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1 From the Imperial Cancer Research Fund, Cancer Epidemiology Unit, Radcliffe Infirmary, Oxford, United Kingdom; the Department of Public Health and Policy, London School of Hygiene and Tropical Medicine; and the Department of Human Nutrition, University of Otago, Dunedin, New Zealand.
2 Supported by the Imperial Cancer Research Fund, the Cancer Research Campaign, and the Vegetarian Society of the United Kingdom.
3 Reprints not available. Address correspondence to PN Appleby, Imperial Cancer Research Fund, Cancer Epidemiology Unit, Gibson Building, Radcliffe Infirmary, Oxford OX2 6HE, United Kingdom. E-mail: appleby{at}icrf.icnet.uk.
| ABSTRACT |
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Key Words: Vegetarian vegan omnivore diet lipids mortality ischemic heart disease cardiovascular disease coronary artery disease cancer testosterone hypothyroidism appendicectomy appendectomy alcohol
| INTRODUCTION |
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The primary aim of the Oxford Vegetarian Study was to evaluate mortality in its vegetarian subjects. Particular attention was paid to cardiovascular mortality and the incidence of and mortality from common cancers that are thought to be diet related (including cancers of the digestive tract and breast), in comparison with rates for the nonvegetarian controls. Secondary aims were to compare plasma lipid concentrations among different diet groups and to assess the effects of different foods and nutrients on these concentrations, as well as to investigate other aspects of health in the diet groups.
| STUDY DESIGN |
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A total of 11140 subjects were recruited between September, 1980, and January, 1984. Upon entry to the study, subjects completed a questionnaire concerning their diet (in the form of a simple food frequency questionnaire), other lifestyle factors related to health (smoking, alcohol consumption, and amount of exercise), date of birth, occupation, height and weight, medical history (including family history of serious diseases and, for women, reproductive history), and membership in vegetarian organizations. Subjects were divided into appropriate diet groups for subsequent analysis by using their answers to questions about consumption of foods of animal origin (meat, fish, milk, cheese, and eggs). At the same time, each subject was identified at the UK National Health Service central register and subsequently followed-up for information on death and cancer registration. For those subjects who subsequently died, death certificates were obtained and coded for underlying cause of death by a single investigator (JIM) by using the International Classification of Diseases, ninth revision (3). This coding was carried out blind to the subject's diet and other lifestyle characteristics.
Between April 1984 and January 1986, all surviving subjects under age 70 y were sent a kit consisting of a 10-mL heparin-containing tube, a syringe, and an explanatory letter for their general practitioner, who was asked to take a blood sample and send it to our laboratory in Oxford for analysis. We obtained plasma lipid measurements for 3773 subjects, a response rate of
40%. Total-cholesterol concentration was measured directly and LDL- and HDL-cholesterol concentrations were calculated by subtraction as described elsewhere (4). Triacylglycerol concentration was not measured because, for practical reasons, it was not possible to ensure that the blood samples were collected under fasting conditions.
In a separate exercise, between September 1985 and July 1986 all surviving subjects were sent a dietary record booklet that contained some general questions relating to their usual diet and a 4-d diet diary for completion on the first 2 weekdays after receiving the booklet and both days of the following weekend, as described elsewhere (5). The 4-d diet diaries included photographs of 3 portion sizes for each of 14 common foods; this method has been shown to produce reasonable estimates of nutrient intake in comparison with 7-d records of weighed food consumption (6). At the same time, subjects were also sent a simple form asking whether they had had an appendectomy, and if so, to give their age at the time and further details of the operation which were used to classify each appendectomy as either emergency or nonemergency. Among the general questions in the dietary record booklet was one that asked subjects to list the periods of their life, if any, during which they had not eaten meat. By combining the answers to these 2 separate questions we were able to compare self-reported emergency appendectomy rates in meat eaters and non-meat-eaters.
| PLASMA LIPIDS |
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| MORTALITY |
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When the first 5 y of follow-up were excluded from the analysis, the death rate ratios became closer to unity and were no longer statistically significant, partly because the smaller number of deaths meant that the CIs were much wider [death rate ratios (and 95% CIs) for non-meat-eaters compared with meat eaters: 0.99 (0.76, 1.30) for all causes of death, 0.89 (0.51, 1.54) for ischemic heart disease, and 0.89 (0.60, 1.32) for all malignant neoplasms]. These large reductions in the apparent effect of diet group may be because the healthy volunteer effect was more pronounced in the vegetarian subjects, who were likely to have been more strongly motivated and, therefore, generally healthier than the nonvegetarian subjects at recruitment. It is also likely that there was some crossover among diet groups during the first 5 y of the study, which would dilute the apparent benefits of a meatless diet. The largest benefit noted, for mortality from all malignant neoplasms, is not in accord with the results of a recent meta-analysis of vegetarian cohort studies (11). It is also difficult to interpret results for such an all-embracing endpoint as death from all malignant neoplasms, and thus the more recent analysis of mortality data from the study described below concentrates on ischemic heart disease as a more clearly defined endpoint.
Mortality in relation to foods, animal fats, and dietary fiber
The effects of various dietary factors on mortality from ischemic heart disease and all causes of death were examined in a recent analysis (12). Subjects were grouped not only according to their diet (meat eater, semivegetarian, or vegetarian/vegan), but also by their consumption of meat, eggs, milk, cheese, fish, green vegetables, carrots, fresh or dried fruit, nuts, and alcohol, according to the answers they provided on the recruitment questionnaire. Subjects were also divided into thirds by estimated intake of total fat, saturated fat, and dietary cholesterol from land animal sources, and into thirds by estimated dietary fiber intake based on their reported consumption of fiber-rich foods. Attention was paid to the possibility of previous cardiovascular disease or diabetes at recruitment, with the main analysis restricted to subjects with no history of preexisting disease. All death rate ratios were adjusted for age, sex, smoking, and social class, and comparisons were made without reference to an external population as was the case in the earlier article. The analysis included a total of 525 deaths before age 80 y during an average of 13.3 y of follow-up; 392 of the deaths were in subjects with no history of cardiovascular disease or diabetes at recruitment, including 64 deaths from ischemic heart disease. Vegetarians and vegans had lower mortality than meat eaters (defined as subjects eating meat at least once a week) for both ischemic heart disease and all causes of death [death rate ratios (and 95% CIs): 0.63 (0.42, 0.93) and 0.91 (0.75, 1.09), respectively] but these effects were reduced when subjects with a history of cardiovascular disease or diabetes were excluded [death rate ratios (and 95% CIs): 0.83 (0.48, 1.43) for ischemic heart disease and 1.02 (0.82, 1.27) for all causes of death]. The most striking results from the analysis were the strong positive associations between increasing consumption of animal fats and ischemic heart disease mortality [death rate ratios (and 95% CIs) for the highest third of intake compared with the lowest third in subjects with no prior disease were 3.29 (1.50, 7.21) for total animal fat, 2.77 (1.25, 6.13) for saturated animal fat, and 3.53 (1.57, 7.96) for dietary cholesterol; P for trend: <0.01, <0.01, and <0.001, respectively]. In contrast, no protective effects were noted for dietary fiber, fish, or alcohol consumption. Consumption of eggs and cheese were both positively associated with ischemic heart disease mortality in these subjects (P for trend, < 0.01 for both foods). In Figure 2,
the ischemic heart disease death rate ratios compared with the reference group for each of the selected dietary factors are shown. The effects of individual foods on all-cause mortality were generally indeterminate, although there was a suggestion of an inverse association with nut consumption and a U-shaped relation with the consumption of both eggs and milk.
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| OTHER ASPECTS OF HEALTH AND DISEASE |
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Sex hormone concentrations in male vegans and omnivores
In an investigation of factors thought to influence the risk of developing prostate cancer, concentrations of total testosterone, total estradiol, and sex hormone binding globulin (SHBG) were determined using plasma samples from 108 male subjects (51 vegans and 57 omnivores) who were nonsmokers, were not using long-term medication, and had no history of cardiovascular disease (15). There were no significant differences in mean concentrations of testosterone (total or free) or estradiol between vegans and omnivores, but SHBG was 23% higher in the vegans (P = 0.001). In 40 of these subjects who completed a diet diary, there were statistically significant correlations (adjusted for age, body mass index, and diet group) between total testosterone and polyunsaturated fatty acid intake (partial r = 0.37), and between SHBG and each of total fat, saturated fatty acids, polyunsaturated fatty acids, and alcohol (partial r = 0.43, 0.46, 0.33, and -0.39, respectively).
Thyroid-stimulating hormone in male vegans
The soil in some parts of Britain is deficient in iodine. The most important dietary source of iodine in the general population is dairy products, partly due to the high iodine content of some cattle feed. Therefore, vegans in Britain may be at risk for iodine deficiency (16). To explore this hypothesis, thyroid stimulating hormone (TSH) concentration was measured in plasma samples from 48 vegan and 53 omnivorous men (17). The geometric mean TSH concentration, adjusted for age and body mass index, was 47% higher in the vegans than in the omnivores (P = 0.001). Five vegans but none of the omnivores had a TSH concentration above the reference upper limit of 5 mU/L (P = 0.022), although only one of these subjects was found to have a thyroxine concentration below the reference range of 70140 nmol/L. The 3 subjects with the highest TSH concentrations (but no others) all reported taking kelp supplements regularly; kelp is a rich source of iodine. After excluding the results for these subjects, the adjusted geometric mean TSH concentration was still 29% higher in the vegans (P = 0.012). It was concluded that the use of kelp can be associated with raised TSH and that the iodine intake of vegans who do not take kelp or other suitable supplements may be low and requires further investigation.
Asymptomatic hypothyroidism and hypercholesterolemia
The relation between biochemically diagnosed hypothyroidism and plasma cholesterol concentration was discussed in an article published in 1991 (18). Thyroid function tests were performed on 3 groups: 272 apparently healthy subjects (179 vegetarians, 93 meat eaters) with plasma cholesterol concentrations >7 mmol/L; 90 subjects who were matched for age, sex, and diet group and had plasma cholesterol concentrations <4.1 mmol/L; and 25 randomly-selected subjects. Of the subjects with high plasma cholesterol, 5.9% had biochemical evidence of hypothyroidism (5.0% of the vegetarians and 7.5% of the meat eaters; difference not significant) compared with none from either the low plasma cholesterol group or the randomly selected group. Most of these subjects with hypothyroidism had thyroid microsomal antibodies (some at very high titres) indicating that the etiology was probably autoimmune. It was concluded that hypothyroidism is relatively common in apparently healthy people with raised plasma cholesterol concentrations, but is no more common in vegetarians than in meat eaters.
Alcohol intake and cardiovascular-related disease
Data from the Oxford Vegetarian Study were used to test the hypothesis that the U-shaped curve relating alcohol consumption and cardiovascular disease may be an artifact of selection whereby individuals with high consumption and high risk of disease migrate to a low- or zero-consumption category just before inclusion. Standardized rates of self-reported previous cardiovascular-related disease were compared by diet group (meat eater, fish eater, vegetarian, vegan), smoking habits, alcohol consumption, and social class for men and women separately (19). There was no significant association between reported cardiovascular-related disease and alcohol consumption for either men or women, thus the data did not support the hypothesis. However, there was an association between diet group and cardiovascular-related disease in women, with a 15% excess in the observed number of meat-eating women with previous disease compared with the expected number after adjustment for age, smoking, drinking, and social class. A similar, though smaller, 8% excess of cardiovascular-related disease was found in male meat eaters.
| FUTURE STUDY |
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The size of the study has precluded meaningful investigation of the mortality from and incidence of specific diet-related cancers. Over time, the numbers of cases and deaths from specific cancers will rise, but the gap between recruitment and the event grows ever larger, making classifications based on the original questionnaire increasingly unreliable. Meta-analyses of vegetarian cohort studies can address this problem to some extent and mortality data from the Oxford Vegetarian Study have been incorporated into a meta-analysis of vegetarian cohort studies described elsewhere in this supplement (11).
A better solution is to design and perform larger cohort studies in which the greater number of subjects provides reasonable numbers of events for specific cancers and other diseases within a period of time during which dietary and other lifestyle factors might be assumed to remain constant; these factors could also be investigated with follow-up questionnaires. With an estimated 5% of the British population now following a vegetarian diet (20), the recruitment of large numbers of vegetarians to a cohort study poses less of a problem than it did in the early 1980s. In addition, improvements in the design of food frequency questionnaires and diet diaries mean that the dietary information collected in contemporary studies is both more comprehensive and more reliable.
The European Prospective Investigation into Cancer and Nutrition (EPIC) Study of diet and cancer should yield reliable information on the relations between diet and both mortality and morbidity (21). In the United Kingdom, 85000 individuals have been recruited to the study, of whom 25000 are vegetarians, and therefore this study should produce much more data on the long-term health of Western vegetarians.
| ACKNOWLEDGMENTS |
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| REFERENCES |
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