586 C.~c.er C~u=e~ ~d Conu'oL Vol 8. 1997

Plant foods and colon cancer Table 8. Associations between colon cancer and plant foods adjusting for nutrients found in plant foods in the US multicenter study population Adlustment Men Women Dietary fiber Vegetable Vitamins Dietary fiber Vegetable Vitamins protein protein OR" (Cl) OR" (CI) OR" (Ci) ORa (el) OR= (Cl) OR= (CI) No. (cases/controls) - (1,09911,290) (1,099/1,290) (1,099/1,290) (894/1,120) (894/1,120) (894/1,120) Fruits Low 1.0 i 1.0 i 1.0 -- 1.0 -- 1.0 -- 1.0 -- 2 1.1 (0.9-t.5) 1.1 (0.8-1.4) 1.1 (0.8-1.4) 1.2 (0.9-1.6) 1.2 (0.9-1.5) 1.2 (0.9.1.5) 3 1.2 (0.9-1.6) 1.2 (0.9-1.6) 1.2 (0.9-1.5) 1.0 (0.8-1.4) 1.0 (0.7-1.3) 1.0 (0.7-1.3) 4 1.2 (0.9.1.6) 1.1 (0.9-1.5) 1.1 (0.9.1.5) 1.1 (0.8-1.5) 1.0 (0.8-1.4) 1.0 (0.7-1.4) High 1.3 (1.0-1.8) 1.1 (0.9-1.5) 1.2 (0.8-1.6). 1.2 (0.9-1.7) 1.1 (0.8-1.5) 1.0 (0.7-1.5) Vegetables Low 1.0 ~ 1.0 ~ 1.0 w 1.0 w 1.0 ~ 1.0 -- 2 1.1 (0.9-1.5) 1.1 (0.9-1.4) 1.1 (0.9-1.4) 0.9 (0.7-1.2) 0.9 (0.7-1.2) 0.9 (0.6-1.1) 3 1.0 (0.8-1.3) 1.0 (0.8-1.3) 1.0 (0.8-1.3) 0.9 (0.7-1,2) 0.9 (0.7-1.2) 0.9 (0.7-1.2) 4 1.0 (0.8-1.3) 1.0 (0.7-1.3) 0.9 (0.7-1.2) 0.8 (0.6-1.0) 0.8 (0.6-1.0) 0".7 (0.5-1.0) High 0.8 (0.5-1.1) 0.7 (0.5-1.0) 0.6 (0.5-0.9) 0.8 (0.5-1.1) 0.8 (0.6-1.1) 0.6 (0.4-0.9) Whole grains Low 1.0 w 1.0 w 1.0 ~ 1.0 ~ 1.0 ~ 1.0 ~ 2 0.9 (0.7-1.1) 0.9 (0.7-1.1) 0.8 (0.7-1.1) 1.5 (1.1-2.0) 1,5 (1.1-2.0) 1.5 (1.1-2.0) 3 1.1 (0.9-1.4) 1.1 (0.8-1.4) 1.0 (0.8-1.4) 1.5 (1.1-1.9) 1.5 (1.1-2.0) 1.5 (1.1-2.0) 4 1.0 (0.7-1.3) 1.0 (0.7-1.3) 0.9 (0.7-1.2) 1.5 (1.1-2.1) 1.6 (1.2-2.1) 1.5 (1.1-2.1) High 0.9 (0.6-1.2) 0.8 (0.6-1.1) 0.8 (0.6-1.0) 1.2 (0.9.1.7) 1.3 (0.9-1.7) 1.2 (0.6-1.6) Refined grains Low 1.0 ~ 1.0 ~ 1.0 ~ 1.0 ~ 1.0 ~ 1.0 -- 2 1.4 (1.1-1.8) 1.4 (1.1-1.9) 1.4 (1.1-1.9) 1.2 (0.9-1.6) 1.2 (0.9-t .6) 1.2 (0,9-1.6) 3 1.4 (1.1-1.9) 1.5 (1.1-2.0) 1.5 (1.2-1.9) 1.0 (0.7-1.3) 1.0 (0.6-1.4) 1.0 (0.7-1.3) 4 1.2 (0.9-1.6) 1.3 (1.0-1.7) 1.2 (0.9-1.6) 1,1 (0.9-1.6) 1.2 (0.9-1.6) 1,2 (0.9-1.6) High 1.5 (1.1-2.0) 1.6 (1.2-2.3) 1.5 (1.1-2.1) 1.1 (0.8-1.5) 1.2 (0.8-1.7) 1.1 (0.8-1.6) Nuts and seeds: Low 1.0 ~ 1.0 ~ 1.0 ~ 1.0 -- 1.0 ~ 1.0 -- 2 0.9 (0.8-1.1) 0.9 (0.8-1.1) 0.9 (0.7-1.1) 1.2 (1.0-1.5) 1.2 (1.0-1.5) 1.2 (1.0-1.4) 3 1.1 (0.8-1.5) 1.1 (0.8-1.5) 1.1 (0.8-1.4) 0.9 (0.7-1.3) 0.9 (0.7-1.3) 0.9 (0.7-1.3) High 1.0 (0.7-1.4) 1.0 (0.7-1.4) 0.9 (0.6-1.2) 1.2 (0.8-1.7) 1.3 (0.9-1.8) 1.1 (0.8-1.6) a OR = odds ratio; CI = 95% confidence intervals. All models are adjusted for age, body mass index (wt/ht2 for men, wt/ht~'s for women), lifetime vigorous leisure time physical activity, total energy intake, dietary calcium, use of aspirin/NSAIDS, and presence or absence of a family history of a first-degree relative with coloractal cancer. Model 3 also adjusts for all vitamins shown in Table 7. Cut-points used for men and women are the same as those shown in Table 2. - a finding noted previously in both human and animal s~udies.~':' Canned fruit contributed approximately six percent of sucrose and glucose to the diet of study participants. Although we did not observe a protective effect for fruit juice, it is possible that this category of fruits is more subject to inaccurate recall. It is possible that reported fruit juice is not 100 percent fruit juice, and that people reported fruit drinks, which contain a high sugar content, despite the fact that we asked about juice rather than drinks. Another interpretation of this obser- vation is that individuals eating canned fruit may be consuming lower levels of labile phytochemicals than individuals consuming fresh fruits and vegetables. Plant foods are major contributors of fiber in the diet. Fiber has been associated with reduced risk of colon cancer in other studies)~ We also observed decreased risk for both soluble and insoluble fiber, with the strongest associations being observed for older people and those with proximal tumors. Several mechanisms exist whereby fiber could decrease colon cancer risk, including: decreas- ing transit time; increasing fecal bulk; increasing adsorption of bile acids, fatty acids, and minerals; and providing a fermentable substrate for colonic bacteria. The products of fermentable volatile fatty acids include butyrate which, in addition to being a major colonic epithelial cell. fuel, may play a role in apoptosis and cell C~taccr C,~us~s and Control. Vol 8. 1997 587

IIII Table 9. Interaction between family history of first degree relative with colorectal cancer and intake of plant foods in the US multicenter study population All subjects < 67 years 67+ years 01stal Proximal OR= (CI) ORa (el) OR" (el) OR= (CI) OR" (el) Men Family history/vegetable intake Absent High 1.0 u 1.0 u 1.0 ~ 1.0 -- 1.0 -- Absent Low 1.2 (0.9-1.6) 1.2 (0.8-1.8) 1.3 (0.9-1.9) 1.1 (0.8-1.5) 1.4 (1.0-2.1) Present High 1.9 (1.1-3.4) 2.3 (1.0-5.4) 1.7 (0.8-3.8) 1.9 (1.0-3.6) 2.0 (1.0-4.2) Present Low 3.1 (1.8-5.2) 3.7 (1.5-8.9) 2.9 (1.5-5.8) 2.5 (1.3-4.6) 3.9 (2.1-7.2) Family history/refined grains Absent Low 1.0 -- 1.0 -- 1,0 ~ 1.0 -- 1.0 -- Absent High 1.4 (1.0-1,8) 1,5 (1.0-2.3) 1,2 (0.8-1.9) 1.4 (1.0-2.1) 1.3 (0.9-1.9) Present Low 1.8 (1.0-3.2) 1.5 (0.6-4.0) 1,9 (1.0-3.8) 1.2 (0.5-2.5) 2.2 (1.2-4.3) Present High 4.0 (2.3-7.2) 7.2 (2.9-17.8) 2,4 (1.1-5.3) 4.4 (2.3-8.5) 3.4 (1.7-6.9) Women Family history/vegetable intake Absent High 1.0 -- 1.0 ~ 1.0 ~ 1.0 ~ 1,0 u Absent Low 1.5 (1.1-2.0) 1.9 (1.2-2.8) 1.3 (0.8-2.0) 1.3 (0.9-1.9) 1.7 (1,2-2.5) Present High 1.7 (1.0-3.1) 2,3 (1.0-5.2) 1.3 (0.6-2.9) 1.3 (0.6-2.7) 2.3 (1,2-4.5) Present Low 2.0 (1.1-3.6) 1.9 (0.7-4.9) 2.1 (1.0-4.3) 1.9 (0.9-3,8) 2.7 (1.2-4.7) Family history/refined grains Absent Low 1.0 -- 1.0 -- 1.0 ~ 1.0 ~ 1.0 ~ Absent High 1.0 (0.8-1.4) 0.9 (0.6-1.5) 1.2 (0.8-1.9) 1.0 (0.7-1.5) 1.1 (0.7-1.6) Present Low 1.8 (1.0-3.2) 1.9 (0.6-5.8) 1.8 (0.9-3.5) 1.9 (0.9-3.7) 1.8 (0.9-3,5) Present High 1.5 (0.9-2.8) 2.2 (0,9-5.3) 1.0 (0.4-2.4) 1.0 (0.4-2.1) 2.1 (1.1-4.3) OR = Odds ratio; CI = confidence interval. Model adjusted for age, body mass index (wt/ht~ for men, wt/htl"s for women), lifetime vigorous leisure time physical activity, use of aspirin/NSAID, total energy intake, and calcium. replication.2~ Fruits and vegetables also are major sources of pectin which is generally water soluble; outside of the colon, pectin reduces the rate of glucose absorption and decreases the rate of absorption and/or availability of lipids?° Stronger associations of fiber with proximal tumors may reflect the role of fiber in bile acid absorption, which may play a larger role in proximal cfdistal tumors21 While it has been hypothesized that starch may decrease risk of colon cancer because of its fermentable proper- des,S= in this study we did not observe an association with colon cancer. It also has been argued that the relationship of fiber to colon cancer could be explained by phytic acid commonly found in nuts and seed and grains." We did not find a protective effect for nuts and seeds or refined grains; phytic acid commonly found in these foods could alter risk in either way as it binds dietary calcium, a factor which has been suggested to be protective for colon cancer.~ The associations of vit='w~ins commo.[y found in plant foods with colon cancer have been less clear in the litera- ture. Vitamins with antioxidant properties, including ~-carotene and vitamin C, have been examined in several studies and have been shown to decrease colon cancer risk in some, although not all studies.~a' p-carotene increased recurrence of large polyps in an intervention trial.~ In this study, we observed an increase in risk asso- ciated with vitamin A activity {rom plant foods (designed 588 Cancer Causes and Control. Vol 8. 1997 as ~-carotene in the NCC database) among women with proximal tumors: vitamin C was not found to alter risk of colon cancer. However, given the association we observed with specific foods, such as tomatoes, there are suggestions that other carotenoids, such as lycopene, may be associated more strongly with a lower risk of colon cancer than ~-carotene. Of the vitamins examined, vitamins Bs and thiamin showed the most protection for colon cancer. Vitamin Bs, also commonly found in fruits and vegetables, is involved in the metabolism of sulfur-containing amino adds. Pyri- doxal phosphate, the coenzyme form of vitamin Bs, is required for transulfhydration reactions in which cysteine is synthesized from methionlne, the major methyl donor in the body.~ Deficiencies of Bs can result in increased excretion of metabolites of methionine. Both folate and Bs may reduce colon cancer risk by reducing the likeli- hood of DNA hypomethylation, an early step in the colon cancer process.~* Folate was protective only among women with distal tumors, which is similar to reports by others.~°,~ Niacin is converted into active forms of niacinamide nucleotides, NAD and NADP(H), in mucosal cells. These nucleotides are involved in oxidative reactions, fatty acid synthesis, cholesterol and steroid hormone synthesis, synthesis of glutamate, synthesis of deoxyribonucleotides,

and" protein synthesis. NAD is a substrate in adenosine diphosphoribose (ADP-ribose) transfer reactions; a rapid biochemical response to carcinogen-induced DNA damage is synthesis of ADP-ribose polymers from NAD.4' These observations suggest that niacin is involved in the regulation of many cellular processes.~2 Niacin is also a component of the glucose tolerance factor that potentiates the action of insulin; it has been hypothesized that insulin is associated with cancer.~ At the cellular level, thiamin is involved in energy transformation and the synthesis of nicotinamide adenine dinucleotide phosphate (NADPH), a co-enzyme form of niacin. Absorption of thiamin is impaired by low levels of folate and high levels of alcohol.37 For many foods and nutrients, associations were slightly stronger for proximal tumors. These observations may be explained in part by bioactive dietary constituents such as phytoestrogensTM found in plant foods. The role of such compounds when present in large amounts may be markedly different before and after menopause in women, while only gradually changing their impact with age in men; this may account for the slightly stronger associations observed for plant foods for women than for men. Phytoestrogens may influence the methylation of the estrogen receptor gene,'S which is silenced in colon tumors.~ Endogenous estrogens have been hypothesized to be associated more with proximal tumors than with distal tumors; ~1 it is possible that phytoestrogens have similar associations. There are study limitations. Since the purpose of this study was to examine plant foods and colon cancer, we limited our analyses to nutrients from foods, the associa- tions reported here do not take supplements into account. Thus, studies which have included nutrients from supplements may observe different associations. Also, exposure information in this study is based on one uniform time period (two years prior to diagnosis); if other periods of exposure are more relevant to disease, then associations reported here may not capture the most important time period of action. Another limitation is our inability to examine many bioacdve compounds found in plant foods. Although we have attempted to do this by examining food groups, a complete analysis is impossible using existing nutrient databases. As we obtain more information on phytochemicals, we will be able to examine bioacdve components of plant foods in relation to colon cancer. It also is possible that case subjects may have reported their diet differently because of their disease, however fruit- and vegetable-specific associations argue against any selective recall. While it could be argued that the findings reported here are the result of making many comparisons, the primary objective of the study was to evaluate colon cancer asso- ciations for gender-, age-, and site-specific groups. We Plant foods and colon cancer believe that the purpose of epidemiologic studies is to conduct a scientific inquiry into etiology and possible biological mechanisms by summarizing and interpreting the data in a relevant and informative manner given back- ground theory and knowledge. It is undesirable to sacrifice power for the sake of maintaining the study's type I error probability. Further, it has been argued that a universal null hypothesis is rarely applicable in obser- vational studies such as the one conducted here.° In summary, results suggest that plant foods and many dietary constituents contained in plant foods are associ- ated with colon cancer. Some of these constituents of plants, such as dietary fiber, have been reported previously as decreasing risk of colon cancer. Other factors, such as several B vitamins, have not been reported previously as decreasing risk of colon cancer;, in this population they appear to be associated inversely with colon cancer. These associations provide additional insight into possible mechanisms whereby plant foods may alter colon cancer risk. Our data suggests that mechanisms exist whereby plant foods decrease risk of colon cancer unrelated to standard micronutrients, since adjustment for known measurable constituents of plant foods did not apprecia- bly alter the observed associations between plant foods and risk of colon cancer. Thus, it seems prudent to consume a diet high in vegetables, certain fruits, and whole grains as a way to reduce risk of colon cancer. Acknowledgement n We acknowledge the contribu- tions to data collection by Sandra Edwards, Dr Richard Kerber, and Dr Kristin Anderson. References I. Slavin.~. Epidemiological evidence for the impact of whole grains on health. CHt Re~ Food Sci Muir 1994; 34: 427-34. 2. Steinmetz KA, PotterJD. Vegetables, fruits, and cancer. If. Mechanisms. Cancer Causes Control 1991; 2: 427-42. 3. Potter JD, Slattery ML, Bostick RM, Gapstur SM. Colon cancer:. A review of the epidemiology. Epidemiol Rev 1993; 15: 499-545. 4. Howe G, Benito E, Duff'y S, et al. Dietary intake of fiber and decreased risk of cancers of the colon and rectum: evidence from the combined analysis of 13 case=control studles.JNCI 1992; 84: 1887-96. 5. West DW, Slattery ML, Robison LM, et al. Dietary intake and colon Cancer'. Sex and anatomical site-specific associa- tions. AmJ Epideraiol 1989; 130: 883-94. 6. Whittemore AS, Wu=Williams AH, Lee M, et al. 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