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*
University of Leuven, Department of Public Health, Division of Nutritional Epidemiology, 3000 Leuven, Belgium and
Wageningen University, Human Nutrition and Epidemiology, 6700 EV Wageningen, The Netherlands
3To whom correspondence should be addressed. E-mail: Pascale.Vanhoydonck{at}med.kuleuven.ac.be.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • vitamin C • ß-carotene • iron • cohort study • male smokers • mortality risk • cardiovascular disease • cancer
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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–3
). In fact, there is fairly irrefutable evidence for oxidative stress in cigarette smokers as indicated by high levels of circulating F2-isoprostanes (4
) and urinary excretion rates of oxidized DNA products (5
).
The destructive chain reaction initiated by free radicals can be broken by dietary antioxidants, which can convert free radicals into harmless derivates (6
,7
). Vitamin C, ß-carotene and vitamin E are powerful dietary antioxidant nutrients, which may play a helpful role in the prevention of diseases initiated or promoted by oxygen radicals, such as CVD and cancers (8
–12
). Vitamin C is an effective water-soluble antioxidant that scavenges oxygen-derived free radicals; it is widely available in all types of vegetables and fruits (7
). ß-Carotene from green and yellow vegetables, carrots and a variety of fruits provides protection against lipid peroxidation because of the hydrophobic chain of polyene units that can quench singlet oxygen, neutralize thiyl radicals and combine with and stabilize peroxyl radicals (12
). Vitamin E (
-tocopherol) is a fat-soluble compound found primarily in plant products (vegetables oils, margarine, nuts, seeds and cereal grains) that serves many physiologic functions against cancer and is particularly effective in protecting LDL from oxidation. On the other hand, iron may be considered to be a dietary prooxidant because it is associated predominantly with oxygen transport and can catalyze free radical formation. It has been hypothesized that high iron intake or iron stores promote atherogenesis by increased free radical formation and oxidative stress (13
,14
). Several studies support the hypothesis that iron-induced lipid peroxidation is crucially involved in the early steps of human atherosclerosis (13
,15
,16
). In addition, iron-amplified oxidative stress may also lead to DNA damage and oxidative activation of precarcinogens and may support tumor cell growth (14
). A diet high in polyunsaturated fatty acids (PUFA) seems to increase the formation of radicals although epidemiologic studies are limited.
Smokers constitute an ideal group with which to investigate the protective effects of diets rich in antioxidants and low in prooxidants. Most of the studies on dietary anti- and prooxidants and mortality risk have focused on supplemental intakes or plasma/serum levels instead of the dietary intakes. To our knowledge, the dietary pattern of anti- and prooxidant intake in relation to mortality risk in smokers has not been addressed in prospective studies.
This issue is important because the oxidative damage caused by smoking may be counteracted by high dietary intake of antioxidants, low prooxidant intake or a combination of both to reduce risk among smokers for free radical–associated diseases.
We evaluated in a Belgian population of male smokers whether a relatively low antioxidant intake combined with a high prooxidant intake leads to a higher risk of all-cause, CVD and cancer mortality compared with the reverse situation. We constructed an oxidative balance score that evaluated the oxidative balance of the dietary pattern of a subject by means of the combined intake of anti- and prooxidants. Dietary vitamin C and ß-carotene were taken as markers of antioxidant intake and dietary iron of prooxidant intake. The three nutrients used were selected a priori while taking into account the limitations of the available dataset.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The Belgian Interuniversity Research on Nutrition and Health (BIRNH study) was conducted from 1980 to 1984. After 10 y, the vital status of all subjects was ascertained. The aims, design and methodology of the BIRNH study were described previously (17
). In each of the 42 counties of Belgium, three to five municipalities were randomly chosen and the most populated was always included. In the selected municipalities, a random sample of the population was drawn from the voting list. Of the Belgians invited, 38.6% of the men (n = 5949) and 34.4% of the women (n = 5353) aged 25–74 y volunteered in the study. No specific inclusion criteria were applied; participants who went to the clinic visit and filled out self-administered questionnaires were included. Data of 187 men were excluded from the statistical analysis due to missing information, leaving 5762 men with a prevalence of 48% (n = 2814) current smokers. The data were analyzed only for male smokers because of the few female smokers in the population.
Measurements.
All subjects filled out a standardized questionnaire, which included questions about age, educational level and smoking. The smoking questionnaire contained detailed information on history of tobacco smoking (average number of cigarettes per day, number of years of smoking, age at which they began).
The dietary habits of each participant were assessed with a prestructured 24-h dietary record method using household measures. All subjects were asked to record each of the food items consumed on a specific day, either a weekday or a weekend day. The participants were interviewed and all questionnaires were checked and verified by trained dietitians on the first working day after the dietary survey. A computer program based on the Paul and Southgate food composition table (18
) was used to calculate the nutrients of the food items.
A nonfasting blood sample was taken and analyzed for a number of biochemical variables. Serum total and HDL cholesterol concentrations were measured with an enzymatic colorimetric method (CHOD-PAP method; Boehringer Mannheim, Mannheim Germany). HDL cholesterol concentrations were measured after heparin-manganese precipitation (19
).
Mortality.
The vital status of each subject was ascertained 10 y after baseline examinations for cause-specific mortality. The vital status was determined for 99.6% of the population through the National Death registers. Causes of death were ascertained with help of the family doctor and/or in case of doubt, the doctor who completed the death certificate. In some cases, more information on the cause of death was collected from hospitals or medical records. The mortality data were coded according to 9th revision of the International Classification of Diseases (ICD). Data have been analyzed in the present investigation with respect to death due to cardiovascular disease (ICD 390–459), total cancers (ICD 140–208) and all-causes combined.
Data analysis.
An oxidative balance score was constructed to evaluate the oxidative balance of the dietary pattern of a subject by means of the combined intake of vitamin C, ß-carotene and iron. To calculate the oxidative balance score, we first determined the thirds of intake for each single nutrient in the population of male smokers. The cut-off points were as follows: < 57.5 mg, 57.5–126.3 mg, >126.3 mg for vitamin C; <1.3 mg, 1.3–3.6 mg, >3.6 mg for ß-carotene; and <12.7 mg, 12.7–19.2 mg, >19.2 mg for iron intake. The thirds of intake (low to high) were scored from 1 to 3 for iron intake and 3 to 1 for vitamin C and ß-carotene intake. The three separate scores were summed to obtain the oxidative balance score (range from 3 to 9). This score was then divided into three groups (low, intermediate and high). The lowest oxidative balance score group (score 3–5), included smokers with a diet relatively high in anti- and/or low in prooxidants as reflected by the intake of vitamin C, ß-carotene and iron intake. The highest oxidative balance score group (score 7–9), included smokers with a relatively low dietary anti- and/or high prooxidant intake and the intermediate oxidative balance score group (score 6), included smokers with either low anti- and low prooxidant intake or high anti- and high prooxidant intake. The three groups had almost equal numbers.
Baseline characteristics of participants were classified according to the three groups of oxidative balance scores. Subjects smoking any type of tobacco were classified as current smokers. Educational level was classified into three groups: low (up to completed primary school), intermediate (high school) and high (professional higher education or university). The number of pack-years was calculated from the number of cigarettes per day divided by 20 (number of cigarettes per package) and multiplied by the years of smoking.
Differences in baseline characteristics between the three oxidative balance score groups were tested with ANOVA, using the Scheffé test for multiple comparisons. Differences in educational level were tested with 
2 trend tests. A Cox proportional hazard survival analysis was applied to investigate the association between the oxidative balance score and risk of all-cause, cardiovascular disease (CVD) and cancer mortality. The proportionality assumption was evaluated by visual inspection of the log-log survival curves, which had an almost inverse parallel distribution. Adjustments were made for age, educational level, body mass index (BMI), daily total energy intake and number of pack-years. Educational level and the oxidative balance score data were entered into the models as indicator variables. Men with a low educational level and a low oxidative balance score served as reference groups in the analysis. The analyses were repeated to compare smokers in the high oxidative balance score group with those in the low and intermediate groups combined. With Akaike’s information criterion (AIC), the Cox model fits were evaluated for the oxidative balance score and models including (combinations of) the separate nutrients vitamin C, ß-carotene and iron. AIC computes the estimated mean square error of the prediction for each selected covariance model. Statistical analysis of the data were carried out using the statistical software program SAS version 8.1 (SAS Institute, Cary, NC). Differences with a P-value < 0.05 were regarded as significant and all P-values were based on two-sided tests.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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. These differences correspond approximately to the amount of vitamin C in one orange per day, the amount of ß-carotene in one-half serving of carrots per day and the amount of iron in one-half serving of meat per day.
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Smokers with the highest oxidative balance score (with a diet poor in vitamin C and ß-carotene and/or rich in iron) were 2 y younger than those with the lowest score (with a diet rich in vitamin C and ß-carotene and/or poor in iron) (P < 0.05) (Table 2)
. Of the total population of smokers, 42% had a low educational level. Men with the highest oxidative balance score smoked significantly more cigarettes per day but had a somewhat shorter duration of smoking compared with men with the lowest score. The number of pack-years was significantly higher in smokers with the highest compared with the lowest oxidative balance score.
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Mortality.
After adjustment for age, men with the highest oxidative balance score had a higher all-cause mortality risk [relative risk (RR) = 1.50, P < 0.01, 95% confidence interval (CI): 1.19, 1.90] compared with men with the lowest score (Table 3)
. Additional multivariate adjustments for BMI, educational level, total energy intake and number of pack-years slightly attenuated the age-adjusted association (RR = 1.44, P < 0.01, 95% CI: 1.13, 1.82). Higher CVD mortality risk was found in male smokers with the highest compared with the lowest oxidative balance score, but the difference was not significant in uni- and multivariate (RR = 1.31, P = 0.20, 95% CI: 0.86, 2.00) Cox models. Smokers in the group with the highest oxidative balance score had a higher total cancer mortality risk compared with the group with the lowest score after controlling for age and other confounders (RR = 1.87, P < 0.01, 95% CI: 1.24, 2.80 and RR = 1.62, P < 0.05, 95% CI: 1.07, 2.45, respectively). The association between the oxidative balance score and mortality risk for all-cause and total cancer was driven principally by smokers with the highest oxidative balance score, suggesting a threshold effect for risk rather than a linear trend.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The higher mortality risk with a diet relatively low in vitamin C and ß-carotene and high in iron in male Belgian smokers confirms previous epidemiologic observations focused on the three single nutrients. Evidence from prospective studies suggests that a high dietary intake of antioxidants is protective for CVD and cancer, although findings have not been consistent and trial data have not been conclusive. Some investigators have shown a RR from 1.5 to 2 of CVD and cancer mortality in men with low vitamin C or ß-carotene intakes (9
, 20
,21
) or low concentrations in adipose tissue (22
) or in serum/plasma (23
–27
). In contrast, results of the prospective Health Professionals Follow-Up Study (28
) and the Kupio Heart Study (25
) did not show any appreciable cardiovascular benefit of vitamin C supplementation among healthy men. Findings from clinical trials on the effects of ß-carotene supplementation (20–50 mg ß-carotene/d) [ATBC-Study (29
); CARET-Study (30
); Physicians’ Health Study (31
); Dermatology Practices Based Study (32
)] have shown no benefits (mean RR of 1.16) (11
) in terms of the incidence of CVD and cancer among smokers or nonsmokers. On the other hand, observational studies suggest that intakes of fruits and vegetables (green and yellow) rich in vitamin C and ß-carotene protect against the deleterious action of free radicals that may lead to CVD and cancer (33
–36
). Alternatively, vitamin C or ß-carotene may require the presence of cofactors in fruits and vegetables to have beneficial antioxidant activities. Several studies are compatible with the hypothesis that increased iron stores (serum ferritin 
200 µg/L) or intakes (especially heme iron) are associated with greater risk of CVD and cancer by increasing free radical formation and oxidative stress (15
,16
,37
–40
).
The present prospective study reported new results on dietary patterns and mortality risk in a smokers’ cohort. The "oxidative balance score of vitamin C, ß-carotene and iron intake" was constructed as a predictor for mortality risk instead of the single nutrients because the score better reflects the oxidative balance of the dietary pattern of a subject in relation to chronic diseases. It was evident that smokers with the most unbalanced diet with respect to these anti- and prooxidants were at higher risk for all-cause, cancer and to a lesser extent, CVD mortality than smokers with low or intermediate scores.
The oxidative balance score included dietary anti- and prooxidants that have specific functions in oxidative stress situations. A combination of vitamin C and ß-carotene was used because they represent water-soluble and liposoluble antioxidant nutrients that have a complementary effect in protecting different tissues against oxidative stress. In addition, vitamin C and ß-carotene are present in the same food groups, but generally in different fruits and vegetables (e.g., citrus fruits are rich in vitamin C; spinach, carrots and apricots are rich in ß-carotene). Iron, as a prooxidant, which is present in meat, fruit and vegetables, enriched the whole diet approach of our composite index. However, it is important to notice that the percentage absorption from heme iron (especially in meat products) is 5- to 10-fold higher than that from nonheme iron (in a vegetable diet) (41
). In the present study, meat consumption was positively associated with mortality risk as has been observed by others (39
,40
). The intake of heme iron would have been better to use as a marker of prooxidant intake instead of the total amount of iron. However, no data on heme vs. nonheme iron intakes were available. Furthermore, dietary iron intake was the only marker of prooxidant intake in our oxidative balance score. PUFA seem to be sensitive to oxidation and may increase formation of radicals. Kardinaal et al. (42
) found that adipose tissue PUFA levels modified the association of low ß-carotene levels in adipose tissue and risk of myocardial infarction with the highest risk in subjects with low ß-carotene and high PUFA concentrations. Nevertheless, the present study showed no differences in PUFA intake among different oxidative balance score groups (Table 2)
. Another possible weakness of our study lies in the choice of markers of antioxidants. Dietary vitamin E intake (in vegetable oils, margarines, cereals and vegetables) may also prevent carcinogenesis and atherogenesis through its antioxidant properties and have synergistic effects with vitamin C; unfortunately, no data on dietary vitamin E were available. The oxidative balance score performed slightly better in the adjusted models for all-cause and cancer mortality than the separate or combinations of nutrients. However, the oxidative balance score might not be the score of choice with which to predict cardiovascular mortality risk because ß-carotene alone explained more of the variance in mortality than the oxidative balance score.
In this study, the low participation rate of the invited population may raise questions about the representativeness of our sample. However, a nonresponse investigation indicated no clear differences between participants and nonparticipants for dietary intake, but a slightly higher percentage of male smokers among the refusals (43
). Error in the all-cause mortality data was unlikely because the age- and sex-specific mortality rates of our study were similar to the official Belgian mortality Institute of Statistics. Unfortunately, the vital status of each subject was ascertained 10 y after baseline examinations for mortality, which may have produced some extra nondifferential misclassification in the cause-specific mortality data. A single dietary assessment might not be sufficient to characterize the nutritional exposure in the relevant time frame. On the other hand, it is expected that dietary habits in the early 1980s were rather stable among adult members of the Belgian population. Differences in mortality risk according to the three components of the dietary oxidative balance score were estimated, adjusting for age, BMI, educational level, daily total energy intake and number of pack-years. These five variables were associated with the risk of all-cause, CVD and total cancer mortality and were determinants of the oxidative balance scores in our male smoker population. After controlling for confounders, the association between the oxidative balance scores and mortality risk was even more pronounced. This was explained largely by negative confounding by age; the high score group was on average younger than the other two groups. Confounding by major risk factors such as blood pressure or serum cholesterol seems unlikely because the factors did not differ among the oxidative balance score groups. However, we cannot exclude that other determinants (such as physical activity or other nutrients) could be part of the association between the oxidative balance scores and mortality risk. The findings of the present study linking increased risk of mortality (especially total cancer mortality) with a high oxidative balance score diet are suggestive, but do not prove that the relation is causal and that the oxidative balance of dietary pattern with regard to combined anti- and prooxidant intake can be considered as a marker for cancer risk. These results have been presented in terms of intake of vitamin C, ß-carotene and iron, which were calculated from data on consumption of foods. Therefore, our results do not establish that the association was specific to vitamin C, ß-carotene and iron as distinct from other nutrients that are also found in these fruits, vegetables and meat. The performance of a dietary oxidative balance score with other and more markers of anti- and prooxidants intakes (e.g., vitamin E, flavonoids, selenium or PUFA) in relation to mortality risk in a smoker’s cohort should be explored further.
To summarize, the oxidative balance of the dietary pattern with regard to intake of vitamin C, ß-carotene and iron affected the risk of mortality in combination with smoking. Male smokers with relatively low intakes of vitamin C and ß-carotene combined with high intakes of iron were at higher risk of death, especially due to cancer. Smokers with a diet unbalanced in anti- and prooxidants may therefore benefit from a recommendation to consume more servings of fresh fruits and vegetables and less meat.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 The Unilever Chair in Nutritional Epidemiology, University of Leuven, Belgium, funded this research project.
4 Abbreviations used: AIC, Akaike’s information criterion; BMI, body mass index; CI, confidence interval; CVD, cardiovascular disease; en%, energy percent; ICD, International Classification of Diseases; PUFA, polyunsaturated fatty acids; RR, relative risk.
Manuscript received 9 October 2001. Initial review completed 6 November 2001. Revision accepted 14 January 2002.
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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