Does ÃŸ-CaroteneExplain Why Reduced Cancer Risk Is Associated with Vegetable and Fruit Intake?1

Increased intake of vegetables, fruits, and carotenoids and elevated blood levels of 0-carotene are consistently associated with reduced risk of lung cancer in epidemiologie studies. Epidemiologie research also suggests that carotenoids may reduce the risk of other cancers, although the evidence is less extensive and consistent. The simplest explanation is that /3-carotene is protective. However, the possible roles of other carot enoids, other constituents of vegetables and fruits, and associated dietary patterns have not been adequately explored. To evaluate these alternative hypotheses, we are undertaking three lines of research, (a) With dietary data from the 1987 National Health Interview Survey and the 19821984 Epidemiologie Follow-up of the first National Health and Nutrition Examination Study, we have determined which food groups and nutrients are highly correlated with vegetable and fruit intake, (b) We have developed and characterized a liquid chromatography method for optimal recovery and resolution of the common carotenoids in blood, specifically luicin, zeaxanthin, f? -cr>ptoxanthin, lycopene, Â«-carotene, and ^-carotene. (c) In a population-based case-control study of lung cancer in white men in New Jersey, we are assessing whether estimates of the intake of the individual carotenoids might produce stronger inverse associations than estimates of provitamin A carotenoids based on current food composition tables. The hypothesis that /3-carotene can reduce the risk of cancer has been proposed relatively recently. Previously, attention focused on vitamin A because of its recognized role in normal cell differentiation and because high doses of retinoids (vitamin A analogues) limited carcinogenesis in animal experiments. In the 1980s interest in /3-carotene escalated for several reasons. First, /3-carotene is the most abundant and the most efficiently converted of the provitamin A carotenoids (vitamin A precur sors) in vegetables and fruits. Second, a protective role for ÃŸcarotene explained the early epidemiologie evidence that in creased vegetable and fruit intake reduced cancer risk. Third, serum levels of /3-carotene are responsive to dietary intake, unlike serum levels of vitamin A, which are maintained within a narrow range in well-nourished populations by vitamin A stored in the liver. Finally, a plausible mechanism was postu lated for /3-carotene, as an antioxidant, that did not require its conversion to vitamin A. Prospective Studies of Carotenoid Intake and Cancer Before questioning whether the /3-carotene hypothesis really explains the epidemiologie findings, it is necessary to review the evidence. First, prospective studies and then a limited number of retrospective studies will be considered. In a pro1Presented at "Nutrition and Cancer. " the first conference of the International Conference Series on Nutrition and Health Promotion, April 17-19, 1991. Atlanta, GA. 2To whom requests for reprints should be addressed, at Environmental Epi demiology Branch, National Cancer Institute, Executive Plaza North 443, Be thesda, MD 20892. spective study, dietary information and/or blood samples are collected from a group of nondiseased people, and this cohort is followed over time. When a sufficient number of cancer diagnoses or deaths have occurred, the data collected earlier are compared for the cases and all the noncases in the cohort or for the cases and matched controls selected from the cohort. Thus exposure, whether measured by dietary intake or blood nutrient levels, is ascertained before clinical disease. Seven prospective studies of carotenoid intake and cancer were published (1-8), with the earliest appearing in 1979 (1); locations included Japan (1, 2), Norway (4), the Netherlands (8), and the United States (3, 5-7). The exposure most fre quently evaluated was vegetable and fruit intake. Only three studies (3,7,8) actually assessed carotenoid intake by including in the interview most of the major sources of carotenoids in the diet and developing a quantitative index by weighting the fre quencies of consumption of these foods by their measured carotenoid content, based on food composition tables. Not all of these studies looked at the same cancers; only two (3, 7) systematically investigated the most prevalent cancers in their cohort. Three (1, 2, 5, 7) of the five studies (1, 2, 3, 5, 7, 8) that analyzed all cancers combined found a reduced risk with increased intake of vegetables and fruit and/or carotenoids. Five (1-4, 6, 8) of six studies (1-4, 6-8) found a reduced risk of lung cancer with increased intake. A reduced risk of breast (7), cervical (1, 2), stomach (1, 2), and oral-pharyngeal (3) cancer was noted in the single study that investigated each cancer. However, risk of bladder cancer was decreased in only one (7) of two (3, 7) studies; and no protective effect was seen for the intake of vegetables and fruit or of carotenoids for prostate cancer in three studies (1-3, 7), for colon cancer in two studies (3, 7), or for skin cancer in one study (3). Thus in these prospective studies of diet and cancer, high levels of vegetable and fruit intake are consistently associated with a reduced risk of lung and possibly other cancers. However, the protective factor is difficult to identify. Only one study systematically investigated the relationship of all the common nutrients to the risk of lung cancer; carotenoid intake alone was significantly associated with reduced risk (3). The roles of constituents of vegetables and fruits other than nutrients and of individual carotenoids were not evaluated in any of these studies. In addition, the one study that compared the impact of vegetable, fruit, and carotenoid intake found that fruit was the most predictive of reduced lung cancer risk (8). Dietary retinol (preformed vitamin A) was not protective in three (3, 7, 8) of four lung cancer analyses (3, 4, 7, 8), which suggests that ÃŸcarotene does not first have to be metabolized into retinol to be effective. Prospective Studies of Blood Carotenoid Levels and Cancer Prospective studies have looked not only at vegetable and fruit and carotenoid intake but also at carotenoid concentra-