To the best of our knowledge, this is the first study to compare dietary intakes of the different forms of tocopherols (α-, β-, γ-and δ-tocopherol) and lung cancer risk. Our principal findings were that, after accounting for the other forms of tocopherols and vitamin C intake, there was a strong inverse relationship between dietary α-tocopherol and lung cancer risk. To the extent possible, as explained in the methods, we have addressed the scientific validity of these findings because our models addressed the inter-correlations between the tocopherols and total calories.
Much of the research on vitamin E and lung cancer has centered on the role of α-tocopherol. The α-tocopherol, beta-carotene (ATBC) trial examined the effect of α-tocopherol (synthetic dl-α-tocopheryl acetate) or synthetic β-carotene on lung cancer incidence among 29,133 Finnish male smokers aged 50–69 years. After 5 to 8 years (median, 6.1 years), lung cancer incidence did not differ in the α-tocopherol compared to the placebo group.15
Several prospective cohort studies of dietary α-tocopherol and lung cancer risk have been published. The New York State cohort (n
= 395 cases),16
Netherlands cohort (n
= 939 cases),17
Finnish cohort (n
= 117 cases),18
NHANES 1 Follow-up (n
= 248 cases),19
Singapore Chinese Health cohort (n
= 482 cases)20
and the Nurses Health Cohort (n
= 593 cases)21
studies all reported nonsignificant reductions in lung cancer risk with increasing intake of dietary α-tocopherol. In a recent pooled analysis, vitamin E from foods was inversely associated with lung cancer risk, but the trend was also not statistically significant.22
Of 4 prospective studies23–26
that assessed serum α-tocopherol levels and lung cancer risk, two23,24
reported significant inverse association. In the ATBC trial of male smokers, a significant 19% reduction in lung cancer risk was observed among men who were in the highest versus
lowest quintile of α-tocopherol concentrations at baseline.23
In a nested case-control study within the Beta-Carotene and Retinol Efficacy Trial (CARET), a significant 48% reduction in lung cancer risk was observed in highest versus
lowest quartile of α-tocopherol concentrations.24
Yet in a nested case–control study26
within the Japanese Collaborative cohort and the Yunnan Tin Miners prospective study,25
no association was observed between serum α-tocopherol levels at baseline and lung cancer risk. Of the 3 studies24–26
that described serum γ-tocopherol levels, none reported a significant association. The range in serum tocopherol levels varied across studies, and the studies with small range (for e.g., the Yunnan Tin Miners study25
) may not have had the ability to detect a significant relationship.
Overall, the epidemiologic evidence to date suggests that low levels of both dietary and serum α-tocopherol may predispose to lung cancer risk. However, comparability of these epidemiologic analyses may have been limited by various factors, such as use of different food composition databases, laboratory assays for α- and γ-tocopherol plasma/serum measurements, and differences in underlying lipoprotein levels, which are carriers of vitamin E. Our large lung cancer case–control study (n = 1,088 cases) adds meaningful data on α-, γ-, β- and δ-tocopherol to the literature. We found consistent independent associations for increased dietary α-tocopherol intake and risk reduction but did not find independent associations for γ-, β- and δ-tocopherol in lung cancer risk. In stratified analyses, in particular, we found that current smokers and those with longer duration of smoking were afforded greater protection from dietary α-tocopherol. Cigarette smoke, an established risk factor for lung cancer, is an important source of reactive oxygen species (ROS) in the lungs. Thus, 1 would expect that, in current compared to former smokers or those with a longer duration of smoking, dietary α-tocopherol intake would be less effective because it is plausible that ROS production from cigarettes may overwhelm the protective effects associated with α-tocopherol intake.
For dietary α-tocopherol intake, we observed protective trends in both nonusers and users of vitamin/mineral supplements. However, the amounts and frequency of use of vitamins/minerals were unavailable to compute total (dietary plus supplemental) α-tocopherol intake and to analyze in greater detail the associations of supplemental dose and risk.
Emphysema, which is strongly influenced by smoking,27
is a chronic inflammatory condition28
and a risk factor for lung cancer.29
Dietary vitamin E (α-, γ-, β- and δ-tocopherol) has been shown to have potent antiinflammatory properties.30
We observed significant protective trends against lung cancer risk with increased dietary intake of α-tocopherol largely in the subjects who did not report a diagnosis of emphysema. Chronic inflammation in emphysema results in a cycle of lung injury and repair that may overwhelm the antiinflammatory effects associated with dietary vitamin E intakes.
Similar inverse associations between α-tocopherol intake and lung cancer risk were noted for early and late stage disease, and histology. However, there were too few small cell lung cancers in each quartile of α-tocopherol intake for meaningful interpretation of the data.
When we assessed the top food contributors of α-tocopherol in our population as risk factors, as expected, we found a significant inverse association with increased intake of peanut butter, salad dressing and fruit and vegetables (). While these results validate our findings regarding α-tocopherol and lung cancer risk, it is also possible that other constituents in foods rich in tocopherols may be etiologically important.
We recognize the methological limitations investigating the association of dietary intake of the different forms of vitamin E and risk of lung cancer. Thus, we carefully constructed our models to account for the independent effects of the 4 different forms of dietary tocopherols and other dietary factors such as vitamin C intake. We also recognize that our study would be strengthened by more objective measurements of α-, β-, γ- and δ-tocopherol status, such as serum or cellular levels; however, serum samples are available only in a subset of subjects.
Our case–control study had other limitations. This study was originally designed to examine genetic susceptibility to lung cancer, while the present data represent secondary analysis. Like all case–control studies, our analysis raises concern about recall bias and residual confounding. In an attempt to reduce biased reporting of dietary intake in cases and controls, cases reported their diet during the year prior to diagnosis, and controls reported their diet during the year prior to enrollment into the study. The FFQ is practical for large epidemiology studies such as ours, but its use may introduce measurement error,31,32
leading to biased estimates of the association between a given dietary factor and cancer. It has been argued that because of misclassification errors, the FFQ is not always able to detect weak associations,33,34
thereby attenuating the true association.
In an effort to improve the accuracy, our interviewers were trained in FFQ administration, while FFQ responses were reviewed and requeried by staff nutritionists. Portion sizes were assessed with visual aids. It is well recognized that the FFQ can reliably classify individuals by quartile of intake.35
While recall bias may exist, in our study the control population consumed comparable daily mean dietary α-tocopherol intakes (6.1 and 6.5 mg/d for men and women, respectively) to values reported from a national sample of US adults (mean α-tocopherol intake: men, 6.7 mg/d; women, 4.7 mg/d).36
The estimated average requirement (EAR) for vitamin E (α-tocopherol) is 12 mg/d and the recommended dietary allowance (RDA) is 15 mg/d. Thus, like national surveys, we found that even our healthy controls did not consume adequate amounts of vitamin E.2
It is well-known that estimates of dietary vitamin E intake are especially difficult to assess because dietary fat intake serves as an important carrier of vitamin E and is typically under-reported in dietary surveys. The quantity of fats or oils added during cooking is difficult to recall precisely but can contribute greatly to tocopherol intake and absorption. Additionally, respondents may not report the type of oils in preparation if they are not preparing their foods; as a result, default selections are made in the analysis that may improperly account for the tocopherol content of these foods. If indeed tocopherols are important in lung cancer prevention, underestimation of intake could drive the associations toward the null.
In conclusion, we report consistent inverse association between dietary α-tocopherol intake but no independent associations for β-, γ- and δ-tocopherol after adjustment for the other tocopherols and vitamin C. Our data should be useful in stimulating additional epidemiologic and basic science research in the relationship of different forms of vitamin E and cancer.