Dietary Antioxidants and Lung Cancer Risk: A Case-Control Study in Uruguay

Abstract: To examine the protective role of dietary antioxidants (carotenoids, vitamin C, vitamin E, glutathione, and flavonoids) in lung cancer risk, a case-control study involving 541 cases of lung cancer and 540 hospitalized controls was carried out in Uruguay. The relevant variables were energy adjusted using the residuals method and then categorized in quartiles. Adjusted odds ratios (ORs)for antioxidants were calculated through unconditional logistic regression. With the exception of lycopene and vitamin C, the remaining antioxidants were associated with significant reductions in risk of lung cancer. Of particular interest was the inverse association between dietary glutathione and lung cancer [OR of quartile with highest intake compared with lowest quartile = 0.42, 95% confidence interval (CI) = 0.270.63]. Also, carotenoids and vitamin E were associated with significant reductions in risk of lung cancer (OR = 0.43, 95% CI = 0.29-0.64 for total carotenoids and OR = 0.50, 95% CI = 0.39-0.85 for vitamin E). A joint effect for high vs. low intakes of beta-carotene and glutathione was associated with a significant reduction in risk (OR = 0.32, 95% CI = 0.220.46). It could be concluded that dietary antioxidants are associated with a significant protective effect in lung carcinogenesis and that the inverse association for glutathione persisted after controlling for total vegetables and fruits.

Introduction
Oxidative stress resulting from tobacco smoke plays a crucial role in lung carcinogenesis ( 1-3). Tobacco smoke contains a large number of free radicals, estimated as 10-15 per puff ( 4-6). On the other hand, dietary antioxidants, defined for the purposes of this study as substances of different chemical structure with the common feature of scavenging free radicals, have been associated with an inverse association with lung cancer risk in smokers ( 7). Vitamins C and E, are, together with carotenoids, among the most important antioxidants in the human diet ( 8). Other bioactive substances with antioxidant activity, like glutathione and flavonoids, have been less studied ( 9, 10).

This study has been carried out with the objective of estimating the relative protection of different dietary antioxidants in the risk of developing lung cancer.

Material and Methods
This study is the result of two case-control studies: the first was carried out between 1993 and 1996 with the objective of determining the role of fat and cholesterol in lung carcinogenesis; the second is part of an ongoing large multisite case-control study on diet and cancer initiated two months after the completion of the first study. Both studies used the same questionnaire, with minor modifications, and the questionnaires were administered by the same interviewers.

Selection of Cases
In the time period 1993-1997, all newly diagnosed patients with lung cancer were considered eligible for this study. In total, 590 patients with lung cancer were identified in the four major hospitals in Montevideo. From this initial number, 541 were successfully contacted and interviewed (response rate 91.6%), whereas 49 patients were not included in the study. Reasons for nonparticipation were 1) refusal (31 patients, 5.3%) and 2) advanced disease (18 patients, 3.1%). Female patients were considered noneligible a priori because of an anticipated low accrual of cases; thus the study was restricted to men. The cases were distributed by cell type as follows: 1) squamous cell (238 patients, 44.0%), 2) small cell (66 patients, 12.2%), 3) adenocarcinoma (129 patients, 23.8%, 4) large cell (22 patients, 4.1%), and 5) carcinoma not otherwise specified (21 patients, 3.9%). Sixty-five patients (12.0%) were not histologically verified, mainly because of the peripheral location of the tumors. In these patients, the diagnosis of lung cancer was based on clinical, radiologic, and endoscopic findings performed during the workup evaluations.

Selection of Controls
Male hospitalized patients with conditions not related to tobacco smoking and without recent changes in the diet were considered eligible for the study. A total of 600 patients fulfilling these requirements were randomly identified in the same four hospitals through the log book of admissions. Five hundred forty patients were successfully face-to-face interviewed in the hospital (response rate 90.0%). The remaining 60 patients (10.0%) refused the interview. The control series was distributed by diagnostic condition as follows: eye disorders (157 patients, 29.1%), abdominal hernia (120 patients, 22.2%), acute appendicitis (58 patients, 10.7%), injuries (52 patients, 9.6%), fractures (51 patients, 9.4%), skin diseases (36 patients, 6.7%), varicose veins (24 patients, 4.4%), hydatid cyst (18 patients, 3.4%), osteoarticular disorders (15 patients, 2.8%), and anemia (9 patients, 1.7%).

Design of the Study
Controls were frequency matched to cases on age ( 10-yr period), residence (Montevideo, other counties), and urban/rural status (mainly urban, mainly rural) according to a control-to-case ratio of 1.0. No proxy respondents were accepted, and all interviews were performed in the hospitals, shortly after admittance for cases and controls. Interviewers were blinded regarding the objectives of the study.

Questionnaire
A questionnaire administered to each participant included the following sections: 1) sociodemographic variables, 2) family history of cancer in a first-degree relative, 3) anthropometric variables [self-reported height, self-reported weight, and body mass index (wt/ht2)], 4) a complete history of tobacco use [age at start, age at termination, lifetime average of cigarettes per day, duration of smoking, type (color) of tobacco, type of cigarette (manufactured, handrolled, filter, plain, mixed)], 5) a complete history of alcohol consumption (age at start, age at termination, lifetime amount consumed in milliliters of ethanol, type of beverage), 6) a complete occupational history (job title, age at hire, age at termination, duration of employment), and 7) a food frequency questionnaire (FFQ). The FFQ comprised 64 food items considered representative of the usual diet of Uruguayans. Although this FFQ was not validated against a dietary record, it was submitted to a reproducibility study ( 11) and was used in several studies on diet and lung cancer ( 12-15). Briefly, an original list of 90 foods was selected after consultation with an expert dietitian as representative of the usual diet of the Uruguayan population. Then, after pilot testing, stepwise regression analysis was performed to identify (for each nutrient) the most discriminating food items, as suggested by Willett ( 16). This resulted in the final list of 64 food items ( 11). Then 80 healthy visitors to the same hospitals previously mentioned were randomly selected and interviewed by the same interviewers participating in the study. After eight months, they were submitted to a second interview. The results showed Pearson correlations that ranged from 0.30 for calcium to 0.79 for carbohydrate intake.

For each food, a commonly used unit or portion size was specified, and participants were asked how often, on average, over the past year, or the year before onset of symptoms for the cases, they had consumed that amount of each food. The responses were open-ended, allowing each food to be treated as a continuous variable ( 16). Responses were converted to times per year, multiplying by the appropriate time units. The nutrient composition of each food was estimated from local food tables ( 17). Total intake for each nutrient was calculated as the sum of the products of the frequency weight and the nutrient content for each food. Because data on glutathione and carotenoids are not available in Uruguay, values reported by Jones and co-workers ( 18) and Mangels and colleagues ( 19) were used. The values of Mangels and colleagues were used because of their widespread acceptability, allowing comparisons. Similarly, values for quercetin, kaempferol, and total flavonoids were not available in Uruguay. Therefore, we decided to use the values obtained by Hertog and associates ( 20-22).

Also, vegetables and fruits were examined. The following food items were categorized in approximate tertiles: carrot, tomato, lettuce, onion, garlic, Swiss chard, spinach, potato, sweet potato, winter squash, cabbage, cauliflower, zucchini, red pepper, orange, tangerine, apple, pear, grape, peach, banana, fig, fruit cocktail, all vegetables, all fruits, all vegetables and fruits.

Statistical Analysis
The distribution of all study subjects (cases and controls) was categorized in quartiles (or tertiles) for each nutrient or food item. Crude and adjusted odds ratios (ORs) were estimated through unconditional logistic regression ( 23), since individual matching was not used. The data were analyzed using a model that included the frequency matching variables (age, residence, urban/rural status), potential confounders (tobacco smoking in pack-yr, total energy, total fat), and the study variables (carotenoids, vitamin C, vitamin E, glutathione, total flavonoids, quercetin, kaempferol) introduced separately in the model. Macro- and micronutrients were adjusted for total calorie intake by use of the residuals method of Willett and Stampfer ( 24). Energy adjustment was carried out by regressing the nutrient (dependent variable) and the energy intake (independent variable), as measured by the same instrument after logarithmic transformation. The residuals from the model were then added to the mean total energy intake.

The test for trend after multivariate adjustment for covariates was determined by the chi2 statistic across the vector of indicator variables for the exposure of interest. For all ORs, 95% confidence intervals (CI) were calculated. All calculations were performed in the EGRET program ( 25).

Results
The distribution of cases and controls by sociodemographic variables and selected risk factors is shown in Table 1. Because cases and controls were frequency matched on age, residence, and urban/rural status, the proportion of both series was almost identical. Cases were less educated than controls, whereas monthly income was similar in cases and controls. The proportion of family history of lung cancer in a first-degree relative was higher in cases than in controls, whereas cases were leaner than controls. As expected, the proportion of smokers was much higher among cases than among controls. Also, the proportion of heavy drinkers was higher among cases than among controls.

The foods that make the greatest contribution to estimated usual dietary intakes of beta-carotene, vitamin C, vitamin E, glutathione, and flavonoids are shown in Table 2. The major contributors of beta-carotene were sweet potato, winter squash, and carrot, whereas the main source of vitamin C was orange. Corn oil and lettuce were important sources of vitamin E, whereas beef, potato, winter squash, and orange were the four top sources of glutathione. Almost 53% of flavonoid intake was from tea, whereas apple and lettuce were important sources. As expected, carrots (88%) and tomato (87%) were the main contributors of a-carotene and lycopene, respectively. Finally, orange was the main source of beta-cryptoxanthin (76.5%).

Mean values of total energy intake and nutrients for cases and controls are shown in Table 3. Fat intake was significantly higher among cases than among controls. Values for beta-carotene, alpha-carotene, and beta-cryptoxanthin were higher among controls than among cases. Vitamins C and E showed similar means among cases and controls, whereas flavonoids displayed significantly higher values among controls.

Age- and calorie-adjusted Pearson correlation coefficients among major antioxidants are shown in Table 4. The nutrients were normalized by logarithmic transformation. High coefficients were observed among total carotenoids, vitamins C and E, and glutathione, whereas lower correlations were observed between flavonoids and the other antioxidants.

ORs of lung cancer for vegetables and fruits are shown in Table 5. Carrot, spinach, winter squash, orange, apple, and peach displayed significant inverse associations (OR for carrot = 0.55, 95% CI = 0.39-0.78 for the highest tertile of intake compared with the lowest). Inverse but nonsignificant associations were observed for tomato, lettuce, sweet potato, peach, and banana (OR for the highest tertile of intake of sweet potato compared with the lowest = 0.72, 95% CI = 0.51-1.00). Onion, Swiss chard, and pear were not associated with lung cancer risk (OR for onion = 1.05, 95% CI = 0.75-1.47). Also, garlic, cabbage, cauliflower, zucchini, red pepper, grape, and fig were not associated with risk (results not shown). Total vegetable and total fruit intakes were strongly protective (OR for the highest tertile of intake of total vegetables compared with the lowest = 0.48, 95% CI = 0.34-0.66).

ORs of lung cancer for dietary antioxidants are shown in Table 6. Increasing intake of beta-carotene, alpha-carotene, lutein, and beta-cryptoxanthin was associated with reduced lung cancer risk (OR for highest quartile of beta-carotene intake = 0.42, 95% CI = 0.28-0.63). No such effect was suggested for lycopene (OR for highest quartile of lycopene intake = 0.83, 95% CI = 0.56-1.21). As expected from the previous findings, total carotenoid intake was associated with a significant protective effect in the two highest quartiles of intake (OR for the highest quartile of total carotenoid intake = 0.43, 95% CI = 0.290.64). All carotenoids, with the exception of lycopene, displayed significant dose-response patterns. Vitamin C intake was not associated with reduction in risk of lung cancer (OR = 1.03, 95 % CI = 0.70-1.52 for the highest quartile of intake). Elevated vitamin E intake was associated with a significant reduction in risk (OR for the highest quartile of vitamin E compared with the lowest quartile = 0.50, 95% CI = 0.340.74), as was glutathione intake (OR in the highest quartile = 0.42, 95% CI = 0.27-0.63). When glutathione was analyzed by source of origin, the results were similar (OR for the highest quartile of glutathione from fruits = 0.50, 95% CI = 0.34-0.75). Also, quercetin and total flavonoid intakes were associated with significant reductions in risk (OR = 0.59, 95% CI = 0.40-0.87 for the highest quartile of intake of total flavonoids), whereas the dose response for kaempferol was nonsignificant.

ORs of lung cancer for dietary antioxidants by cell type are shown in Table 7. No major differences were observed for each cell type, Whereas vitamin C intake was not associated with lung cancer risk in squamous cell and adenocarcinoma of the lung, a nonsignificant reduction in risk was observed for small cell lung cancer (OR = 0.5, 95% CI = 0.2-1.4). Also, glutathione intake was strongly protective among patients with squamous cell and adenocarcinoma, whereas no association was observed among patients with small cell lung cancer (OR = 0.8, 95% CI = 0.3-1.7).

ORs of lung cancer for the joint effect of beta-carotene and glutathione are shown in Table 8. Both nutrients were dichotomized in low and high intakes, according to the median value of intake. A marked reduction in risk was observed when both variables were set into the high category of intake (OR = 0.32, 95% CI = 0.22-0.46).

ORs for food items and food groups across antioxidants are shown in Table 9. Adjusting for beta-carotene, alpha-carotene, total glutathione, and total flavonoids did not substantially alter the relationship of intake of total vegetables to risk. However, when total fruits and total vegetables and fruits were adjusted for glutathione, the estimate was no longer significant (OR for the highest quartile of total fruit intake compared with the lowest = 0.7, 95% CI = 0.5-1.2).

We investigated the extent to which risk reduction for antioxidants was independent of total vegetable, total fruit, and total vegetable and fruit intakes (Table 10). Whereas alpha-carotene, beta-carotene, and glutathione displayed independent effects, lutein, cryptoxanthin, and total flavonoids showed weaker associations, with the CIs for fourth quartile ORs included in the null. No associations were observed for lycopene and vitamin E, whereas vitamin C was associated with an increased risk, which was significant after controlling for total vegetables and fruits (OR for the highest quartile = 1.9, 95% CI = 1.2-2.9).

Discussion
According to the results of the present study, significant inverse associations were observed for carotenoids, vitamin E, glutathione, and flavonoids. These findings were observed in previous studies ( 8, 10, 26-30) for carotenoids, vitamin E, and flavonoids, whereas the protective effect of glutathione is, to our knowledge, a new finding in the nutritional epidemiology of lung cancer. Also, total vegetable and total fruit intakes were associated with significant protective effects.

A recent international report concluded that high dietary carotenoid intake probably decreases the risk of lung cancer ( 8). The main mechanism responsible for this decreased risk is the strong antioxidant effect of these substances ( 7), although other mechanisms have been suggested. Among these, modulation of carcinogen metabolism, increase in cell differentiation, and enhancement of the immune function have been supported by experimental studies ( 7). The antioxidant effect of carotenoids is related to their extended system of conjugated double bonds. In particular, tobacco smoke is genotoxic through the activity of nitrogen dioxide. In short-term tests, carotenoids inhibited the genotoxicity of nitrogen dioxide and of reactive oxygen species ( 7). Recently, two prospective randomized clinical trials concluded that supplemental lB-carotene was associated with a significant increase in lung cancer incidence and mortality ( 42, 43). This finding suggests that supplemental beta-carotene could have cocarcinogenic effects in well-nourished individuals. Several mechanisms have been suggested to explain this troublesome and unexpected finding: 1) the combination of tobacco smoke and the high partial pressures of oxygen in the lung may trigger autoxidation of beta-carotene, resulting in the formation of further free radicals, 2) high concentrations of beta-carotene in the lumen of the digestive tract may inhibit the absortion of alpha-carotene and lycopene, and 3) beta-carotene could inhibit the apoptosis of preneoplastic cells. Whatever the mechanism(s) could be, these findings cast doubts on the supplementation with beta-carotene ( 7, 8).

Vitamin E intake has been inversely associated with lung cancer risk in most studies ( 8, 30). In a recent study ( 30), the joint effect of vitamins E and C was associated with a reduction in risk of 40%. Vitamin E is the most important intracellular antioxidant in the body. As such, it protects polyunsaturated fat in cell membranes from oxidation by oxygen radicals ( 8).

Vitamin C is the most abundant water-soluble antioxidant in the body ( 8). The relationship between vitamin C intake and lung cancer has been the subject of numerous studies ( 8, 28, 30, 33, 34), which suggested a moderate protective effect. In the present study, vitamin C intake was not associated with decreased lung cancer risk.

Glutathione is a cysteine-containing tripeptide with antioxidant and anticarcinogenic properties that is present in plant and animal foods that form the bulk of the human diet ( 18). According to the present study, total glutathione intake was associated with a strong reduction in the risk of lung cancer. This inverse association with lung cancer risk is, to our knowledge, a new finding. A previous study on oral cancer and dietary glutathione intake showed a strong reduction in the risk of this malignancy ( 9). In this previous study, the glutathione effect appears to be limited to glutathione from fruits, and this protective effect disappeared after controlling for dietary fiber intake ( 9). In our study the reduction in risk was similar when glutathione from different food sources was analyzed and persisted after controlling for dietary fiber intake. Shklar and others ( 35, 36) reported that a mixture of antioxidants (beta-carotene, vitamin E, glutathione, and ascorbic acid) was more effective than single agents in preventing carcinogenesis in the hamster buccal pouch model.

Flavonoids are diphenylpropanoids, which occur in plant foods and are important constituents of the human diet ( 20). Dietary flavonoids occur predominantly in onions, apples, lettuce, pears, tea, and, in smaller amounts, red wine. They are strong antioxidants and scavengers of free radicals ( 37-39). Previous epidemiological studies were not entirely consistent. Whereas according to Hertog and co-workers ( 40) flavonoid intake was not associated with risk of cancer of all sites or with cancers of the digestive and respiratory tracts, the recent study of Knekt and colleagues ( 10) showed a marked reduction in risk of lung cancer associated with total flavonoid intake. Both studies were prospective. As Hertog and co-workers stated, the power of their study was too limited to exclude an effect of flavonoids on risk of cancer at specific sites in elderly men. In the Finnish study, 151 lung cancer cases occurred during a follow-up of 194,822 person-years ( 10), and the means of total flavonoid intake were similar to those found in our study (3.5 and 4.2 mg/day for lung cancer cases and controls, respectively, in the Finnish study and 4.3 and 5.1 for cases and controls, respectively, in the present study). These values are smaller than those reported by Hertog and co-workers, reflecting the low intake of vegetables, fruits, and tea in the Uruguayan population. As Knekt and colleagues suggested, the low intake of flavonoids could result in a low antioxidative potential; this could not be enough to protect current smokers against the amount of oxidative stress. Similarly, the study of Knekt and colleagues and our report failed to show a protective effect of onions, making improbable a masked effect of organosulfur compounds, rich in allium-containing vegetables, in our estimates for flavonoids. Also, a recent case-control study on tea (a major source of quercetin) and lung cancer reported a significant inverse association ( 15). An important finding of the present study was the less marked protective effect of flavonoids than that observed for vegetables and fruits when both variables were simultaneously included in the model. Experimental studies were also not consistent. Early studies reported that quercetin and kaempferol were mutagenic in bacterial test systems ( 41-44), and quercetin was also found to induce bladder tumors in rats ( 43). More recent studies suggest that flavonoids protect against chemically induced intestinal and mammary tumors in animals ( 46, 47). In the study of Pereira and others ( 47), quercetin increased the yield of colonic tumors in azoxymethane-treated rats but decreased significantly the multiplicity of mammary tumors in dimethylbenz[a]anthracene-treated rats, suggesting that the effect of quercetin could be organ specific. It should be noted that quercetin was administered at a dose of 20 g/day of weight, which is considerably higher than the intake calculated in our study.

According to previous studies ( 26, 48), vegetables were associated with stronger reductions in risk of lung cancer than carotenoids, after adjustment for each other. In our study, beta-carotene and alpha-carotene were associated with significant effects after adjustment for vegetables. The same applies to total glutathione. On the other hand, the protective effect of total vegetables, total fruits, and total vegetables and fruits remained significant after adjustment for dietary antioxidants. The only exception was a less marked inverse association for total fruits when this variable was adjusted for glutathione. Thus glutathione appears to have a significant independent effect after controlling for vegetables and fruits.

The present study has limitations. It is limited by the retrospective design, which is open to recall bias, particularly in queries about past diet. Because the relationship of diet with lung cancer is not publicized in Uruguay, differential misclassification among cases and controls appears to be unlikely. A second limitation is related to the use of hospitalized controls, which could be submitted to dietary influences. Paradoxically, the use of hospitalized controls could be the best strategy against a differential recall by cases and controls, since hospitalized controls are usually submitted to forces of recall similar to the cases ( 31). A third limitation is related to the use of a common portion size, independent of the age of the patients. This problem could be minimized by the fact that the proportion of young and elderly patients is rather small. Therefore, a common portion size for middle-aged men ( 40-69yr) could not distort severely the estimated ORs. Finally, the extrapolation of carotenoid, glutathione, and flavonoid values from other databases to the Uruguayan diet could be a severe limitation. On the other hand, the similar values reported by Knekt and associates ( 10) somehow validate our estimations. The lack of Uruguayan values for carotenoids, glutathione, and flavonoids makes use of a different approach impossible. The high response rate, the exclusion of proxy respondents, and the statistical power are strengths of this study.

As in all studies of lung cancer involving tobacco smokers, this variable is a potential confounder. We have tried to minimize this problem by including a continuous term for pack-years. Nevertheless, it should be acknowledged that residual confounding could persist. In our study, we included former and current smokers in the calculation of the variable pack-years. Because this approach could minimize the residual confounding by tobacco smoking, separate analysis by smoking status was performed, and the results were virtually unchanged.

In summary, the present study replicates previous findings concerning the protective effect of carotenoids in lung cancer when they are not administered in supplements. Moreover, vitamin E, glutathione, and flavonoids were associated with significant reductions in risk of lung cancer.

Acknowledgments and Notes
This study was supported by grants from the Comision Honoraria de Lucha contra el Cancer (Uruguay) and the International Agency for Research on Cancer (Lyon, France). Address reprint requests to Dr. Eduardo De Stefani, Director, Registro Nacional de Cancer, Avda. Brasil 3080 dep 402, Montevideo, Uruguay.

Submitted 5 November 1998; accepted in final form 2 March 1999.

Table 1. Distribution of Cases and Controls by Sociodemographic Variables and Selected Risk Factors

Legend for Chart:

A - Variable
B - Cases, n
C - Cases, %
D - Controls, n
E - Controls, %

A B C D E

Age, yr

30-39 8 1.5 8 1.5
40-49 54 10.0 54 10.0
50-59 113 20.9 111 20.6
60-69 222 41.0 223 41.3
70-79 133 24.6 133 24.6
80-89 11 2.0 11 2.0

Residence

Montevideo 272 50.3 272 50.4
Other counties 269 49.7 268 49.6

Urban/rural status

Urban 403 74.5 404 74.8
Rural 138 25.5 136 25.2

Education, yr

0-2 147 27.2 136 25.2
3-5 217 40.1 182 33.7
>/=6 177 32.7 222 41.1

Monthly income, US dollars

>/=152 214 39.6 193 35.7
Unknown 111 20.5 156 28.9

Family history of lung cancer

No 423 91.4 442 95.1
Yes 40 8.6 23 4.9

Body mass index

22.5-24.4 142 26.2 131 24.3
24.5-26.7 123 22.7 146 27.0
>/=26.8 121 22.4 149 27.6

Tobacco smoking, pack-yr

Nonsmokers 42 7.8 189 35.0

1-34 64 11.8 151 28.0
35-53 118 21.8 92 17.0
54-82 155 28.7 58 10.7
>/=83 162 29.9 50 9.3

Alcohol intake, ml ethanol/day

Nondrinkers 77 14.2 123 22.8

1-60 155 28.7 183 33.9
61-120 101 18.7 98 18.1
>/=121 208 38.4 136 25.2

No. of patients 541 00 540 100
Table 2. Contributions of Foods to Usual Dietary Intakes of Antioxidants Among Controls[a]

Legend for Chart:

A - Food
B - beta-Carotene
C - Vitamin C
D - Vitamin E
E - Glutathione
F - Flavonoids

A B C D E F

Sweet potato 52.8 2.6 1.8 1.7 0.0
Winter squash 19.7 4.0 1.1 7.6 0.0
Carrot 8.6 0.3 2.1 1.4 0.0
Swiss chard 6.9 4.2 1.6 0.8 0.0
Spinach 5.8 3.5 1.3 0.7 0.0
Lettuce 2.7 2.3 5.8 1.1 14.6
Tomato 1.9 5.6 4.9 5.1 3.5
Fruit cocktail 0.5 0.1 0.1 0.1 0.0
Orange 0.4 19.5 1.2 7.5 0.0
Cabbage 0.3 1.0 1.0 0.3 0.1
Apple 0.2 3.1 4.6 3.5 15.3
Peach 0.2 0.8 1.3 1.1 0.0
Banana 0.1 2.9 1.2 2.6 0.0
Pear 0.1 0.4 0.8 0.9 3.2
Potato 0.1 12.1 2.4 16.5 0.0
Corn oil 0.0 0.0 16.9 0.1 0.0
Milk 0.0 1.8 3.6 0.0 0.0
Tea 0.0 0.0 0.0 0.0 52.9
Beef 0.0 0.0 3.4 23.2 0.0
Onion 0.0 0.5 0.0 0.0 4.9
Kidney beans 0.0 0.4 0.9 0.0 3.2
a: Values are percentages.

Table 3. Macro- and Micronutrients in Cases and Controls[a]

Legend for Chart:

A - Nutrient
B - Cases
C - Controls
D - P Value (t-test)

A B
C D

Total energy, kcal/day 2,135.9\+/-\598.1
1,979.2\+/-\584.8 <0.001

Protein, g/day 89.6\+/-\29.3
80.5\+/-\25.7 <0.001

Carbohydrate, g/day 260.1\+/-\80.3
254.3\+/-\82.4 0.24

Total fat, g/day 78.8\+/-\30.1
69.0\+/-\27.3 <0.001

Saturated fat, g/day 31.3\+/-\12.8
27.1\+/-\11.6 <0.001

Cholesterol, mg/day 486.8\+/-\241.3
415.1\+/-\192.9 <0.001

Vitamin A, IU 10,437.9\+/-\7,912
11,022.7\+/-\8,598 0.24

beta-Carotene, mug/day 4,083.1\+/-\3,873
4,709.2\+/-\4,172 0.01

alpha-Carotene, mug/day 131.0\+/-\299
206.9\+/-\415 <0.001

Lutein, mug/day 2,241.4\+/-\2,434
2,283.0\+/-\1,806 0.75

Lycopene, mug/day 1,603.4\+/-\1,416
1,666.6\+/-\1,439 0.47

beta-Cryptoxanthin, mug/day 98.8\+/-\115
118.3\+/-\112 0.005

Total carotenoids, mug/day 8,157.7\+/-\6,331
8,984.2\+/-\5,941 0.02

Vitamin C, mg/day 143.4\+/-\64.4
137.9\+/-\60.3 0.15

Vitamin E, mg/day 6.8\+/-\2.7
6.8\+/-\2.7 0.59

Glutathione, rag/day 48.6\+/-\17.8
48.7\+/-\17.4 0.95

Quercetin, mg/day 5.2\+/-\5.3
6.8\+/-\7.3 <0.001

Kaempferol, mg/day 2.1\+/-\3.9
3.2\+/-\5.6 <0.001

Total flavonoids, mg/day 6.0\+/-\6.2
7.9\+/-\8.6 <0.001
a: Values are means +/- SD.

Table 4. Age- and Calorie-Adjusted Correlations Between Dietary Antioxidants[a]

Legend for Chart:

A - Nutrient
B - Carotenoids
C - Vitamin C
D - Vitamin E
E - Glutathione
F - Flavonoids

A B C D E F

Carotenoids 1.0 0.40[a] 0.53 0.49[b] 0.17[a]
Vitamin C -- 1.0 0.51[b] 0.45[a] 0.27[a]
Vitamin E -- -- 1.0 0.40[a] 0.34[a]
GI utathi one -- -- -- 1.0 0.18[a]
Flavonoids -- -- -- -- 1.0
a: Statistical significance is as follows: a, p = 0.01; b, p = 0.001.

Table 5. ORs of Lung Cancer for Vegetables and Fruits[a]

Legend for Chart:

A - Food
B - Tertiles, I
C - Tertiles, II
D - Tertiles, III
E - P Value (for trend)

A B C D E

Carrot

Servings/yr <12 13-52 >/=53
Cases/controls 234/136 168/192 149/212
OR (95% CI) 1.0 0.76 0.55 <0.001
(0.50-1.15) (0.39-0.78)

Tomato

Servings/yr /=79
Cases/controls 189/171 184/176 168/193
OR (95% CI) 1.0 0.95 0.76 0.09
(0.69-1.32) (0.55-1.07)

Lettuce

Servings/yr /=79
Cases/controls 188/172 189/171 164/197
OR (95% CI) 1.0 1.06 0.84 0.27
(0.76-1.46) (0.61-1.17)

Onion

Servings/yr /=79
Cases/controls 165/195 188/172 188/173
OR (95% CI) 1.0 1.25 1.05 0.87
(0.90-1.74) (0.75-1.47)

Swiss chard

Servings/yr /=49
Case s/controls 183/177 179/181 179/182
OR (95% CI) 1.0 1.05 0.98 0.84
(0.76-1.46) (0.71-1.38)

Spinach

Servings/yr <12 13-48 >/=49
Cases/controls 202/158 172/188 167/194
OR (95% CI) 1.0 0.88 0.69 0.02
(0.62-1.24) (0.50-0.97)

Winter squash

Servings/yr 79
Cases/controls 204/156 197/163 140/221
OR (95% CI) 1.0 0.96 0.57 0.001
(0.69-1.34) (0.41-0.80)

Sweet potato

Servings/yr /=53
Cases/controls 185/175 199/161 157/204
OR (95% CI) 1.0 1.02 0.72 0.07
(0.73-1.42) (0.51-1.00)

Orange

Servings/yr /=105
Cases/controls 208/152 190/170 143/218
OR (95% CI) 1.0 0.78 0.54 <0.001
(0.56-1.09) (0.39-0.75)

Apple

Servings/yr /=105
Cases/controls 206/151 188/175 147/214
OR (95% CI) 1.0 0.89 0.59 0.002
(0.64-1.23) (0.43-0.83)

Pear

Servings/yr /=25
Cases/controls 176/183 198/163 167/194
OR (95% CI) 1.0 1.38 0.93 0.68
(0.99-1.91) (0.66-1.30)

Peach

Servings/yr /=25
Cases/controls 192/167 190/171 159/202
OR (95% CI) 1.0 1.02 0.70 0.04
(0.73-1.42) (0.51-0.98)

Banana

Servings/yr /=105
Cases/controls 185/175 198/162 158/203
OR (95% CI) 1.0 1.22 0.77 0.13
(0.88-1.68) (0.55-1.08)

Total vegetables

Servings/yr /=538
Cases/controls 211/149 188/172 142/219
OR (95% CI) 1.0 0.72 0.48 <0.001
(0.52-1.00) (0.34-0.66)

Total fruits

Servings/yr /=485
Cases/controls 218/142 173/187 150/211
OR (95% CI) 1.0 0.63 0.52 <0.001
(0.46-0.88) (0.37-0.73)
a: Adjusted for age, residence, urban/rural status, education, family history of a lung cancer in 1st-degree relative, body mass index, tobacco smoking (pack-yr), and total energy and total fat intakes. OR, odds ratio; CI, confidence interval.

Table 6. ORs of Lung Cancer for Dietary Antioxidants[a]

Legend for Chart:

A - Nutrient
B - Quartiles, I
C - Quartiles, II
D - Quartiles, III
E - Quartiles, IV
F - P Value (for trend)

A B C D

E F

beta-Carotene

IQR, mug/day <1,938 1,939-3,330 3,331-5,862

>/=5,863 --

Cases/controls 158/112 151/120 130/140

102/168 --

OR 1.0 0.83 0.61

0.42 --

95% CI -- 0.56-1.22 0.42-0.89

0.28-0.63 <0.001

alpha-Carotene

IQR, mug/day <109 110-291 292-600

>/=601 --

Cases/controls 163/107 148/123 134/136

96/174 --

OR 1.0 0.76 0.76

0.38 --

95% CI -- 0.52-1.12 0.52-1.11

0.25-0.56 <0.001

Lutein

IQR, mug/day <1,030 1,031-1,761 1,762-3,240

>/=3,241 --

Cases/controls 151/119 147/124 133/137

110/160 --

OR 1.0 0.91 0.77

0.57 --

95% CI -- 0.62-1.33 0.53-1.14

0.39-0.85 0.004

Lycopene

IQR, mug/day <916 917-1,486 1,487-2,055

>/=2,056 --

Cases/controls 138/132 146/125 133/137

124/146 --

OR 1.0 1.14 0.87

0.83 --

95% CI -- 0.78-1.67 0.59-1.28

0.56-1.21 0.18

beta-Cryptoxanthin

IQR, mug/day <40 41-78 79-167

>/=168 --

Cases/controls 162/108 159/112 107/163

113/157 --

OR 1.0 0.85 0.45

0.53 --

95% CI -- 0.57-1.25 0.31-0.66

0.35-0.78 <0.001

Total carotenoids

IQR, mug/day <4,811 4,812-7,324 7,325-11,508

>/=11,509 --

Cases/controls 160/110 150/121 128/142

103/167 --

OR 1.0 0.81 0.59

0.43 --

95% CI -- 0.56-1.19 0.40-0.85

0.29-0.64 <0.001

Vitamin C

IQR, mg/day <90.5 90.6-134.7 134.8-176.1

>/=176.2 --

Cases/controls 141/129 128/143 138/132

134/136 --

OR 1.0 0.86 1.04

1.03 --

95% CI -- 0.59-1.27 0.71-1.52

0.70-1.52 <0.84

Vitamin E

IQR, mg/day <4.8 4.9-6.1 6.2-8.4

>/=8.5 --

Cases/controls 157/113 146/125 132/138

106/164 --

OR 1.0 0.79 0.64

0.50 --

95% CI -- 0.54-1.15 0.43-0.93

0.34-0.74 <0.001

Glutathione from meat

IQR, mg/day <12.2 12.3-17.7 17.8-24.3

>/=24.4 --

Cases/controls 135/135 130/141 134/136

142/128 --

OR 1.0 0.69 0.65

0.50 --

95% CI -- 0.47-1.04 0.42-1.00

0.31-0.84 0.01

Glutathione from vegetables

IQR, mg/day <11.9 12.0-17.6 17.7-23.6

>/=23.7 --

Cases/controls 147/123 135/136 147/123

112/15 --

OR 1.0 0.69 0.94

0.54 --

95% CI -- 0.48-1.02 0.65-1.38

0.37-0.79 0.01

Glutathione from fruits

IQR, mg/day <3.3 3.4-5.7 5.8-10.8

>/=10.9 --

Cases/controls 172/98 146/125 105/165

118/152 --

OR 1.0 0.65 0.44

0.50 --

95% CI -- 0.45-0.96 0.30-0.65

0.34-0.75 0.01

Total glutathione

IQR, mg/day <36.2 36.3-46.3 46.4-58.1

>/=58.2 --

Cases/controls 151/119 163/113 113/152

114/156 --

OR 1.0 1.07 0.47

0.42 --

95% CI -- 0.74-1.57 0.32-0.70

0.27-0.63 <0.001

Quercetin

IQR, mg/day <2.3 2.4-4.2 4.3-7.9

>/=8.0 --

Cases/controls 144/126 150/123 136/132

111/159 --

OR 1.0 1.01 0.93

0.58 --

95% CI -- 0.69-1.47 0.64-1.37

0.39-0.85 0.007

Kaempferol

IQR, mg/day <0.2 0.3-0.4 0.5-2.8

>/=2.9 --

Cases/controls 136/143 151/116 139/128

115/153 --

OR 1.0 1.34 1.07

0.79 --

95% CI -- 0.92-1.95 0.73-1.56

0.55-1.17 0.16

Total flavonoids

IQR, mg/day <2.5 2.6-4.7 4.8-8.9

>/=9.0 --

Cases/controls 141/129 151/120 141/131

108/160 --

OR 1.0 1.06 1.03

0.59 --

95% CI -- 0.72-1.54 0.70-1.51

0.40-0.87 0.01
a: Adjusted for age, residence, urban/rural status, education, family history of a lung cancer in 1st-degree relative, body mass index, tobacco smoking (pack-yr), and total energy and total fat intakes. IQR, interquartile range.

Table 7. ORs of Lung Cancer for Dietary Antioxidants by Cell Type[a]

Legend for Chart:

A - Nutrient
B - Squamous Cell, n[b]
C - Squamous Cell, OR
D - Squamous Cell, 95% CI
E - Adenocarcinoma, n[b]
F - Adenocarcinoma, OR
G - Adenocarcinoma, 95% CI

A B C D
E F G

beta-Carotene 36 0.3 (0.2-0.6)
24 0.3 (0.2-0.6)

alpha-Carotene 42 0.4 (0.2-0.6)
20 0.3 (0.2-0.6)

Lutein 49 0.5 (0.3-0.9)
23 0.5 (0.3-0.9)

Lycopene 55 0.8 (0.5-1.3)
31 0.9 (0.5-1.8)

beta-Cryptoxanthin 52 0.4 (0.3-0.8)
22 0.4 (0.2-0.8)

Total carotenoids 39 0.4 (0.2-0.6)
25 0.3 (0.2-0.6)

Vitamin C 62 1.0 (0.6-1.7)
32 1.1 (0.6-2.0)

Vitamin E 52 0.5 (0.3-0.8)
29 0.5 (0.3-0.9)

Glutathione 43 0.4 (0.2-0.6)
31 0.4 (0.2-0.7)

Quercetin 47 0.6 (0.4-0.9)
30 0.9 (0.5-1.7)

Kaempferol 56 0.8 (0.5-1.3)
30 1.2 (0.6-2.3)

Total flavonoids 47 0.6 (0.4-1.0)
29 0.9 (0.5-1.8)
a: Adjusted for age, residence, urban/rural status, education, family history of lung cancer in a l st-degree relative, body mass index, tobacco smoking (pack-yr), and total energy and total fat intakes. ORs and 95% CIs represent highest vs. lowest quartile.

b: Number of cases in 4th quartile.

Table 8. Joint Effect of beta-Carotene and Glutathione[a,b]

Legend for Chart:

A - Glutathione
B - beta-Carotene
C - Cases/Controls
D - OR
E - 95% CI

A B C D E

Low Low 202/136 1.0 --
Low High 108/95 0.73 0.50-1.09
High Low 107/96 0.53 0.35-0.80
High High 124/213 0.32 0.22-0.46
a: Glutathione and beta-carotene are dichotomized in low and high categories according to median values of both variables: 46.3 mg/day for glutathione and 3,330.4 mug/day for beta-carotene.

b: Adjusted for age, residence, urban/rural status, education, family history of lung cancer in a 1st-degree relative, body mass index, tobacco smoking (pack-yr), and total energy and total fat intakes.

Table 9. Risk of Lung Cancer Associated With Vegetables and Fruits With Adjustment for Antioxidants[a-c]

Legend for Chart:

A - Food
B - Antioxidants, beta-Carotene
C - Antioxidants, alpha-Carotene
D - Antioxidants, Glutathione
E - Antioxidants, Flavonoids

A B C
D E

Carrot 0.6 (0.4-0.8) 1.5 (0.8-2.7)
0.6 (0.4-0.8) 0.5 (0.4-0.8)

Spinach 0.7 (0.5-1.1) 0.7 (0.5-1.0)
0.7 (0.5-0.9) 0.7 (0.5-0.9)

Winter squash 0.8 (0.6-1.3) 0.6 (0.4-0.9)
0.7 (0.4-1.0) 0.5 (0.4-0.8)

Sweet potato 1.6 (0.9-2.7) 0.7 (0.5-1.0)
0.8 (0.5-1.1) 0.6 (0.5-0.9)

Orange 0.5 (0.4-0.8) 0.6 (0.4-0.9)
0.7 (0.5-1.0) 0.5 (0.4-0.8)

Apple 0.6 (0.4-0.9) 0.7 (0.5-1.0)
0.8 (0.5-1.1) 0.6 (0.4-0.9)

All vegetables 0.6 (0.4-1.1) 0.6 (0.4-0.8)
0.6 (0.4-0.9) 0.4 (0.3-0.7)

All fruits 0.5 (0.4-0.8) 0.6 (0.4-0.9)
0.7 (0.5-1.2) 0.5 (0.4-0.8)

All vegetables 0.5 (0.4-0.8) 0.5 (0.3-0.8)
and fruits 0.6 (0.4-1.0) 0.4 (0.2-0.6)
a: Highest vs. lowest tertile.

b: Further adjusted for age, residence, urban/rural status, education, family history of lung cancer in a 1st-degree relative, body mass index, tobacco smoking (pack-yr), and total energy and total fat intakes.

c: Values are ORs with 95% CI in parentheses.

Table 10. Risk of Lung Cancer Associated With Dietary Antioxidants With Adjustment for Total Vegetables, Total Fruits, and Total Vegetables and Fruits[a-c]

Legend for Chart:

A - Food
B - Food Groups, Total vegetables
C - Food Groups, Total fruits
D - Food Groups, Total vegetables and fruits

A B C D

beta-Carotene 0.6 (0.3-0.9) 0.4 (0.3-0.6) 0.5 (0.3-0.8)
alpha-Carotene 0.5 (0.3-0.7) 0.4 (0.3-0.7) 0.5 (0.3-0.8)
Lutein 0.8 (0.5-1.3) 0.6 (0.4-0.9) 0.7 (0.5-1.1)
Lycopene 1.2 (0.8-1.8) 0.9 (0.6-1.3) 1.1 (0.7-1.7)
Cryptoxanthin 0.5 (0.3-0.8) 0.6 (0.3-1.0) 0.7 (0.4-1.2)
Carotenoids 0.5 (0.3-1.1) 0.4 (0.3-0.7) 0.6 (0.4-0.9)
Vitamin C 1.4 (0.9-2.1) 1.5 (0.9-2.2) 1.9 (1.2-2.9)
Vitamin E 0.9 (0.5-1.3) 0.9 (0.6-1.4) 1.1 (0.7-1.8)
Glutathione 0.5 (0.3-0.8) 0.4 (0.2-0.7) 0.5 (0.3-0.8)
Flavonoids 0.7 (0.5-1.0) 0.7 (0.4-1.1) 0.8 (0.5-1.2)
a: Highest vs. lowest quartile.

b: Further adjusted for age, residence, urban/rural status, education, family history of lung cancer in a 1 st-degree relative, body mass index, tobacco smoking (pack-yr), and total energy and total fat intakes.

c: Values are ORs with 95% CI in parentheses.

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~~~~~~~~

By Eduardo De Stefani; Paolo Boffetta; Hugo Deneo-Pellegrini; Maria Mendilaharsu; Julio C. Carzoglio; Alvaro Ronco and Luis Olivera

E. De Stefani, M. Mendilaharsu, A. Ronco, and L. Olivera are affiliated with the Registro Nacional de Cancer, Montevideo, Uruguay. P. Boffetta is affiliated with the Unit of Environmental Cancer Epidemiology, International Agency for Research on Cancer, Lyon, France. H. Deneo-Pellegrini and J. C. Carzoglio are affiliated with the Laboratorio de Anatomia Patologica, Instituto Nacional de Oncologia, Montevideo, Uruguay.

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