meat consumption and risk of lung cancer; a case-control study from uruguay

11
ELSEVTER Lung Cancer 14 (1996) 195-205 LUNG CANCER Meat consumption and risk of lung cancer; a case-control study from Uruguay Hugo Deneo-Pellegrini”,b, Eduardo De Stefani”,*, Alvaro Ronco”, Maria Mendilaharsu”, Julio C. Carzoglio”*b “Registro National de Cancer, Institute National de Oncologia, Avda. Brasil 3080 dep 402, Montevideo, Uruguay bDepartamento de Patologia, Institute National de Oncologia, Avda. Brasil 3080 dep 402. Montevideo, Uruguay Received 11 October 1995; accepted 7 November 1995 Abstract A case-control study was conducted at the Instituto National de Oncologia, Uruguay, in order to investigate the relationship between meat consumption and lung cancer risk. The study included 256 cases of lung cancer and 284 controls, frequency matched with the cases on age, residence and urban/rural condition. A significant increase in risk of lung cancer associated with red meat, beef and fried meat was observed. The increase in risk was more evident in squamous cell lung cancer. This association remained after controlling for total energy and saturated fat intake, suggesting a possible role of heterocyclic amines in lung carcinogenesis. Keywords: Lung cancer; Meat consumption; Heterocyclic amines 1. Introduction Although tobacco smoking is the main etiologic exposure for lung cancer development, with an attributable risk greater than 85%, occupation and diet are important determinants for this disease. Numerous reports have shown a protective effect of total vegetable intake and carotenoids [l-5]. Also, an increased risk associated with high cholesterol and fat intake were recently reported [6-lo]. * Corresponding author, Registro National de Cancer, Avda. Brasil 3080 dep 402. Montevideo, Uruguay. 0169-5002/96/$15.00 0 1996 El sevier Science Ireland Ltd. All rights reserved SSDI 0169-5002(95)00546-6

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ELSEVTER Lung Cancer 14 (1996) 195-205

LUNG CANCER

Meat consumption and risk of lung cancer; a case-control study from Uruguay

Hugo Deneo-Pellegrini”,b, Eduardo De Stefani”,*, Alvaro Ronco”, Maria Mendilaharsu”, Julio C. Carzoglio”*b

“Registro National de Cancer, Institute National de Oncologia, Avda. Brasil 3080 dep 402, Montevideo, Uruguay

bDepartamento de Patologia, Institute National de Oncologia, Avda. Brasil 3080 dep 402. Montevideo, Uruguay

Received 11 October 1995; accepted 7 November 1995

Abstract

A case-control study was conducted at the Instituto National de Oncologia, Uruguay, in order to investigate the relationship between meat consumption and lung cancer risk. The study included 256 cases of lung cancer and 284 controls, frequency matched with the cases on age, residence and urban/rural condition. A significant increase in risk of lung cancer associated with red meat, beef and fried meat was observed. The increase in risk was more evident in squamous cell lung cancer. This association remained after controlling for total energy and saturated fat intake, suggesting a possible role of heterocyclic amines in lung carcinogenesis.

Keywords: Lung cancer; Meat consumption; Heterocyclic amines

1. Introduction

Although tobacco smoking is the main etiologic exposure for lung cancer development, with an attributable risk greater than 85%, occupation and diet are important determinants for this disease. Numerous reports have shown a protective effect of total vegetable intake and carotenoids [l-5]. Also, an increased risk associated with high cholesterol and fat intake were recently reported [6-lo].

* Corresponding author, Registro National de Cancer, Avda. Brasil 3080 dep 402. Montevideo, Uruguay.

0169-5002/96/$15.00 0 1996 El sevier Science Ireland Ltd. All rights reserved SSDI 0169-5002(95)00546-6

196 H. Deneo-Pellegrini et al. /Lung Cancer 14 (1996) 195-205

Meat consumption has been considered as a risk factor for colorectal cancer and other neoplastic sites, mainly due to its high fat content. It also could increase the risk of lung cancer due to the presence of mutagenic substances produced mainly during the cooking process [l 11. In effect, meat prepared through broiling or frying is a main source of heterocyclic amines, powerful multi-organ carcinogens, includ- ing lung tissue, in experimental systems [12,13]. Also, epidemiological studies have reported consistent associations of cooked beef with an increased colorectal cancer risk [14].

A case-control study was designed in order to investigate a possible increase in risk of lung cancer associated with the intake of a diet rich in cholesterol and fat. In this report we communicate the results of the consumption of different kinds of meat products.

2. Subjects and methods

2.1. Selection of cases

The patients included in this report were participants in an on-going case-control study of lung cancer in Montevideo, Uruguay. The case series for this study consists of male residents in Uruguay, 30 through 84 years of age, with incident lung cancer during the period 1994-1995. The present report is based on data from 256 patients interviewed as of July 29, 1995. All 256 interviews were with the patients themselves and were performed personally (face-to-face) by trained social workers in the Hospital. Squamous cell carcinoma was the most frequent cell type (125 patients, 48.8%), followed by adenocarcinoma (55 patients, 21.5%), and small cell carcinoma (29 patients, 11.3%) (Table 1). Thirty-two (32) patients (12.5%) were diagnosed as having lung cancer on clinical, radiological and endoscopical grounds but the disease was not microscopically confirmed. They were included in the case series. No proxy interviews were accepted. There were only 11 women with lung cancer and they were excluded from the study.

Table 1 Classification of cases by histologic type

Type No. cases %

Squamous cell 125 48.8 Small cell 29 11.3 Adenocarcinoma 55 21.5 Large cell 7 2.7 Unclassified 8 3.1 Clinical diagnosis 32 12.5 Total 256 100.0

H. Deneo-Pellegrini et al. / Lung Cancer 14 (1996) 195-205 191

Table 2 Distribution of controls by disease category

ICD9 Category Number

800-829 Fractures 101 35.6 360-379 Eye disorders 58 20.4 550-553 Abdominal hernia 43 15.1 830-959 Injuries 30 10.6 540 Appendicitis 15 5.3 680-709 Skin diseases 11 3.9 710-739 Bone and joint diseases 10 3.5 122 Hydatid cyst 9 3.1 451-456 Varicose veins 7 2.5

284 100.0

2.2. Selection of controls

Hospitalary controls, afflicted with non-neoplastic conditions, were frequency matched on age, hospital, and residence with the cases. Patients with nutritional disorders were considered non-eligible for this study. The most colon conditions were fractures (101 patients, 35.6%), eye disorders (58 patients, 20.4%) abdominal hernia (43 patients, 15.1%) and trauma (30 patients, 10.6%) (Table 2).

2.3. Questionnaire

Both cases and controls were submitted to a detailed questionnaire, including sections on demography, tobacco history (age at start, age at quit, type (color) of tobacco, major brands used, lifelong amount in cigarettes per day, duration, duration of hand-rolling, duration of filter), alcohol consumption (beer, wine and hard liquor in ml ethanol/day), family history for first degree relatives, anthropo- metric variables (height, weight), lifelong occupational history, and a food fre- quency questionnaire on 64 food items. This questionnaire allowed the calculation of total energy. All cases and controls were interviewed in the hospital.

2.4. Food-frequency questionnaire

The dietary questionnaire used in this study included 64 food items plus vitamin and mineral supplements and queries about alcoholic beverages and soft drinks. Also coffee, coffee with milk, tea, and tea with milk were ascertained. For each food, a commonly used unit or portion size was specified, and participants were asked how often, on average over the past year, they consumed that amount of each food. The responses were open-ended allowing each food to be treated as a continuous variable [15]. The responses were converted in times per year, after multiplying them per the corresponding units (i.e. 52 weeks per year). The authors considered that this type of recording food consumption reflects more accurately

198 H. Deneo-Peilegrini et al. /Lung Cancer 14 (1996) 195-205

the true consumption, instead of forcing responses into preexisting categories, which, could result in misclassification of nutrient intake [16].

2.5. Calculation of nutrients

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. Since data on the carotenoids are not available in Uruguay, values reported by Mangels et al. [IS] were used. Each nutrient was calorie-adjusted, according to the residual analysis method of Willett and Stampfer [19].

2.6. Statistical analysis

Each food group was categorized in quartiles. Crude and adjusted odds ratios (OR) were estimated through unconditional logistic regression [20]. Potential con- founders were included in the multivariate models. Three different regression models were fitted to the data. In the first model the meat variables were adjusted for age, residence (Montevideo, southern counties and northern counties), urban condition (lifelong urban, mainly urban, mainly rural and lifelong rural), education (in years), family history of lung cancer in a first degree relative, body mass index (continuous), pack-years (continuous). This model describes the relation of absolute intake of meat to lung cancer risk. The second model included all the previous variables plus total energy intake and describes the relation of proportional intake of meat to lung cancer risk. The third model included all the previous potential confounders plus a term for saturated fat intake, allowing the estimation of chemicals aside from saturated fat that are present in meat. All calculations were performed in the GLIM package [21].

3. Results

The distribution of cases and controls according to sociodemographic character- istics, family history of lung cancer, body mass index and tobacco smoking is shown in Table 3. Controls were slightly older when compared with cases. On the other hand, the distribution of residence, urban/rural condition, education and monthly income was very similar between both series. A strong positive association between tobacco smoking (in pack-years) and lung cancer is shown in the same Table, whereas a body mass index displayed an inverse relationship with lung cancer risk. Family history of lung cancer was associated with an increased risk of the disease. Mean values for selected variables in cases and controls are shown in Table 4. Cases showed higher mean values for dairy products, pulses, total energy intake, protein, total fat, saturated fat, cholesterol, when compared with controls. On the other hand, cases displayed lower means than controls for vegetables, fruits, vitamin A and beta-carotene. Lung cancer risk was associated with a moderate and

H. Deneo-Pellegrini et al. / Lung Cancer 14 (1996) 195-205 199

non-significant increase in risk, associated with red meat, beef, poultry, fish, boiled and broiled meat, whereas fried meat consumption was associated with a significant dose-response pattern and a 2-fold increase in risk for the highest quartile of consumption. Adjustment for saturated fat (model 3), attenuated this association

Table 3 Distribution of cases and controls by sociodemographic variables, family history, body mass index and tobacco smoking

Variable Cases Controls P-value

No. %

Age 30-39 4 40-49 23 50-59 53 60-69 112 70-79 64 Residence Montevideo 122 Southern counties 102 Northern counties 32 Urban/rural condition Lifelong urban 126 Mainly urban 61 Mainly rural 37 Lifelong rural 32 Education (years) 0 24 l-5 156 6+ 76 Monthly income (US dollars) I147 117 148f 110 Missing 29 Family history of lung cancer No 233 Yes 23 Body mass index 118.9 71 19.0-20.6 71 20.7-22.9 61 23.0+ 53 Cigarette smoking (pack-years) Never smokers 17 l-31 22 32-54 61 55-86 77 87f 79 Number of patients 256

(1.6) 11

(9.0) 38 (20.7) 63 (43.8) 99 (25.0) 73

(47.7) 125 (39.8) II7 (12.5) 42

(49.2) 129 (23.8) 64 (14.5) 40 (12.5) 51

(9.4) 28 (60.9) 156 (29.7) 100

(45.7) 117 (43.0) 121 (11.3) 46

(90.9) 272 (9.1) 12

(27.7) 64 (27.7) 65 (23.8) 73 (20.7) 82

(6.6) 96 (8.6) 88

(23.8) 43 (30.1) 30 (30.9) 27

(100) 284

No.

(3.9) (13.4) (22.2) (34.9) (25.7) 0.16

(44.0) (41.2) (14.8) 0.62

(45.4) (22.5) (14.1) (18.0) 0.37

(9.9) (54.9) (35.2) 0.35

(41.2) (42.6) (16.2) 0.23

(95.7)

(4.3) 0.04

(22.5) (22.9) (25.7) (28.9) 0.08

(33.8) (31.0) (15.1) (10.6)

(9.5) <O.OOl (100)

200 H. Deneo-Pellegrini et al. / Lung Cancer 14 (1996) 195-205

Table 4 Means for selected characteristics for cases and controls

Variable Cases Controls Significance of F

Age (years) 62.8 61.4 0.11 Body mass index 20.9 21.5 0.05 Amount smoked (cigarettes/day) 31.8 14.8 10.001 Years of smoking 43.4 27.4 <O.OOl Pack-years 12.5 31.2 <O.OOl Alcohol (l/day) 141.2 127.2 0.36 Emd 117.1 103.8 0.20 Dairy products” 750.8 588.4 <O.OOl Cereals” 1271.1 1229.1 0.36 Desserts” 185.9 164.4 0.15 Pulses” 71.5 54.6 0.01 Vegetables” 606.7 717.7 0.74 Raw vegetables” 293.7 328.4 0.08 Fruits” 391.3 413.1 0.43 Total energy (kcal) 2699.7 2579.7 0.10 Protein (g/day) 95.6 90.5 0.05 Total fat (g/day) 113.2 105.5 0.05 Saturated fat (g/day) 28.8 25.0 0.005 Cholesterol (g/day) 389.9 352.9 0.05 Vitamin A (fig/day) 2218.1 2348.8 0.32 Beta-carotene &g/day) 1425.6 2129.1 0.004 Vitamin C (mg/day) 144.5 137.8 0.26 Coffee” 84. I 51.6 0.02 Tea” 72.8 102.7 0.02

“Times per year.

(Table 5). No effect for lamb consumption was observed. The effect of meat consumption for squamous cell lung cancer is shown in Table 6. The association of red meat, beef, and fried meat with this cell type was stronger, compared with the risks associated with small cell cancer and lung adenocarcinoma (Table 6). ORs for the highest quartile of red meat and fried meat consumption were 2.24 and 2.18 for squamous cell carcinoma. On the other hand, lung adenocarcinoma showed a modest and non-significant association with each type of meat consumption (results not shown). The joint effect of tobacco smoking (in pack-years) and meat products displayed a multiplicative effect, with an OR of 10.8 for the joint effect of tobacco smoking and above median consumption of fried meat.

4. Discussion

Several case control studies examined the relationship of lung cancer and meat consumption [9,22-261. Whereas Swanson et al. reported a reduction in risk of lung cancer associated with pork meat consumption in a Chinese population [22], a marked increase in risk was observed in Kerala, South India for beef consumption

Table 5

H. Deneo-Pellegrini et al. / Lung Cancer 14 (1996) 1955205 201

Relative risks of lung cancer for consumption of different types of meat. All cell types (a) (b)

Variable Model I Model 2 Model 3

All meat 1 1.0 2 1.12 3 1.38 4 1.56 Red meat 1 1.0 2 1.21 3 1.51 4 1.66 Processed meat 1 2 3 4 Beef 1 2 3 4 Lamb 1 2 3 Poultry 1 2 3 Fish I 2 3 Fried meat 1 2 3 4 Boiled meat 1 2 3 4 Broiled meat I 2 3

1.0 0.74 0.91 1.17

1.0 1.01 I .69 1.66

1.0 1.05 1.11

1.0 1.52 1.40

1.0 1.07 1.22

1 .o 0.97 1.39 1.99

1.0 2.04 1.53 1.50

1.0 1.38 1.16

4 1.56

(0.64-l .94) (0.79-2.41) (0.89-2.73)

(0.70-2.09) (0.8662.65) (0.95-2.91)

(0.43- 1.29) (0.5221.56) (0.6772.03)

(0.5881.78) (0.96-3.00) (0.9442.94)

(0.688 I .62) (0.62- 1.98)

(0.91-2.54) (0.8992.19)

(0.66 1.74) (0.74-2.01)

(0.57-1.66) (0.7662.56) (1.12-3.52)

(1.19-3.50) (0.85-2.75) (0.855265)

(0.81-2.37) (0.5552.47) (0.8662.82)

1.0 1.07 1.27 1.28

1.0 1.14 1.42 1.55

1.0 0.68 0.77 0.85

1.0 1.03 1.73 1.66

1.0 1.04 1.03

1.0 1.45 1.27

1.0 1.05 1.12

I.0 1.00 1.40 1.92

1.0 1.91 1.42 1.24

1.0 1.46 1.17 I .64

(0.61- 1.87) (0.7222.24) (0.70-2.34)

(0.66- 1.99) (0.80-2.49) (0.882.74)

(0.39- 1.19) (0.44- 1.36) (0.47- 1.56)

(0.58- 1.82) (0.9773.09) (0.93-2.96)

(0.677 1.62) (0.57- 1.85)

(0.8662.44) (0.80-2.00)

(0.6551.71) (0.6771.85)

(0.5881.71) (0.75-2.58) (1.0883.41)

(1.11-3.29) (0.7992.57) (0.699224)

(0.8442.53) (0.5552.49) (0.9OC2.98)

1.0 0.94 1.02 0.99

1.0 1.07 1.25 1.36

I.0 0.62 0.66 0.70

1.0 1.02 1.72 1.50

1.0 I .09 0.97

1.0 1.38 I .23

1.0 1.08 1.18

1.0 1.01 1.37 I .78

1.0 1.86 1.46 1.32

1.0 1.48 1.17 1.56

(0.533 I .67) (0.57p 1.84) (0.5331.86)

(0.61-1.87) (0.71-2.22) (0.76243)

(0.3551.11) (0.37-1.31) (0.38-1.31)

(0.57-1.80) (0.9663.08) (0.84-2.70)

(0.70- I .70) (0.54-1.76)

(0.82-2.33) (0.77- 1.95)

(0.66- 1.75) (0.70- 1.97)

(0.58-1.74) (0.74-2.55) (0.99-3.20)

(1.083.22) (0.80-2.65) (0.7332.40)

(0.8552.59) (0.55-2.52) (0.8552.87)

202

Table 6

H. Deneo-Pellegrini et al. 1 Lung Cancer 14 (1996) 195-205

Relative risks of lung cancer for consumption of different types of meat. Squamous cell carcinoma (a)

(b)

Variable Model 1 Model 2 Model 3

All meat 1 1.0 2 1.20 3 1.73 4 2.11 Red meat 1 1.0 2 1.42 3 2.39 4 2.63 Processed meat 1 2 3 4 Beef 1 2 3 4 Lamb 1 2 3 Poultry 1 2 3 Fish I 2 3 Fried meat 1 2 3 4 Boiled meat 1 2 3 4 Broiled meat I 2 3

1.0 0.68 0.70 1.04

1 .o 0.98 1.96 2.07

1.0 0.85 0.95

1.0 1.71 1.59

1 .o 0.81 1.32

1.0 I .09 1.35 2.28

1.0 1.63 1.16 1.66

1.0 1.42 2.14

4 1.99

(0.60-2.43) (0.86-3.47) (1.06-4.19)

(0.70-2.90) (1.17-4.88) (1.30-5.29)

(0.35-1.30) (0.36- 1.38) (0.54-l .99)

(0.48-1.99) (0.97-3.97) (1.04-4.12)

(0.49- 1.46) (0.48-1.88)

(0.90-3.25) (0.92-2.75)

(0.44-1.50) (0.73-2.39)

(0.57-2.07) (0.62-2.94) (1.14-4.54)

(0.86-3.10) (0.57-2.36) (0.86-3.21)

(0.73-2.78) (0.90-5.11) (0.97-4.08)

1.0 1.20 1.65 1.88

1.0 1.34 2.25 2.51

1.0 0.63 0.65 0.82

1.0 1.01 2.01 2.16

1.0 0.84 0.87

1.0 1.66 1.51

1.0 0.79 1.25

1.0 1.13 1.37 2.30

1.0 1.60 1.08 1.45

1 .o 1.51 2.14 2.17

(0.59-2.42) (0.82-3.33) (0.90-3.91)

(0.66-2.76) (1.10-4.63) (1.24-5.07)

(0.32- 1.21) (0.33-1.28) (0.40- 1.67)

(0.49-2.06) (0.99-4.10) (1.08-4.34)

(0.49- 1.44) (0.43-1.75)

(0.87-3.17) (0.87-2.62)

(0.43- 1.47) (0.69-2.27)

(0.59-2.17) (0.63-2.99) (1.15-4.60)

(0.84-3.04) (0.52-2.23) (0.73-2.88)

(0.76-2.98) (0.89-5.12) (1.04-4.49)

1.0 1.14 1.46 1.58

1.0 1.28 1.96 2.24

1.0 0.54 0.53 0.66

1.0 1.03 1.98 1.99

1.0 0.87 0.80

1.0 1.60 1.52

1.0 0.84 1.35

I.0 1.21 1.36 2.18

1.0 1.52 1.09 I .50

1.0 1.54 2.14 2.08

(0.56-2.33) (0.71-2.99) (0.74-3.36)

(0.62-2.63) (0.94-4.07) (1.09-4.59)

(0.27-1.08) (0.26-1.08) (0.32-l .38)

(0.50-2.12) (0.96-4.08) (0.98-4.05)

(0.50-1.52) (0.40-I .62)

(0.83-3.08) (0.87-2.66)

(0.45-1.56) (0.74-2.48)

(0.62-2.35) (0.62-3.00) (1.07-4.42)

(0.79-2.91) (0.53-2.26) (0.74-2.99)

(0.77-3.08) (0.89-5.19) (0.98-4.38)

H. Deneo-Pellegrini et al. / Lung Cancer 14 (1996) 195-205 203

(OR 12.5) [24]. According to the cohort study of Hirayama [25], meat consumption was associated with a 19% increased risk of lung cancer, which was statistically significant. Recently, no association was found between fried meat intake and lung cancer risk in a Finnish cohort study [26]. According to our study, red meat, beef and fried meat consumption were significantly associated with an increased risk of squamous cell lung cancer, after controlling for potential confounders. Consump- tion of meat could be a marker of a fat effect, as previously shown [6-lo] in other studies. On the other hand, it is not possible to dismiss the role of heterocyclic amines, formed in the cooking process of beef; these compounds are powerful mutagens and carcinogens in different sites including lung tissue in experimental systems [l 11. The incidence of lung adenocarcinomas in CDFl mice has been 35.9 in the treated group, compared with 9.1 in control group (P < 0.001) [13]. Experimental studies have shown the formation of DNA adducts with heterocyclic aromatic amines; Takayama et al. [27], detected 7 adducts in organs of rats fed with PhIP. Adduct levels were highest in the heart, lung and pancreas. Thus, at least two mechanisms appear to give biologic plausibility to the association between meat consumption and risk of lung cancer. Firstly, red meat is a marker of saturated fat effect, which was a risk factor for lung cancer in other studies [6-81. Secondly, fried meat is a source of heterocyclic aromatic amines, powerful mutagens in experimen- tal systems. We tried to control for the fat effect including a term for saturated fat in our model 3, and both red meat and fried meat remained as significant determinants of lung cancer risk, suggesting an effect of other chemicals, which could be heterocyclic amines resulting from the cooking (frying) method of meat preparation.

As in other studies on lung cancer risk factors, residual confounding from tobacco smoking is a major problem. We controlled all estimates including a term for pack-years of cigarette smoking as a continuous variable. Although it is not possible to exclude residual confounding from tobacco smoking as a possible reason for our findings, this appears to be an unlikely explanation.

Our study used only hospitalary controls. The advantages and drawbacks of using hospitalary controls in case-control studies has been extensively reviewed in previous studies [28]. One major advantage of using hospital controls is that one can reasonably assume that patients admitted to the same hospital as the cases are members of the same (secondary) population base [28]. Also, hospitalary controls are less prone to recall bias, thus alleviating the problem of misclassification of the exposure [28]. In conclusion, exposure to beef consumption appears to increase the risk of lung cancer; the effect is more marked in squamous cell lung cancer and displays a multiplicative effect with tobacco smoking.

Acknowledgements

This research was supported by a grant from the Comision Honoraria de Lucha contra el Cancer, Uruguay.

204 H. Deneo-Pellegrini et al. / Lung Cancer 14 (1996) 195-205

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