Cancer Causes and Control, 2, 11 - 16
Dietary patterns of female nonsmokers with and without exposure to environmental tobacco smoke
Loic Le M a r c h a n d , L y n n e R. W i l k e n s , J e a n H . H a n k i n , a n d N a n c y J. H a l e y
(Received 26 September 1990; accepted 23 October 1990) The relationship of passive smoking to diet was examined in 82 female nonsmokers who provided a quantitative diet history in 1986. Exposure to environmental tobacco smoke (ETS) was assessed by urinary cotinine measurement. Mean values for each dietary variable, adjusted for age, ethnicity, education, and last week's ethanol intake, were compared among unexposed women and women with low or high ETS exposure. Linear relationships with amount of ETS exposure were also sought. Intakes of beta-carotene and cholesterol were found to be inversely related to ETS exposure. Since these nutrients have been associated with lung cancer risk, they are potential confounders of the passive-smoking/lung-cancer relationship. Although we estimate the confounding effect of these dietary factors to be modest, they should be measured carefully in future studies of this relationship.
Key words: Carotenoids, diet, lung neoplasms, passive smoking, urinary cotinine.
Introduction
Subjects a n d m e t h o d s
Smokers have been shown to follow a diet which is rich in fat and lacking in vegetables and fruits. ~'2 If nonsmokers who associate with smokers were to share similar dietary habits, their risk of lung cancer could be increased, since a low-vegetable/low-beta-carotene diet has consistently been associated with an elevated lungcancer risk.3 Additionally, a high fat intake has been positively associated with this cancer in some studies) '5 It would be important then to assess diet in studies of passive smoking and lung cancer in order to control for the potential confounding effect of these dietary factors. We had the opportunity to study the diet of female nonsmokers for whom exposure to environmental tobacco smoke (ETS) was assessed with a biochemical marker of nicotine uptake.
Subjects for these studies were selected among population controls who took part in two lung cancer case-control studies conducted by our group between 1979 and 1985 on the island of Oahu, Hawaii. 3,6 A stratified sampling approach was used to optimize the range of exposure to ETS. Female nonsmokers were cross-classified on whether or not they were married to a smoker, and on whether or not they were employed, using the information collected in the original interview. Approximately equal numbers of subjects were randomly selected among these four groups. Among the 142 women selected, three were disqualified because they had started smoking since the initial interview, three had expired, 18 could not be located, and 29 declined to participate. Thus, interviews were completed for 89 women (64 percent of the eligible
Drs Le Marchand and Hankin and Ms V/ilkens are wttb the Epidemiology Program, Cancer Research Center of Hawaii, University of Hawaii, USA. Dr Haley ~ at the American Health Foundattbn, Valhalla, New York, USA. Address correspondence to Dr Le Marchand at the Cancer Research Center of Hawaii, 1236 Lauhala Street, Suite 407, Honolulu, HI 96813, USA. This work was supported in part by Public Health Service grant CA-33619 from the National Cancer Institute, and the International Agency for Research on Cancer. © 1991 Rapid Communications of Oxford Ltd
11
L. Le M a r c b a n d et al
subjects). A urine sample was obtained from 82 of the subjects. The interviews were conducted in the subjects' homes between March and September 1986. They consisted of a quantitative diet history focusing on diet during the past year and based on a list of more than 40 food items selected to cover the major sources of vitamin A. Quantitative intakes were estimated with the aid of colored photographs showing the foods in three typical portion sizes. 7 Subjects were also questioned about their use of alcoholic beverages and vitamin supplements. Individual nutrient intakes were computed using the US Department of Agriculture food-composition tables, supplemented with data from Hawaii, Japan, and the Philippines, and with other published sources and home recipes. 7 Because insufficient data on the carotenoid content of foods are available, we used the estimation approach recommended by the Food and Agriculture/ World Health Organization Expert Group, which specifies the percentage distribution of the vitamin A content into retinol, beta-carotene, and other carotenoids with vitamin A activity for different food groups. 3 A spot urine sample was collected from each subject at the end of the interview. Samples were frozen at - 70°C until shipment in dry ice to the American Health Foundation for cotinine and creatinine analyses. Cotinine was quantified by radioimmunoassay according to the method of Haley et al, s using the modification to the antibody by Langone et al. 9 The inter- and intra-assay coefficients of variation at 2 ng/ml were 11 percent and seven percent, respectively. Creatinine was determined on a Kodak Ektachem 400 Clinical Chemistry Analyzer. Table 1. Background characteristics of female nonsmokers exposed and unexposed to environmental tobacco smoke Characteristics
Unexposeda
Exposed
No. of subjects Age (mean 4- SD) Ethnicity (%) Japanese Caucasian Chinese Filipino Hawaiian Education (%) < High school > High school Quetelet (kg/m2) (mean + SD) Alcohol consumption Current (%) Never and past (%) Last week's ethanol intake (g) (mean 4- SD)
42 61.2 4- 6.8
40 59.2 ± 8.5
53.5 3o.2 9.3 4.7 2.3
48.4 27.4 9.7 8.1 6.5
64.3 35.7
59.6 40.5
24.1 4- 3.1
24.6 4- 4.4
86.0 14.0 9.2 4- 26.3
84.1 15.9 9.8 4- 31.6
~Subjects with undetectableurinary cotinine. 12
Since creatinine excretion is fairly constant among nonsmokers of the same sex and similar age, 1° we standardized cotinine levels for urine flow by taking the ratio cotinine/creatinine. Women with undetectable cotinine ( < 2 ng) were considered unexposed. Exposed women were categorized into two groups of high and low exposure, based on the median value for the ratio. The means for the dietary variables were compared among exposure categories by multiple covariance analysis.t1 Multiple regression analysesII were used to test for a linear relationship between food or nutrient intakes and the extent of exposure to ETS (independent variable). Intake values were transformed [log (x + 1)] to approach normality. Adjustment variables included age, ethnicity, education, and ethanol intake during the past week. The latter variable was included because drinking has been associated with specific dietary practices in this 12 as well as other ~3 populations, and because smoking and alcohol often have combined effects on disease risks (albeit not on lung cancer risk).
Results Overall, 48.8 percent of the study subjects had detectable levels of cotinine in their urine. The median value for the cotinine/creatinine ratio among the entire study population was 2.0 ng/mg. The highest value was 26.0 ng/mg. This value is lower than the levels usually observed in smokers, confirming that all subjects were correct in reporting themselves as nonsmokers. 14 Historically, urine cotinine/creatinine ratios of < 50 ng/mg have been considered consistent with nonsmoking status. The background characteristics of the subjects exposed and unexposed to ETS are presented in Table 1. As a group, exposed subjects had a somewhat lower mean age, higher proportions of Filipinos and Hawaiians, and more education than the unexposed. Alcohol consumption was similar in the two groups. Table 2 presents the mean daily nutrient intakes by level of cotinine/creatinine ratio, adjusted for ethnicity, age, education, and the previous week's ethanol intake. Intakes of vitamin A from foods and from supplements decreased as exposure to ETS increased. A similar inverse relationship was observed for each of the two food sources of vitamin A, namely, retinol and carotenoids, including beta-carotene. Cholesterol and fat intakes were also negatively associated with exposure level; however, the test for trend was statistically significant for cholesterol intake only (P --- 0.05). Vitamin C intake, either from food sources or from supplements, was not significantly associated with exposure level.
Dietary patterns of passive smokers associated with a decreased risk of lung cancer,3 we also compared the consumption of their main food sources among the subjects (Table 3). Exposure to ETS was not associated with consumption of dark green vegetables or tomatoes, which are good sources of the carotenoids lutein and lycopene, respectively. Finally, no association was observed between exposure level to ETS and consumption of oranges, which are the main source of vitamin C in our population. Because urinary cotinine predominantly reflects the exposure which occurred three to four days prior to the sample collection, our results would have been
To investigate the consistency of our observations among the main food sources of beta-carotene, we computed (Table 3) covariate-adjusted mean daily consumption of carrots, papaya, sweet potatoes, mangoes and pumpkin--which contributed 38, 10, 10, eight and seven percent, respectively, of the beta-carotene intake in the study population. Significant, inverse, linear associations were observed between the cotinine/ creatinine ratio and intake of carrots, papaya, and pumpkin. A negative trend of borderline statistical significance was also observed for mangoes. Since certain other vegetable constituents have been
Table 2. Adjusted mean a daily nutrient intake by level of exposure to environmental tobacco smoke Exposed~ Nutrient Vitamin A from foods (IU) Vitamin A from supplements (IU) Retinol (#g) Total carotenoids with vitamin A activity (t~g) Beta-carotene (~g) Other carotenoids with vitamin A activity (/~g) Total vitamin C (mg) Cholesterol (mg) Total fat (g)
Unexposed
Low
(n = 42) b
(n = 24)
High (n = 16)
12,203 29.0 296
8,083 10.6 121
6,033 3.0 127
< 0.001 0.09 0.002
7,486 5,410
5,162 3,678
3,908 2,764
< 0.001 < 0.001
2,072 288 79.6 8.9
1,480 188 53.0 7.2
1,142 214 57.3 7.1
pd
0.001 0.41 0.05 0.10
aAdjusted for ethnicity, age, education, and past week's ethanol intake, by multiple covariance analysis. Intake values were transformed to approach normality. bNumber of women. %ow exposure group: cotinine/creatinine ratio -< 3.97 ng/mg; high exposure group: cotinine/creatinine ratio > 3.97 ng/mg. alP-value for linear trend.
Table 3. Adjusted mean~ daily vegetable and fruit intake (g) by level of exposure to environmental tobacco smoke Exposed c Food Carrots Papaya Sweet potatoes Mangoes Pumpkin Dark green vegetables Tomatoes Oranges
Unexposed
Low
(n = 42) b
(n ~ 24)
High (n = 16)
pd
12.5 36.5 1.8 8,8 1.9 36.0 19.3 53.2
7.6 16.9 1.3 10.0 1,2 28.8 27.1 48.3
5.1 8.4 0.6 3.8 0.6 27.9 22.5 86.5
0.01 0.01 0.26 0.07 0,02 0.17 0.85 0.29
aAdjusted for ethnicity, age, education, and past week's ethanol intake, by multiple covariance ~nalysis. Intake values were transformed to approach normality. Number of women. %ow exposure group: cotinine/creatinine ratio ~ 3.97 ng/mg; high exposure group: cotinine/creatinine ratio > 3.97 ng/mg. alP-value for linear trend.
13
L. Le Marehand et al compromised if the exposure of the subjects to ETS during that time had been atypical. Thus, we repeated our analysis using another exposure classification which has been widely used in passive smoking research, namely, the smoking status of the subjects' husbands (Table 4). Similar intake patterns were observed for vitamin A and cholesterol. Women married to a smoker had lower intakes of total vitamin A and its components, as well as lower intakes of cholesterol and fat, than women married to a 'never-smoker.' With regard to the causation of lung cancer, the appropriate reference period for ETS exposure is longer than that reflected by the cotinine measurements. Thus, the observations made in this study may not be relevant to the causation of lung cancer. However, the data presented in Table 4 also suggest that the lower carotenoid intake of women exposed to ETS is most likely a long-lived dietary pattern, since women married to an ex-smoker had a dietary pattern which is intermediate between those of the two other groups of women.
Discussion Participation in the present study was less than optimal, especially when the overall participation rates among controls in the two original case-control studies are considered (58.7 percent and 70 percent). 3'6 Although reasons for participation in an epidemiologic study appear unlikely to be related to the relationship under study, the possibility of a selection bias cannot be excluded. However, the participants in the present research did not differ from the subjects of our lung cancer case-control
studies, who were eligible but chose not to participate, with regard to years of education, beta-carotene and cholesterol intakes, number of years spent with a smoking husband, and the husband's daily cigarette consumption. In this study, intake of beta-carotene was inversely related to exposure to ETS among female nonsmokers. This association was linear, and consistent across the main food sources of beta-carotene. Although we only measured recent exposure, the subjects who were likely to have been exposed to ETS in the past (i. e., women married to a current- or an ex-smoker) also showed a decreased beta-carotene intake. Thus, like most dietary patterns, it is probable that the dietary differences between nonsmokers exposed and unexposed to ETS are determined early in life, at least since marriage. Since beta-carotene intake has been inversely associated with lung cancer risk, it is a potential confounder in studies of the relation of passive smoking to this disease. Decreased beta-carotene consumption could explain, in part or in total, the moderately elevated lung-cancer risk observed for passive smokers in past studies. Therefore, complete control of the confounding effect of betacarotene intake is essential in assessing the true magnitude of the passive-smoking/lung-cancer association. Of more than 19 studies of this association, we are aware of only two which attempted to adjust for diet. 15,16 The positive association with passive smoking was reported not to be eliminated by this adjustment. In an attempt to estimate how much of the passive smoking effect is not accounted for by beta-carotene consumption, we used the formula given by Schlesselman. 17 For this simulation, we used the relative risk for beta-carotene obtained in our most recent lung cancer
Table 4. Adjusted meana daily nutrient intake by smoking status of husband Smoking status of the husband Nutrient Vitamin A from foods (IU) Vitamin A from supplements (IU) Retinol (¢,g) Total carotenoids with vitamin A activity (#g) Beta-carotene (#g) Other carotenoids with vitamin A activity (#g) Total vitamin C (mg) Cholesterol (mg) Total fat (g)
Never-smoker (n = 20) b 11,017 10.9 218
Ex-smoker (n = 50)
Current smoker (n = 14)
p 1,2c
p 1,3c
9,608 18.5 228
6,852 4,6 87,9
0.46 0.65 0.87
0.07 0.61 0.02
7,053 5,058
5,882 4,229
4,435 3,139
0.35 0.37
0.09 0.08
1,990 217 78.5 8.8
1,651 214 73.3 8.7
1,292 240 36.5 5.0
0.33 0.97 0.77 0.92
0.10 0.81 0.02 0.03
aAdjusted for ethnicity, age, education, and past week's ethanol intake, by multiple covariance analysis. Intake values were transformed to approach normality. bNumber of women (five women with husband's smoking status missing were excluded). cp1 2: P-value for the difference between never-smoker and ex-smoker; P1,3: P-value for the difference between never-smoker and current smoker.
14
Dietary patterns o f passive smokers case-control study in this population. 3 In that study, the odds ratio for women in the lowest quartile of betacarotene intake was 2.7 when compared to those in the highest quartile of intake. We also assumed that this relative risk applied similarly to women exposed and unexposed to ETS. Based on risk estimates from recent reviews on passive smoking and lung cancer, 1°'18'19 we set the observed relative risk for exposure to ETS successively to 1.30, 1.50, and 2.00. Correcting for the effect of beta-carotene had only a moderate effect since the relative risk of 1.30 was lowered to 1.18; that of 1.50 to 1.36; and that of 2.00 to 1.82. There is a certain amount of measurement error in assessing dietary intake. The resulting misclassification may have limited our ability to adjust for the confounding effect of beta-carotene intake since it tends to bias the effect toward the null value. 2° Therefore, we attempted to adjust the estimate of the relative risk for beta-carotene for misclassification using the formula described by Copeland et a121 and the estimates of specificity and sensitivity for beta-carotene intake derived from a recent validity study which compared our diet history against four one-week food records collected during the course of a year. = Accounting for the misdassification on beta-carotene intake had only a small additional effect on the risk estimates for passive smoking exposure. The relative risk of 1.30 was further lowered to 1.15; that of 1.50 to 1.32; and that of 2.00 to 1.77. Sidney et a/23 recently reported similar results in a Kaiser Permanente population. They found a lower mean carotene intake among nonsmokers who reported exposure to passive smoke at home compared to nonsmokers reporting no such exposure. However, these authors did not find a dose-response relationship between carotene intake and amount of exposure. In the present study, we were able not only to consider other nutrients suspected to be associated with lung cancer, in addition to beta-carotene, but also to use a biochemical marker of passive smoking to describe the relationship between intake of these nutrients and exposure to ETS. Among the other nutrients we considered as possibly associated with lung cancer (i.e., lycopene, lutein, vitamin C, cholesterol, and fat), only cholesterol was significantly associated with ETS exposure. Unlike smokers, whose diets are high in cholesterol compared to nonsmokers, I female nonsmokers exposed to ETS appear to consume less cholesterol than their unexposed counterparts. However, our results for lipids should be considered as inconclusive because our dietary questionnaire, which focused on vitamin A, did not include a number of important food sources for cholesterol and fat. If cholesterol intake were to be confirmed as a risk factor for lung cancer
Dietary patterns of female nonsmokers with and without exposure to environmental tobacco smoke
Loic Le M a r c h a n d , L y n n e R. W i l k e n s , J e a n H . H a n k i n , a n d N a n c y J. H a l e y
(Received 26 September 1990; accepted 23 October 1990) The relationship of passive smoking to diet was examined in 82 female nonsmokers who provided a quantitative diet history in 1986. Exposure to environmental tobacco smoke (ETS) was assessed by urinary cotinine measurement. Mean values for each dietary variable, adjusted for age, ethnicity, education, and last week's ethanol intake, were compared among unexposed women and women with low or high ETS exposure. Linear relationships with amount of ETS exposure were also sought. Intakes of beta-carotene and cholesterol were found to be inversely related to ETS exposure. Since these nutrients have been associated with lung cancer risk, they are potential confounders of the passive-smoking/lung-cancer relationship. Although we estimate the confounding effect of these dietary factors to be modest, they should be measured carefully in future studies of this relationship.
Key words: Carotenoids, diet, lung neoplasms, passive smoking, urinary cotinine.
Introduction
Subjects a n d m e t h o d s
Smokers have been shown to follow a diet which is rich in fat and lacking in vegetables and fruits. ~'2 If nonsmokers who associate with smokers were to share similar dietary habits, their risk of lung cancer could be increased, since a low-vegetable/low-beta-carotene diet has consistently been associated with an elevated lungcancer risk.3 Additionally, a high fat intake has been positively associated with this cancer in some studies) '5 It would be important then to assess diet in studies of passive smoking and lung cancer in order to control for the potential confounding effect of these dietary factors. We had the opportunity to study the diet of female nonsmokers for whom exposure to environmental tobacco smoke (ETS) was assessed with a biochemical marker of nicotine uptake.
Subjects for these studies were selected among population controls who took part in two lung cancer case-control studies conducted by our group between 1979 and 1985 on the island of Oahu, Hawaii. 3,6 A stratified sampling approach was used to optimize the range of exposure to ETS. Female nonsmokers were cross-classified on whether or not they were married to a smoker, and on whether or not they were employed, using the information collected in the original interview. Approximately equal numbers of subjects were randomly selected among these four groups. Among the 142 women selected, three were disqualified because they had started smoking since the initial interview, three had expired, 18 could not be located, and 29 declined to participate. Thus, interviews were completed for 89 women (64 percent of the eligible
Drs Le Marchand and Hankin and Ms V/ilkens are wttb the Epidemiology Program, Cancer Research Center of Hawaii, University of Hawaii, USA. Dr Haley ~ at the American Health Foundattbn, Valhalla, New York, USA. Address correspondence to Dr Le Marchand at the Cancer Research Center of Hawaii, 1236 Lauhala Street, Suite 407, Honolulu, HI 96813, USA. This work was supported in part by Public Health Service grant CA-33619 from the National Cancer Institute, and the International Agency for Research on Cancer. © 1991 Rapid Communications of Oxford Ltd
11
L. Le M a r c b a n d et al
subjects). A urine sample was obtained from 82 of the subjects. The interviews were conducted in the subjects' homes between March and September 1986. They consisted of a quantitative diet history focusing on diet during the past year and based on a list of more than 40 food items selected to cover the major sources of vitamin A. Quantitative intakes were estimated with the aid of colored photographs showing the foods in three typical portion sizes. 7 Subjects were also questioned about their use of alcoholic beverages and vitamin supplements. Individual nutrient intakes were computed using the US Department of Agriculture food-composition tables, supplemented with data from Hawaii, Japan, and the Philippines, and with other published sources and home recipes. 7 Because insufficient data on the carotenoid content of foods are available, we used the estimation approach recommended by the Food and Agriculture/ World Health Organization Expert Group, which specifies the percentage distribution of the vitamin A content into retinol, beta-carotene, and other carotenoids with vitamin A activity for different food groups. 3 A spot urine sample was collected from each subject at the end of the interview. Samples were frozen at - 70°C until shipment in dry ice to the American Health Foundation for cotinine and creatinine analyses. Cotinine was quantified by radioimmunoassay according to the method of Haley et al, s using the modification to the antibody by Langone et al. 9 The inter- and intra-assay coefficients of variation at 2 ng/ml were 11 percent and seven percent, respectively. Creatinine was determined on a Kodak Ektachem 400 Clinical Chemistry Analyzer. Table 1. Background characteristics of female nonsmokers exposed and unexposed to environmental tobacco smoke Characteristics
Unexposeda
Exposed
No. of subjects Age (mean 4- SD) Ethnicity (%) Japanese Caucasian Chinese Filipino Hawaiian Education (%) < High school > High school Quetelet (kg/m2) (mean + SD) Alcohol consumption Current (%) Never and past (%) Last week's ethanol intake (g) (mean 4- SD)
42 61.2 4- 6.8
40 59.2 ± 8.5
53.5 3o.2 9.3 4.7 2.3
48.4 27.4 9.7 8.1 6.5
64.3 35.7
59.6 40.5
24.1 4- 3.1
24.6 4- 4.4
86.0 14.0 9.2 4- 26.3
84.1 15.9 9.8 4- 31.6
~Subjects with undetectableurinary cotinine. 12
Since creatinine excretion is fairly constant among nonsmokers of the same sex and similar age, 1° we standardized cotinine levels for urine flow by taking the ratio cotinine/creatinine. Women with undetectable cotinine ( < 2 ng) were considered unexposed. Exposed women were categorized into two groups of high and low exposure, based on the median value for the ratio. The means for the dietary variables were compared among exposure categories by multiple covariance analysis.t1 Multiple regression analysesII were used to test for a linear relationship between food or nutrient intakes and the extent of exposure to ETS (independent variable). Intake values were transformed [log (x + 1)] to approach normality. Adjustment variables included age, ethnicity, education, and ethanol intake during the past week. The latter variable was included because drinking has been associated with specific dietary practices in this 12 as well as other ~3 populations, and because smoking and alcohol often have combined effects on disease risks (albeit not on lung cancer risk).
Results Overall, 48.8 percent of the study subjects had detectable levels of cotinine in their urine. The median value for the cotinine/creatinine ratio among the entire study population was 2.0 ng/mg. The highest value was 26.0 ng/mg. This value is lower than the levels usually observed in smokers, confirming that all subjects were correct in reporting themselves as nonsmokers. 14 Historically, urine cotinine/creatinine ratios of < 50 ng/mg have been considered consistent with nonsmoking status. The background characteristics of the subjects exposed and unexposed to ETS are presented in Table 1. As a group, exposed subjects had a somewhat lower mean age, higher proportions of Filipinos and Hawaiians, and more education than the unexposed. Alcohol consumption was similar in the two groups. Table 2 presents the mean daily nutrient intakes by level of cotinine/creatinine ratio, adjusted for ethnicity, age, education, and the previous week's ethanol intake. Intakes of vitamin A from foods and from supplements decreased as exposure to ETS increased. A similar inverse relationship was observed for each of the two food sources of vitamin A, namely, retinol and carotenoids, including beta-carotene. Cholesterol and fat intakes were also negatively associated with exposure level; however, the test for trend was statistically significant for cholesterol intake only (P --- 0.05). Vitamin C intake, either from food sources or from supplements, was not significantly associated with exposure level.
Dietary patterns of passive smokers associated with a decreased risk of lung cancer,3 we also compared the consumption of their main food sources among the subjects (Table 3). Exposure to ETS was not associated with consumption of dark green vegetables or tomatoes, which are good sources of the carotenoids lutein and lycopene, respectively. Finally, no association was observed between exposure level to ETS and consumption of oranges, which are the main source of vitamin C in our population. Because urinary cotinine predominantly reflects the exposure which occurred three to four days prior to the sample collection, our results would have been
To investigate the consistency of our observations among the main food sources of beta-carotene, we computed (Table 3) covariate-adjusted mean daily consumption of carrots, papaya, sweet potatoes, mangoes and pumpkin--which contributed 38, 10, 10, eight and seven percent, respectively, of the beta-carotene intake in the study population. Significant, inverse, linear associations were observed between the cotinine/ creatinine ratio and intake of carrots, papaya, and pumpkin. A negative trend of borderline statistical significance was also observed for mangoes. Since certain other vegetable constituents have been
Table 2. Adjusted mean a daily nutrient intake by level of exposure to environmental tobacco smoke Exposed~ Nutrient Vitamin A from foods (IU) Vitamin A from supplements (IU) Retinol (#g) Total carotenoids with vitamin A activity (t~g) Beta-carotene (~g) Other carotenoids with vitamin A activity (/~g) Total vitamin C (mg) Cholesterol (mg) Total fat (g)
Unexposed
Low
(n = 42) b
(n = 24)
High (n = 16)
12,203 29.0 296
8,083 10.6 121
6,033 3.0 127
< 0.001 0.09 0.002
7,486 5,410
5,162 3,678
3,908 2,764
< 0.001 < 0.001
2,072 288 79.6 8.9
1,480 188 53.0 7.2
1,142 214 57.3 7.1
pd
0.001 0.41 0.05 0.10
aAdjusted for ethnicity, age, education, and past week's ethanol intake, by multiple covariance analysis. Intake values were transformed to approach normality. bNumber of women. %ow exposure group: cotinine/creatinine ratio -< 3.97 ng/mg; high exposure group: cotinine/creatinine ratio > 3.97 ng/mg. alP-value for linear trend.
Table 3. Adjusted mean~ daily vegetable and fruit intake (g) by level of exposure to environmental tobacco smoke Exposed c Food Carrots Papaya Sweet potatoes Mangoes Pumpkin Dark green vegetables Tomatoes Oranges
Unexposed
Low
(n = 42) b
(n ~ 24)
High (n = 16)
pd
12.5 36.5 1.8 8,8 1.9 36.0 19.3 53.2
7.6 16.9 1.3 10.0 1,2 28.8 27.1 48.3
5.1 8.4 0.6 3.8 0.6 27.9 22.5 86.5
0.01 0.01 0.26 0.07 0,02 0.17 0.85 0.29
aAdjusted for ethnicity, age, education, and past week's ethanol intake, by multiple covariance ~nalysis. Intake values were transformed to approach normality. Number of women. %ow exposure group: cotinine/creatinine ratio ~ 3.97 ng/mg; high exposure group: cotinine/creatinine ratio > 3.97 ng/mg. alP-value for linear trend.
13
L. Le Marehand et al compromised if the exposure of the subjects to ETS during that time had been atypical. Thus, we repeated our analysis using another exposure classification which has been widely used in passive smoking research, namely, the smoking status of the subjects' husbands (Table 4). Similar intake patterns were observed for vitamin A and cholesterol. Women married to a smoker had lower intakes of total vitamin A and its components, as well as lower intakes of cholesterol and fat, than women married to a 'never-smoker.' With regard to the causation of lung cancer, the appropriate reference period for ETS exposure is longer than that reflected by the cotinine measurements. Thus, the observations made in this study may not be relevant to the causation of lung cancer. However, the data presented in Table 4 also suggest that the lower carotenoid intake of women exposed to ETS is most likely a long-lived dietary pattern, since women married to an ex-smoker had a dietary pattern which is intermediate between those of the two other groups of women.
Discussion Participation in the present study was less than optimal, especially when the overall participation rates among controls in the two original case-control studies are considered (58.7 percent and 70 percent). 3'6 Although reasons for participation in an epidemiologic study appear unlikely to be related to the relationship under study, the possibility of a selection bias cannot be excluded. However, the participants in the present research did not differ from the subjects of our lung cancer case-control
studies, who were eligible but chose not to participate, with regard to years of education, beta-carotene and cholesterol intakes, number of years spent with a smoking husband, and the husband's daily cigarette consumption. In this study, intake of beta-carotene was inversely related to exposure to ETS among female nonsmokers. This association was linear, and consistent across the main food sources of beta-carotene. Although we only measured recent exposure, the subjects who were likely to have been exposed to ETS in the past (i. e., women married to a current- or an ex-smoker) also showed a decreased beta-carotene intake. Thus, like most dietary patterns, it is probable that the dietary differences between nonsmokers exposed and unexposed to ETS are determined early in life, at least since marriage. Since beta-carotene intake has been inversely associated with lung cancer risk, it is a potential confounder in studies of the relation of passive smoking to this disease. Decreased beta-carotene consumption could explain, in part or in total, the moderately elevated lung-cancer risk observed for passive smokers in past studies. Therefore, complete control of the confounding effect of betacarotene intake is essential in assessing the true magnitude of the passive-smoking/lung-cancer association. Of more than 19 studies of this association, we are aware of only two which attempted to adjust for diet. 15,16 The positive association with passive smoking was reported not to be eliminated by this adjustment. In an attempt to estimate how much of the passive smoking effect is not accounted for by beta-carotene consumption, we used the formula given by Schlesselman. 17 For this simulation, we used the relative risk for beta-carotene obtained in our most recent lung cancer
Table 4. Adjusted meana daily nutrient intake by smoking status of husband Smoking status of the husband Nutrient Vitamin A from foods (IU) Vitamin A from supplements (IU) Retinol (¢,g) Total carotenoids with vitamin A activity (#g) Beta-carotene (#g) Other carotenoids with vitamin A activity (#g) Total vitamin C (mg) Cholesterol (mg) Total fat (g)
Never-smoker (n = 20) b 11,017 10.9 218
Ex-smoker (n = 50)
Current smoker (n = 14)
p 1,2c
p 1,3c
9,608 18.5 228
6,852 4,6 87,9
0.46 0.65 0.87
0.07 0.61 0.02
7,053 5,058
5,882 4,229
4,435 3,139
0.35 0.37
0.09 0.08
1,990 217 78.5 8.8
1,651 214 73.3 8.7
1,292 240 36.5 5.0
0.33 0.97 0.77 0.92
0.10 0.81 0.02 0.03
aAdjusted for ethnicity, age, education, and past week's ethanol intake, by multiple covariance analysis. Intake values were transformed to approach normality. bNumber of women (five women with husband's smoking status missing were excluded). cp1 2: P-value for the difference between never-smoker and ex-smoker; P1,3: P-value for the difference between never-smoker and current smoker.
14
Dietary patterns o f passive smokers case-control study in this population. 3 In that study, the odds ratio for women in the lowest quartile of betacarotene intake was 2.7 when compared to those in the highest quartile of intake. We also assumed that this relative risk applied similarly to women exposed and unexposed to ETS. Based on risk estimates from recent reviews on passive smoking and lung cancer, 1°'18'19 we set the observed relative risk for exposure to ETS successively to 1.30, 1.50, and 2.00. Correcting for the effect of beta-carotene had only a moderate effect since the relative risk of 1.30 was lowered to 1.18; that of 1.50 to 1.36; and that of 2.00 to 1.82. There is a certain amount of measurement error in assessing dietary intake. The resulting misclassification may have limited our ability to adjust for the confounding effect of beta-carotene intake since it tends to bias the effect toward the null value. 2° Therefore, we attempted to adjust the estimate of the relative risk for beta-carotene for misclassification using the formula described by Copeland et a121 and the estimates of specificity and sensitivity for beta-carotene intake derived from a recent validity study which compared our diet history against four one-week food records collected during the course of a year. = Accounting for the misdassification on beta-carotene intake had only a small additional effect on the risk estimates for passive smoking exposure. The relative risk of 1.30 was further lowered to 1.15; that of 1.50 to 1.32; and that of 2.00 to 1.77. Sidney et a/23 recently reported similar results in a Kaiser Permanente population. They found a lower mean carotene intake among nonsmokers who reported exposure to passive smoke at home compared to nonsmokers reporting no such exposure. However, these authors did not find a dose-response relationship between carotene intake and amount of exposure. In the present study, we were able not only to consider other nutrients suspected to be associated with lung cancer, in addition to beta-carotene, but also to use a biochemical marker of passive smoking to describe the relationship between intake of these nutrients and exposure to ETS. Among the other nutrients we considered as possibly associated with lung cancer (i.e., lycopene, lutein, vitamin C, cholesterol, and fat), only cholesterol was significantly associated with ETS exposure. Unlike smokers, whose diets are high in cholesterol compared to nonsmokers, I female nonsmokers exposed to ETS appear to consume less cholesterol than their unexposed counterparts. However, our results for lipids should be considered as inconclusive because our dietary questionnaire, which focused on vitamin A, did not include a number of important food sources for cholesterol and fat. If cholesterol intake were to be confirmed as a risk factor for lung cancer
