Lung Function in Relation to Intake of Carotenoids and Other Antioxidant Vitamins in a Population-based Study

Holger J. Schünemann1,2, Susan McCann2, Brydon J. B. Grant1,2,3, Maurizio Trevisan2, Paola Muti2 and Jo L. Freudenheim2

1 Department of Medicine, School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY.
2 Department of Social and Preventive Medicine, School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY.
3 Section of Pulmonary, Critical Care, and Sleep Medicine, Veterans Administration Medical Center, Buffalo, NY.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Accumulating evidence suggests that dietary antioxidant vitamins are positively associated with lung function. No evidence exists regarding whether dietary carotenoids other than ß-carotene are related to pulmonary function. In 1995–1998 the authors studied the association of forced expiratory volume in 1 second and forced vital capacity as the percentage of the predicted value (FEV1% and FVC%, respectively) after adjustment for height, age, gender, and race with the intakes of several carotenoids ({alpha}-carotene, ß-carotene, ß-cryptoxanthin, lutein/zeaxanthin, and lycopene) in a random sample of 1,616 men and women who were residents of western New York State, aged 35–79 years, and free from respiratory disease. They observed significant associations of lutein/zeaxanthin and vitamins C and E with FEV1% and FVC% using multiple linear regression after adjustment for total energy intake, smoking, and other covariates. When they analyzed all of these antioxidant vitamins simultaneously, they observed the strongest association of vitamin E with FEV1% and of lutein/zeaxanthin with FVC%. The differences in forced expiratory volume in 1 second and forced vital capacity associated with a decrease of 1 standard deviation of dietary vitamin E or lutein/zeaxanthin were equivalent to the influence of approximately 1–2 years of aging. Their findings support the hypothesis that carotenoids, vitamin C, and vitamin E may play a role in respiratory health and that carotenoids other than ß-carotene may be involved.

airway obstruction; antioxidants; carotenoids; lung diseases, obstructive; oxidants; oxidative stress; respiratory function tests; vitamins

Abbreviations: FEV1, forced expiratory volume in 1 second; FEV1%, forced expiratory volume in 1 second as the percentage of the predicted value; FVC, forced vital capacity; FVC%, forced vital capacity as the percentage of the predicted value; NHANES III, Third National Health and Nutrition Examination Survey


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Decreased pulmonary function consistently predicts mortality in the general population (1GoGo–3Go). As a result of this finding, scientists have focused attention on factors that could influence pulmonary function, among them the role of the balance between oxidants and antioxidants (4GoGo–6Go).

Accumulating evidence suggests that dietary antioxidant vitamins, such as vitamin C, vitamin E, and ß-carotene, are positively associated with lung function. Although vitamins C and E have been studied in some detail, the evidence is still inconsistent (7Go). Dietary intake of ß-carotene was positively associated with pulmonary function in several cross-sectional studies (8GoGo–10Go), but the information on other carotenoids is limited. This lack of information is surprising, because many of the more than 600 carotenoids are found in the diet and have strong antioxidant activity (11Go, 12Go).

Recently, Grievink et al. (13Go) have reported that serum levels of the carotenoids lycopene, {alpha}-carotene, and ß-carotene were positively associated with lung function in an elderly sample of the Dutch population. We also observed that serum levels of carotenoids were positively associated with forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) as indicators of lung function in a general population sample (14Go). However, we found the strongest association for the serum carotenoids ß-cryptoxanthin and lutein/zeaxanthin (14Go). There is no "gold standard" for assessing antioxidant status, and dietary data could provide additional useful information. Until now, no epidemiologic study has investigated the association of lung function with these carotenoids in the diet.

Therefore, the goal of this study was to describe the relation of dietary antioxidant carotenoids ({alpha}-carotene, ß-cryptoxanthin, lutein/zeaxanthin, ß-carotene, and lycopene) and other dietary antioxidant vitamins with pulmonary function (FEV1 and FVC) in the general population.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
This study reports data from a general population sample drawn from Erie and Niagara counties in New York State between September 1995 and December 1998. A detailed description of the study design, participant recruitment, and methodology has been reported (14Go).

Study population
In brief, New York State Department of Motor Vehicles and Health Care Finance Association lists were utilized to randomly select participants aged 35–79 years. Of the 4,946 eligible subjects we initially contacted, 2,537 (1,322 female and 1,215 male) agreed to participate (51.3 percent). Exclusion criteria for this analysis were race other than Caucasian or African American (n = 33); missing information on diet (n = 111); missing information on height, weight, smoking status, or education (n = 170); missing pulmonary function tests (n = 250); unacceptable or not reproducible pulmonary function tests (n = 108); or a history of chronic obstructive pulmonary disease, asthma, or pulmonary fibrosis (n = 249). The remaining 1,616 participants are included in this report. Excluded participants for whom information was available were comparable with included participants in the distribution of gender and race and were similar in their mean age, height, weight, dietary antioxidant intake, and total energy intake (p > 0.05). However, excluded subjects had lower levels of pulmonary function and education and were more likely to be smokers (p < 0.05).

Examination
The examination included an in-person interview about lifestyle habits, a self-administered questionnaire, anthropometric measurements, and spirometry. Spirometry was performed between 6:30 and 9:30 a.m. according to 1994 American Thoracic Society guidelines (14Go, 15Go). We then used multiple linear regression to derive FEV1 and FVC prediction equations for men and women.

Nutrient intake
We assessed usual diet over the 12-month period starting 24 months before the interview and ending 12 months prior to the interview for each participant using the 100-item Health Habits and History Food Frequency Questionnaire ("Block") (16Go). Individual mean daily nutrient intake from foods and beverages was calculated using the DietSys (version 3.7) nutrient analysis software developed specifically for that questionnaire and updated to reflect current values for individual carotenoids; lutein and zeaxanthin were analyzed as lutein/zeaxanthin (17Go, 18Go). Nutrient intake calculations were based on food composition data available from the US Department of Agriculture using the following formula (16Go): portion size (g) x nutrient content (per g) x frequency.

Less than 5 percent of the participants reported intake of carotenoid supplements in the 30 days prior to the interview. Of these participants the majority reported use of ß-carotene, and only one participant used lutein supplements, three used lycopene supplements, and six used cryptoxanthin supplements. Because of the small number of carotenoid supplement users, we did not calculate carotenoid intake from supplements. For vitamins C and E, we collected information on regular supplement use with the food frequency questionnaire, and we repeated the analyses for vitamins C and E adding the intakes of these two vitamins derived from supplements. All nutrient intakes are expressed as daily consumption.

Statistical methods and analysis
Based on values obtained from lifelong nonsmokers who did not report a history of chronic lung disease for men (n = 277) and women (n = 418), we obtained the following predication equations for pulmonary function in men:


and in women:


where race was a dummy variable (Caucasian = 0, African American = 1). We then calculated FEV1 and FVC as the percentage of the predicted value (FEV1% and FVC%, respectively) for all participants adjusted for age, height, and race (14Go).

We examined the distributions of the continuous variables to determine if they were normally distributed and calculated the mean values and standard deviation. The analyzed dependent variables showed normal distributions, and we used natural logarithmic transformation for dietary variables because they were not normally distributed. To examine the correlations among variables we calculated simple Pearson's and partial correlation coefficients (r). To analyze the shape of the relation between antioxidants and lung function, we calculated the mean FEV1% and FVC% levels by quartiles of carotenoids, retinol, and vitamins C and E. We then calculated the differences between the highest and lowest quartiles with adjustment for covariates using general linear models.

To further investigate the association between antioxidant intake and FEV1 or FVC, respectively, we used multiple linear regression analysis. The dependent variables were FEV1% and FVC%, and the independent variables were dietary vitamins C and E, retinol, {alpha}-carotene, ß-carotene, lutein/zeaxanthin, lycopene, and ß-cryptoxanthin. Previously, we found that weight, eosinophil count, education, smoking status, and cumulative tobacco smoke exposure in pack-years of smoking predict FEV1% with the largest variance explained and, therefore, included these variables in the baseline model (14Go). Eosinophil count is a predictor of FEV1 independent of the presence of asthma and, thus, we included it in the model after excluding persons with asthma from the analysis (19Go). We used the same variables in the models predicting FVC%.

First, we investigated each of the antioxidant variables separately after inclusion of total energy intake in the regression models (after logarithmic transformation). We then included all statistically significant dietary antioxidant vitamins simultaneously as independent variables in the regression model. For comparison among the various antioxidant vitamins in the regression models, the vitamin variables were expressed as a change of 1 standard deviation in intake.

We also examined models where the actually measured FEV1 and FVC and not FEV1% and FVC% were the dependent variables. For these analyses the baseline models also included age, height, gender, and race. Furthermore, we repeated the analyses using an external prediction equation based on data from the Third National Health and Nutrition Examination Survey (NHANES III) (20Go). We did not observe important differences using these analytical approaches and present only the results for FEV1% and FVC% obtained with our prediction equations.

To define statistical significance we used the conventional level of p < 0.05 but determined that interaction terms would be significant if the level of significance was p < 0.1. We investigated interaction by including interaction terms of antioxidant vitamin intake, smoking status, and other covariates. For the analyses we utilized the Statistical Package for Social Sciences (21Go) and S-PLUS software (22Go).


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Demographic characteristics, spirometry, and nutrient intake
Table 1 shows the characteristics of the study participants. The average age was 59.6 years and, based on the mean body mass index, participants tended to be overweight. The sample included a slightly higher number of women than men and a small percentage of African Americans. Approximately 43 percent were never smokers, and 13.7 percent were current smokers. Intakes of nutrients were within the expected range, and almost one fourth of the participants reported daily supplemental vitamin intake.


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TABLE 1. Characteristics of participants, Erie and Niagara counties, New York, 1995–1998

 
We observed a moderate to strong correlation among the dietary carotenoids; the correlation coefficients after adjustment for gender, age, and total daily energy intake ranged from r = 0.24 to r = 0.71. Vitamin C intake was also moderately to strongly correlated with carotenoid intake (from r = 0.32 to r = 0.53), but the correlation of dietary vitamin E was weak with carotenoids (r < 0.20) and moderate with vitamin C (r = 0.29).

Analysis of FEV1% and FVC% by quartiles of vitamin intake
Table 2 shows the mean FEV1% and FVC% by quartiles of vitamins C and E, carotenoids, and retinol after adjustment for other covariates (total pack-years of smoking, smoking status, weight, education, eosinophil count, and total daily energy intake). For each of the antioxidant vi-tamins, pulmonary function was higher in the upper quartiles compared with the lowest quartiles. We observed the greatest differences between the bottom and the top quartiles for the antioxidants vitamin C, vitamin E, and lutein/zeaxanthin.


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TABLE 2. Mean FEV1%* and FVC%*,{dagger} by quartiles of dietary vitamins C and E, carotenoid, and retinol intake, Erie and Niagara counties, New York, 1995–1998

 
Multiple linear regression analysis
Table 3 summarizes the results of multiple linear regression analysis after inclusion of all covariates. Multiple linear regression of FEV1% revealed independent associations with pack-years of smoking history, smoking status, education, eosinophil count, and weight; these variables were included in the baseline model. FVC% was associated with pack-years of smoking history, weight, and education, but it showed no statistically significant association with eosinophil count and no additive effect of smoking status after we included pack-years of smoking in the baseline model. For the analysis of dietary variables, models were also adjusted for total daily energy intake. We observed a statistically significant association of vitamins C and E and lutein/zeaxanthin with FEV1% and FVC% when we added these variables individually and separately to the baseline regression models. Among all the carotenoids, lutein/zeaxanthin was the only carotenoid that showed a statistically significant association.


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TABLE 3. Multiple linear regression coefficients for regression on FEV1%{dagger} and FVC%{dagger}, Erie and Niagara counties, New York, 1995–1998{ddagger}

 
Table 4 shows regression coefficients for the significant antioxidant variables when we included all statistically significant variables simultaneously in the model. Although for FEV1% vitamin E was the only significantly correlated antioxidant variable, lutein/zeaxanthin was the only significant correlate of FVC%. We observed no statistically significant interaction of antioxidant intake with smoking (smoking status or pack-years of smoking history). However, because of possible effect modification of smoking on pulmonary function by nutrient intake, we performed analyses separately by smoking status.


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TABLE 4. Multiple linear regression coefficients for regression on FEV1%* and FVC%*, Erie and Niagara counties, New York, 1995–1998{dagger},{ddagger}

 
Important antioxidant correlates of FEV1% by smoking status
Table 5 summarizes the findings when lutein/zeaxanthin and vitamins C and E were added separately or simultaneously to the regression models for never, former, and current smokers after adjustment for confounders. When we added variables separately to the models, in never smokers lutein/zeaxanthin and vitamin E were significant correlates of FEV1 but not vitamin C. No antioxidant variable showed a significant correlation in former smokers. We observed the strongest correlation for all variables in current smokers, but the regression coefficient was not significant for vitamin E. When we added variables simultaneously to the baseline model stratified by smoking, the antioxidant vitamins failed to reach statistical significance. Compared with the model with variables added separately, the coefficient for lutein/zeaxanthin was reduced mainly in current smokers. While the coefficients for vitamin E were similar compared with the other models, we observed the greatest reductions in the regression coefficients for vitamin C in all smoking strata.


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TABLE 5. Multiple linear regression coefficients for regression on FEV1%*, Erie and Niagara counties, New York, 1995–1998{dagger},{ddagger}

 
Important antioxidant correlates of FVC% by smoking status
Table 6 shows the regression coefficients for the important dietary variables by smoking status when we added the variables individually or simultaneously to the regression models. The antioxidant variables were significant or borderline significant correlates of lung function in never smokers when we added the variables individually to the baseline model. As for FEV1%, we did not find significant correlations in former smokers, but in current smokers lutein/zeaxanthin was significantly related to FVC% when all antioxidant variables were added simultaneously to the regression models. In all smoking strata, lutein/zeaxanthin was the strongest correlate that achieved statistical significance in never and current smokers, but vitamins C and E were not statistically significant.


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TABLE 6. Multiple linear regression coefficients for regression on FVC%*, Erie and Niagara counties, New York, 1995–1998{dagger},{ddagger}

 
Other models examined
Adjustment for regular supplemental vitamin use, serum cholesterol, exclusion of eosinophil count, or inclusion of age, height, and vitamin variables after quadratic, cubic, or logarithmic transformation made no substantial difference in the results. We investigated interaction by including the interaction terms of antioxidant vitamin intake, smoking status, and gender, but we did not observe statistically significant interactions. There was also no important interaction among the antioxidant variables. When we stratified the regression analyses by reported daily vitamin supplement intake, we did not observe important differences between users and nonusers for the coefficients of lutein/zeaxanthin. However, there was a reduction in the coefficients of vitamins C and E in regular vitamin users when the variables were added either individually or simultaneously (data not shown). After addition of supplemental vitamin C and E intakes to dietary intake, the regression coefficients were only slightly larger.


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In this population-based study we observed that, among the several prevalent carotenoids in the diet, lutein/zeaxanthin had the strongest association with pulmonary function. We also found a positive association between pulmonary function and dietary intakes of vitamin C and vitamin E. When we considered these antioxidant vitamins simultaneously, only vitamin E correlated significantly with FEV1% and lutein/zeaxanthin with FVC%. Including intakes of supplemental antioxidant vitamins C and E did not significantly alter these results. When we repeated the analysis stratified by smoking status, the associations between antioxidant vita-mins and FEV1% tended to be stronger in the group of current smokers. Lutein/zeaxanthin and vitamin E intakes showed a positive association with FVC% in never smokers, but only lutein/zeaxanthin was associated with FVC% in former and current smokers.

Several previous studies have shown a positive association of dietary ß-carotene with pulmonary function (8GoGo–10Go). Until now, however, studies have focused only on dietary ß-carotene and not on other carotenoids. We have investigated carotenoids other than ß-carotene because of their strong antioxidant function and because they are highly concentrated in human plasma.

Our findings indicate that, among all considered carotenoids, dietary lutein/zeaxanthin has the strongest relation to FEV1 and FVC%. This finding is somewhat surprising because dietary lycopene and ß-carotene intakes are higher than that of lutein/zeaxanthin and because lycopene has been considered to be a more powerful antioxidant than ß-cryptoxanthin and lutein/zeaxanthin (11Go). It has been emphasized, however, that antioxidants' activity measured in vitro, including their relative action compared with that of other carotenoids, may not resemble their activity in complex in vivo conditions (23Go). For example, in comparison with other carotenoids, a stronger protection against damage of the retina has been ascribed to lutein/zeaxanthin (24Go, 25Go), and a negative association with prevalence of angina pectoris and carotid atherosclerosis has been reported for serum ß-cryptoxanthin (26Go). However, there are limited epidemiologic data for carotenoids other than ß-carotene and their relation to human disease.

We previously found that cryptoxanthin and lutein/zeaxanthin in serum were positively related to pulmonary function (14Go). We report now on the relation between dietary antioxidant vitamin intake and pulmonary function. In the current analysis we could confirm the results for lutein/zeaxanthin but not for cryptoxanthin. The lack of an association between dietary cryptoxanthin intake and pulmonary function could be the result of the difficulties associated with accurately measuring cryptoxanthin in the diet. It may be that these limitations are not present for measurement of dietary lutein/zeaxanthin intake or that lutein/zeaxanthin is a stronger antioxidant than ß-cryptoxanthin, and we found a positive association in spite of limitations in the dietary measurement of this compound.

The results of this study also confirm previous findings that dietary intake of vitamin C is associated with pulmonary function when vitamin C is considered individually as a dietary antioxidant vitamin (8GoGo–10Go, 27GoGoGo–30Go). Recently, we have systematically reviewed the relation between antioxidants and pulmonary function (7Go) and found an approximate pooled effect of a 37-ml increase in FEV1 associated with an increased intake of 100 mg of daily vitamin C. The corresponding estimate in this study is approximately 40 ml for an increased intake of 100 mg of daily vitamin C and, thus, in agreement with the pooled estimate.

Cigarette smoke contains large concentrations of oxidants (31Go). As a result one might expect a stronger association of antioxidant vitamins with pulmonary function in smokers if antioxidants could prevent oxidative damage. We failed to observe a statistically significant interaction of serum antioxidants with smoking, but this negative finding should be interpreted with caution. No previous study had sufficient power to detect a statistically significant interaction of vitamin C intake with smoking, but Hu and Cassano (9Go) observed a stronger correlation of vitamin C with FEV1 in current smokers in an analysis of the NHANES III data, the largest data set investigated to date. Our study was not sufficiently powered to observe effect modification by smoking, but our results lend further support to the hypothesis that the effect may be stronger in current smokers. The associations between antioxidants and lung function were weak in former smokers. This finding may be a result of a prior change to a healthier lifestyle in smokers with impaired lung function that included smoking cessation and higher intake of dietary antioxidant vitamins. It is also important to note that, similar to our study, previous studies observed an attenuation of the association between pulmonary function and vitamin C when other antioxidants had been taken into account (9Go, 29Go). This attenuation appears to result from the correlation of the dietary vitamins C and E intake variables due to common food sources, but there is evidence that they act, at least in part, independently in the lung (32Go, 33Go).

The association of vitamin E with lung function has been found with less consistency than that of vitamin C. Our study adds evidence to the epidemiologic studies that found a stronger association of FEV1 with vitamin E than with vi-tamin C (34Go), including NHANES III (9Go). The stronger association of vitamin E with pulmonary function compared with vitamin C may be a result of random error due to sampling, because other studies did not observe a positive association with vitamin E (10Go) or found that the association was weakened after taking the effects of vitamin C into account (29Go). However, the attenuation of an association by another nutrient is often present in the analysis of dietary data, and it is, at least in part, related to the autocorrelation of dietary nutrients. In addition, differences in measurement error between nutrients can result in falsely stronger associations of the nutrient with lower measurement error. Since dietary vitamin E intake is more difficult to measure and is associated with a greater measurement error than vitamin C intake (35Go), a stronger association with vitamin C should be observed. Further support for an association of vitamin E with pulmonary function comes from our earlier analysis and the work of others on serum vitamin E and pulmonary function (9Go, 14Go, 36Go).

In previous studies, consideration of supplemental antioxidant intake was restricted to adjusted regression models using dichotomous dummy variables (9Go, 10Go). These studies did not report significant changes when the analysis was adjusted for supplemental vitamin use, but they left considerable uncertainty about the effect because of the lack of quantified supplement intake. We calculated the intakes of supplemental vi-tamins C and E, because these supplements were used regularly in this population. Including information on the intakes of these supplemental vitamins did not significantly alter the results. However, when we stratified by vitamin use, the association between vitamins C and E with pulmonary function tended to be weaker in regular vitamin supplement users for both dietary and total (diet and supplement) intakes. This observation could indicate that long-term users of these antioxidants reach a possible threshold or ceiling effect. The possibility of a ceiling effect is supported by the observation that the majority of supplement users were also in the highest quartile of dietary vitamin intake.

This study has several limitations. The cross-sectional design and the subsequent uncertainty about the cause-effect relation represent a weakness of our study. Longitudinal studies should provide evidence to answer this problem. Another limitation is the limited power to perform subgroup analysis by smoking status. However, even larger studies such as the NHANES III had limited power for this analytical approach (9Go). Furthermore, the high rate of nonresponders and missing data leaves the possibility for selection bias. Participants excluded because of missing data did not differ from those included in dietary antioxidant or energy intakes, age, height, or weight, but excluded participants had lower lung function, education, and prevalence of never smokers. Because of the possibility for selection bias, our findings can be generalized only with caution. In addition, we cannot exclude that multiple hypothesis testing led to erroneous statistically significant findings.

The strength of this study is the measurement of several dietary carotenoids in relation to lung function, an approach that has not been chosen previously. Because information on the relation of supplemental vitamin intake and pulmonary function is limited, our study adds important information to the current body of evidence. Information about long-term use of supplemental carotenoids is not available. Since less than 5 percent of the participants in this study used supplements containing carotenoids in the month prior to the interview, it is unlikely that carotenoid supplements have been taken regularly and that considering these supplements would have significantly altered the results. Another strength is that there was no important change in the results when we used the NHANES III data as an external prediction equation for FEV1% and FVC%.

Although it is not resolved completely whether vitamins C and E play a strong role in antioxidant defense in the lung and it is not completely explained why dietary lutein/zeaxanthin shows stronger effects than the other carotenoids, the magnitude of the observed effects on pulmonary function is of clinical significance. To bring the estimates into perspective, a decrease of 1 standard deviation of dietary vitamin E (72.5 mg/day) or lutein/zeaxanthin (1.8 mg/day) is equivalent to the negative effect of approximately 1–2 years of aging on FEV1 and FVC, respectively.

In summary, we found a positive association of vitamin C, vitamin E, and lutein/zeaxanthin intake with pulmonary function. We identified lutein/zeaxanthin as the dietary carotenoid with the strongest association with pulmonary function. When we considered carotenoids, vitamins C and E, and retinol simultaneously, the individual effects were reduced and vitamin E was most strongly related to FEV1 and lutein/zeaxanthin with FVC. We also found further evidence that smokers may show stronger associations between dietary antioxidants and lung function. Our findings emphasize that carotenoids may play a role in respiratory health and that studies should include carotenoids other than ß-carotene. Further studies are needed to confirm these results, and longitudinal studies could help to clarify whether this association is related to lung development in childhood and adolescents or whether it is the result of an accumulation of protective effects against oxidative damage throughout life. A meta-regression analysis that pools data from all studies could help to answer the question of possible effect modification of smoking on the relation between antioxidant vitamins and lung function.


    ACKNOWLEDGMENTS
 
Supported in part by grant AA 09802 from the National Institute on Alcohol Abuse and Alcoholism and by a Buswell Fellowship to Dr. Schünemann.

The authors thank the personnel at the Center for Preventive Medicine, University at Buffalo, for their contribution to the study, Dr. John M. Weiner for statistical advice, and Marsha Barber for assistance.


    NOTES
 
Reprint requests to Dr. Holger J. Schünemann, Departments of Medicine and of Social and Preventive Medicine, School of Medicine and Biomedical Sciences, State University of New York, 270 Farber Hall, 3435 Main Street, Buffalo, NY 14214-3000 (e-mail: HJS{at}buffalo.edu).


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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication April 3, 2001. Accepted for publication August 16, 2001.