Fried meat intake is a risk factor for lung adenocarcinoma in a prospective cohort of Chinese men and women in Singapore (original) (raw)

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• Carcinogenesis
• PMC3731803

Carcinogenesis. 2013 Aug; 34(8): 1794–1799.

Lesley M. Butler,1 ,2 ,* Julia A. Montague,3 Woon-Puay Koh,4 ,5 Renwei Wang,2 Mimi C. Yu,6 ,† and Jian-Min Yuan1 ,2

Lesley M. Butler

1Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15261, USA,

2Cancer Epidemiology, Prevention and Control Program, The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA,

Julia A. Montague

3Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, USA,

Woon-Puay Koh

4Office of Clinical Sciences, Duke-NUS Graduate Medical School Singapore, Singapore 169857,

5Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117597, and

Renwei Wang

2Cancer Epidemiology, Prevention and Control Program, The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA,

Mimi C. Yu

6Department of Preventive Medicine Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089, USA

Jian-Min Yuan

1Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15261, USA,

2Cancer Epidemiology, Prevention and Control Program, The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA,

1Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15261, USA,

2Cancer Epidemiology, Prevention and Control Program, The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA,

3Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, USA,

4Office of Clinical Sciences, Duke-NUS Graduate Medical School Singapore, Singapore 169857,

5Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117597, and

6Department of Preventive Medicine Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089, USA

*To whom correspondence should be addressed. University of Pittsburgh Cancer Institute, UPMC Cancer Pavilion, Suite 4C-466, 5150 Centre Avenue, Pittsburgh, PA 15232, USA. Tel: +612-623-3386. Fax: +412-864-7838; Email: ude.cmpu@3Lreltub

†Retired

Received 2013 Jan 8; Revised 2013 Mar 25; Accepted 2013 Apr 1.

Copyright © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Supplementary Materials

Supplementary Data

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GUID: 52671E6F-3629-4DA2-BA1F-565D0447BDBA

Abstract

Probable human carcinogens are generated during Chinese-style high-temperature cooking of meat and have been detected in the ambient air and on the meat surface. Although the inhalation of these compounds is an established risk factor for lung cancer, exposure via fried meat consumption has not yet been prospectively evaluated as a risk factor. The relationship between fried meat intake and lung cancer risk was investigated using data from a prospective cohort study among Chinese in Singapore. Lung cancer cases (n = 1130) were identified from 61 321 men and women, 70% of whom were lifetime never smokers. Proportional hazards regression methods were used to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Overall, there was no association between fried meat intake and risk of all lung cancers combined. For lung adenocarcinoma, fried meat intake had a statistically significant association with increased risk. The association between fried meat intake and risk of lung adenocarcinoma became stronger when analyses were restricted to lifetime never smokers. Compared with the lowest tertile of fried meat intake, the HRs (95% CIs) for the second and third tertiles were 1.43 (0.98, 2.08) and 1.51 (1.03, 2.22), respectively (P for trend = 0.04). The positive association was present among both men and women. There was no association between fried meat intake and risk of non-adenocarcinomas of the lung. Our prospective results for fried meat intake support consumption as an important route of exposure to compounds from Chinese-style high-temperature cooking for the development of lung adenocarcinoma.

Introduction

Lung cancer has been the most common cancer worldwide since 1985 (1) and is the most common cause of cancer death in the USA, accounting for an estimated 28% of all cancer deaths in 2012 (2). Cigarette smoking is the primary cause of lung cancer (3) and a strong risk factor particularly for squamous cell carcinoma of the lung (4). Adenocarcinoma is the most commonly diagnosed lung cancer histologic subtype among lifetime never smokers (5), which accounts for approximately 10–15% of all lung cancer diagnoses worldwide (6,7).

Historically, Asian women have among the highest incidence rates of female lung cancer in the world, in particular adenocarcinoma, despite their low prevalence of smoking (8,9). This observation led to the development of a hypothesis that exposure to the fumes generated from the volatilization of oils from cooking at high temperatures in open woks is an important environmental risk factor for lung cancer among never smokers (10,11). The chemical composition of the emissions from Chinese-style high-temperature frying have since been characterized (12,13), and the emissions themselves have been labeled as ‘probable’ human carcinogens by an International Agency for Research on Cancer working group (14). The relationship between exposure to cooking fumes and lung carcinogenesis has been supported with evidence from experimental (15) and epidemiologic studies among non-smoking Asian women (16).

In addition to exposure to the cooking fumes, the consumption of fried meat may prove to be a non-trivial route of exposure to the compounds formed when meat is prepared in the traditional Chinese high-temperature cooking method (17,18). The surface of fried meat contains mutagenic and potentially carcinogenic compounds (19), such as heterocyclic amines (20,21), acrolein (22), aldehydes (23) and polycyclic aromatic hydrocarbons (24). Epidemiologic studies of fried meat intake and lung cancer risk in populations of USA provide modest support for positive associations (25,26), but consumption of meat cooked using Chinese-style high-temperature methods has not yet been prospectively evaluated as a risk factor for lung cancer. Utilizing the database of the Singapore Chinese Health Study, we prospectively evaluated the association between fried meat intake, as a surrogate for exposure to compounds on the meat surface that were generated during Chinese-style high-temperature cooking, and the risk of developing lung cancer among a large cohort of Chinese men and women in Singapore. We hypothesized that high consumption of fried meat will be positively associated with lung cancer risk, especially among lifetime never smokers, whose underlying risk of lung cancer is relatively low.

Materials and methods

Study population

The design of the Singapore Chinese Health Study has been described previously in detail (27). Briefly, the cohort consisted of 27 959 men and 35 298 women recruited between April 1993 and December 1998, from permanent residents or citizens of Singapore aged 45–74 years and who resided in government-built housing estates (86% of the Singapore population resided in such facilities). We restricted the study to individuals belonging to the two major dialect groups of Chinese in Singapore: the Hokkiens and the Cantonese. For these analyses, we used data from the 27 293 men and 34 028 women, who did not have a history of cancer diagnosis at baseline, based on self-report and computer-assisted record linkage analysis with the Singapore Cancer Registry. No additional exclusion criteria were applied. All study participants provided written consent. The institutional review boards at the National University of Singapore and the University of Pittsburgh have approved this study.

Identification of incident lung cancer cases among cohort members was accomplished by record linkage of the cohort database with respective databases from the population-based Singapore Cancer Registry, a nationwide cancer registry that has been in place since 1968 and has been shown to be comprehensive in its recording of cancer cases (28). To date, only 47 cohort participants were known to be lost to follow-up due to migration out of Singapore. As of 31 December 2007 (an average of 11.5 years of follow-up), 1130 cohort participants developed lung cancer. Of these, 1004 (89%) participants were diagnosed histologically and they were confirmed via manual review of pathology reports by a medically trained research staff; 93 (8%) cases were diagnosed clinically and 33 (3%) were identified through death certificates. Of the cases that were histologically confirmed (n = 1004), 419 (42%) were adenocarcinomas, 222 (22%) were squamous cell carcinomas, 115 (11%) were small cell carcinomas, 153 (15%) were large cell carcinomas, 16 (2%) were undifferentiated and 79 (8%) had unspecified or other histology. In the analysis, we grouped the lung cancer types into adenocarcinomas and non-adenocarcinomas (i.e. all lung cancers other than adenocarcinoma).

Exposure assessment

Enrollment in the cohort entailed completing a baseline in-person interview in the participant’s home. The questionnaire elicited information on smoking, diet, demographics, current physical activity, occupational exposure and medical history. In response to the following question, ‘Have you ever smoked at least one cigarette a day for 1 year or longer’, subjects who answered ‘no’ were classified as ‘never smokers’, those who answered ‘yes, but I quit smoking’ were classified as ‘former smokers’ and those who answered ‘yes, and I currently smoke’ were classified as ‘current smokers’. Ever smokers (former and current) were then asked about age at starting to smoke (four categories: <15, 15–19, 20–29 and 30 years or older); number of cigarettes smoked per day (six categories: 6 or less, 7–12, 13–22, 23–32, 33–42 and 43 or more) and duration of smoking (four categories; <10, 10–19, 20–39, 40 or more years).

We used a 165-item quantitative food frequency questionnaire, developed for and validated in this population, to assess usual diet over the past year (29). Average daily intake of roughly 100 nutrient and non-nutrient compounds was computed for each study subject based on the Singapore Food Composition Database (29). The food frequency questionnaire listed five fried meat items, including pork slices or cubes (stir fried), chicken (deep fried and stir fried) and fish (deep fried and stir fried), and eight intake frequencies (e.g. never or hardly ever, once a month, two to three times a month, once a week, two to three times a week, four to six times a week, once a day, two or more times a day).

Statistical methods

Person-years of follow-up were counted from the date of recruitment to the date of diagnosis of lung cancer, death, migration or 31 December 2007, whichever occurred first. Proportional hazards regression methods were used to examine the associations between meat intake and lung cancer risk (total, adenocarcinomas, non-adenocarcinomas), measured by hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) (30). Quantile variables for meat intake were created based on the distribution of intake among the entire cohort for total red meat, processed meat, total fried meat, fried fish, fried chicken and fried pork. The linear trend tests for meat intake–lung cancer risk associations were based on ordinal values of the levels of intake (e.g. 0, 1 and 2). In all analyses, except where noted, we adjusted for the following factors that were either the determinants of subject recruitment or associated with risk of lung cancer in the study population (27,31): age at baseline interview (years), year of interview (1993–95, 1996–98), dialect group (Cantonese, Hokkien), level of education (no formal education/primary school, secondary school/higher), body mass index (<18.5, 18.5–24.9, ≥25.0kg/m2), dietary intake of β-cryptoxanthin (mg/1000 kilocalories [kcal]/day) (27), total energy intake (kcal/day), gender, number of cigarettes smoked per day (never smokers, 1–12, 13–22, ≥23), number of years of smoking (never smokers, 1–19, 20–39, ≥40) and number of years since quitting smoking (current smokers, <1, 1–4, 5–19, ≥20, never smokers). Neither dietary soy isoflavones (32) nor dietary isothiocyanates (33) were confounders for the fried meat-lung cancer associations. Analyses were carried out for men and women separately and by ever/never smoking status. All exposure-lung cancer risk associations were comparable between men and women, regardless of smoking status. Therefore, results were presented for both sexes combined, with adjustment for gender. Statistical computing was conducted using SAS version 9.3 (SAS Institute, Cary, NC). All _P_-values were two-sided and considered statistically significant if <0.05.

Results

The mean age of all cohort participants at baseline was 56.4 years (standard deviation = 8.0) and 55.5% of them were women. Majority of the cohort were never smokers (69.4%), and women accounted for 72.9% of never smokers. Compared with subjects within the lowest tertile of total fried meat intake, those within the highest tertile were more likely to be female, less educated and to consume less β-cryptoxanthin and more isothiocyanates and soy isoflavones, but were similar with respect to age, body mass index, smoking status and alcohol consumption (Table I). The relationships between the selected covariates and fried meat intake were similar across smoking status categories (Supplementary Table S2, available at Carcinogenesis Online).

Table I.

Distribution of selected factors by tertiles (T) of fried meat intake and smoking status in the Singapore Chinese Health Study

| | Overall | Never smokers | | | | | | | ---------------------------------- | ----------------- | ------------- | --------------- | ------------- | ------------- | --------------- | | Fried meat intake | Fried meat intake | | | | | | | T1 | T2 | T3 | T1 | T2 | T3 | | | Mean age (SD), years | 56(8) | 57(8) | 56(8)* | 56(8) | 56(8) | 55(8)* | | % female | 52.7 | 56.8 | 57.0* | 70.1 | 74.1 | 74.6* | | Highest level of education, %a | | | | | | | | No formal education | 25.6 | 29.0 | 26.9 | 28.2 | 31.8 | 29.8 | | Primary school | 43.6 | 44.0 | 45.5 | 39.7 | 40.2 | 41.9 | | Secondary school or higher | 30.8 | 27.0 | 27.5* | 32.1 | 28.1 | 28.3* | | Mean body mass index (SD)a | 23.0 (3.3) | 23.2 (3.3) | 23.2 (3.2)* | 23.2 (3.3) | 23.3 (3.2) | 23.3 (3.3)* | | Weekly supplement use, % yesa | 6.9 | 6.0 | 5.9* | 8.2 | 7.0 | 6.7* | | Alcohol intake, % non-drinkersa | 81.8 | 82.1 | 79.1* | 87.0 | 87.5 | 84.5* | | Ever smokers, % | 31.4 | 30.2 | 30.0* | — | — | — | | Mean intake (SD) per 1000 kcal/day | | | | | | | | β-cryptoxanthin, μga,b | 176.2 (235.3) | 159.4 (203.5) | 156.7 (195.1)* | 187.7 (243.6) | 170.1 (212.8) | 166.2 (200.5)* | | Isothiocyanate, μmola,b | 6.0 (4.4) | 5.9 (3.8) | 6.2 (4.0)* | 6.4 (4.5) | 6.3 (3.9) | 6.5 (4.1)* | | Soy isoflavones, mga,b | 11.9 (10.0) | 11.5 (8.7) | 12.1 (8.7)* | 12.5 (10.3) | 12.0 (8.9) | 12.7 (8.9)* |

Compared with never smokers, former and current smokers were at a 2.2- and 5.6-fold increased risk of lung cancer, respectively (Table II). The association between smoking status and lung cancer risk varied by histologic subtype, where the strongest association was for non-adenocarcinomas including squamous cell cancers. Smoking characteristics (e.g. number of cigarettes per day and number of years of smoking) were also stronger risk factors for non-adenocarcinomas than for adenocarcinomas of the lung (data not shown).

Table II.

Cigarette smoking in relation to lung cancer risk by histologic subtype among Singapore Chinese men and women

| | Cases, n | HRa | 95% CI | | | -------------------- | --- | ------ | ----------- | | All lung cancers | | | | | Never smokers | 314 | 1.0 | | | Former smokers | 165 | 2.21 | 1.80, 2.72 | | Current smokers | 651 | 5.65 | 4.82, 6.60 | | Adenocarcinomas | | | | | Never smokers | 181 | 1.0 | | | Former smokers | 50 | 1.26 | 0.89, 1.77 | | Current smokers | 188 | 3.07 | 2.41, 3.89 | | Non-adenocarcinomasb | | | | | Never smokers | 102 | 1.0 | | | Former smokers | 97 | 3.63 | 2.68, 4.93 | | Current smokers | 386 | 9.43 | 7.38, 12.05 |

Total fried meat intake was associated with a statistically significant increase in risk of adenocarcinoma of the lung (Table III), but not with risk of non-adenocarcinoma. The associations with intake of fried meats and lung adenocarcinoma risk were similar among men and women (Supplementary Table S3, available at Carcinogenesis Online). The association with total fried meat and lung adenocarcinoma was stronger for never smokers than ever smokers. The fried meat-adenocarcinoma risk associations in never smokers were similar for men (HR = 1.77; 95% CI: 0.83, 3.74) and women (HR = 1.39; 95% CI: 0.88, 2.19), comparing third to first tertile of intake. Among ever smokers, the association for highest versus lowest tertile of intake was attenuated and became statistically non-significant (HR = 1.24; 95% CI: 0.89, 1.72; P for trend = 0.2) (Supplementary Table S4, available at Carcinogenesis Online). Fried fish intake contributed most to the total fried meat index, compared with fried pork or fried chicken, as indicated by the higher tertile cut-point values for fried fish (Table III). Fried fish intake was also the only meat type that demonstrated a statistically significant increased risk for adenocarcinoma of the lung. Steamed fish intake was not associated with risk of all lung cancer or adenocarcinoma (data not shown). Intake of total red meat or preserved meat was not associated with risk of lung cancer or adenocarcinoma (data not shown).

Table III.

Fried meat intake and lung cancer risk by histologic subtype among Singapore Chinese men and women

| | Overall | Never smokers | | | | | | | | | | ----------------------------- | --------------- | --------------- | ---------- | --- | ------ | ----------- | --- | ------ | ---------- | | All lung cancers | Adenocarcinomas | Adenocarcinomas | | | | | | | | | Cases, n | HRa | 95% CI | Cases, n | HRa | 95% CI | Cases, n | HRb | 95% CI | | | Total fried meat (times/year) | | | | | | | | | | | First tertile, <115 | 357 | 1.0 | | 115 | 1.0 | | 47 | 1.0 | | | Second tertile, 115–189 | 399 | 1.13 | 0.98, 1.31 | 150 | 1.31 | 1.03, 1.68 | 67 | 1.43 | 0.98, 2.07 | | Third tertile, ≥190 | 374 | 1.09 | 0.94, 1.27 | 154 | 1.36 | 1.06, 1.74 | 67 | 1.51 | 1.02, 2.22 | | P for trend | | 0.2 | | | 0.02 | | | 0.04 | | | Fried fish (times/year) | | | | | | | | | | | First tertile, <60 | 408 | 1.0 | | 132 | 1.0 | | 62 | 1.0 | | | Second tertile, 60–139 | 471 | 1.10 | 0.97, 1.26 | 174 | 1.27 | 1.01, 1.60 | 73 | 1.15 | 0.82, 1.62 | | Third tertile, ≥140 | 251 | 1.17 | 0.99, 1.37 | 113 | 1.64 | 1.27, 2.13 | 46 | 1.57 | 1.06, 2.33 | | P for trend | | 0.049 | | | <0.001 | | | 0.03 | | | Fried chicken (times/year) | | | | | | | | | | | 0 | 365 | 1.0 | | 122 | 1.0 | | 34 | 1.0 | | | <median, 42 | 406 | 0.91 | 0.79, 1.05 | 146 | 0.93 | 0.73, 1.19 | 70 | 1.42 | 0.94, 2.15 | | ≥median, 42 | 359 | 0.93 | 0.80, 1.08 | 151 | 1.00 | 0.78, 1.29 | 77 | 1.44 | 0.95, 2.18 | | P for trend | | 0.3 | | | 1.0 | | | 0.1 | | | Fried pork (times/year) | | | | | | | | | | | 0 | 610 | 1.0 | | 241 | 1.0 | | 110 | 1.0 | | | <median, 30 | 137 | 1.05 | 0.87, 1.26 | 45 | 0.90 | 0.65. 1.24 | 21 | 1.04 | 0.65, 1.66 | | ≥median, 30 | 383 | 1.07 | 0.94, 1.22 | 133 | 0.98 | 0.79, 1.21 | 50 | 1.06 | 0.75, 1.49 | | P for trend | | 0.3 | | | 0.8 | | | 0.7 | |

We evaluated the fried meat-lung adenocarcinoma risk association in stratified analyses by duration of follow-up using the median value among cases as the cut-point (e.g. <7 and ≥7 years) (Table IV). The positive association for total fried meat intake and lung adenocarcinoma risk was confined to those with shorter duration of follow-up, regardless of smoking status or sex (Supplementary Table S5, available at Carcinogenesis Online). Compared with lung cancer cases diagnosed within the first 7 years of follow-up, cases diagnosed later were statistically not significantly different with respect to age at baseline, sex, fried meat intake or smoking status (data not shown).

Table IV.

Fried meat intake and risk of adenocarcinoma of the lung by duration of follow-up among Singapore Chinese men and women

| | <7 years | ≥7 years | | | | | | | ----------------------------- | -------- | ------ | ---------- | -- | ------ | ---------- | | Cases, n | HR | 95% CI | Cases, n | HR | 95% CI | | | Total fried meat (times/year) | | | | | | | | Overall | | | | | | | | First tertile, <115 | 51 | 1.0a | | 64 | 1.0a | | | Second tertile, 115–189 | 78 | 1.55 | 1.09, 2.22 | 72 | 1.12 | 0.80, 1.58 | | Third tertile, ≥190 | 92 | 1.77 | 1.24, 2.52 | 62 | 1.02 | 0.71, 1.46 | | P for trend | | <0.01 | | | 0.9 | | | Never smokers | | | | | | | | First tertile, <115 | 24 | 1.0b | | 23 | 1.0b | | | Second tertile, 115–189 | 38 | 1.64 | 0.98, 2.74 | 29 | 1.20 | 0.69, 2.09 | | Third tertile, ≥190 | 40 | 1.80 | 1.07, 3.04 | 27 | 1.21 | 0.68, 2.15 | | P for trend | | 0.03 | | | 0.5 | |

Discussion

We reported a statistically significant positive association between fried meat intake and lung adenocarcinoma risk using data from a prospective cohort of Chinese men and women from Singapore. When we restricted our analyses to lifetime never smokers, highest versus lowest tertile of fried meat intake was associated with a statistically significant 51% increase in lung adenocarcinoma risk. In stratified analyses by sex, similar positive associations for fried meat intake and lung adenocarcinoma risk were observed for non-smoking men and women. Our prospective results for fried meat intake support the notion that consumption may be an important route of exposure to compounds formed during Chinese-style high-temperature cooking for the development of non-smoking lung adenocarcinoma.

High-temperature frying of protein-rich foods generates volatile and non-volatile compounds with mutagenic and carcinogenic properties (14,34). The highest levels of mutagenic activity from fried meat are detected in the pan residue and meat crust, compared with lower levels detected in the cooking fumes (34,35). These mutagenic activity levels in the cooked meat (36) and surrounding air (37) are driven primarily by the cooking temperature rather than cooking duration (38). With Chinese-style cooking, small strips or cubes of meat (usually fish) (39,40) are added to a pan or wok with oil that has been pre-heated to high temperatures (≈250°C). The method of heating the oil before adding the ingredients is used to reduce noxious odors, but it also increases the production of fumes that are characteristic of Chinese-style stir frying. A variety of volatile carcinogens and toxicants have been detected in the fumes from high-temperature frying, including acetaldehyde, acrolein, benzene, 1,3-butadiene, ethylene oxide, heterocyclic amines and polycyclic aromatic hydrocarbons (12,13,41–44). Many of the same compounds have also been detected in their non-volatile form in or on the fried meat surface, including acrolein, heterocyclic amines and polycyclic aromatic hydrocarbons (22,24,45).

We provide the first prospective evidence for Chinese-style fried meat intake as a risk factor for adenocarcinoma of the lung. A major focus of previous epidemiologic studies on lung cancer among Asian populations has been on evaluating cooking fume-related exposures (16,18), in part because of the interest in identifying air pollutants other than smoking to explain the high incidence of lung cancer among Chinese women, most of whom are lifetime never smokers (8,9). We asked about frequency of frying meat during the second follow-up interview conducted between 2006 and 2010 among the 38 708 surviving men and women in the cohort. There was a statistically significant (chi-square P < 0.001) relationship between the intake of fried meat and the frequency of frying meat, where individuals who reported frying meat at least four times per week were more likely to consume fried meat four or more times per week (or ≥190 times per year), compared with individuals who reported frying meat less than one time per week (data not shown). Given that cooking-fume exposure is likely to correlate with frequency of fried meat intake, we can speculate that the previously published results suggesting an inhalation route of exposure are consistent with our findings that support a consumption route of exposure to the carcinogens and toxicants generated during Chinese-style high-temperature cooking of meat.

Heterocyclic amines (HCAs) are formed in meat when it is cooked at a high temperature until well-done. There is suggestive experimental (46) and epidemiologic (25,26,47,48) evidence supporting a role for dietary HCAs in lung carcinogenesis. We were not able to estimate dietary HCA intake from our food frequency questionnaire. However, we believe that HCAs are not the causal agents underlying the observed association between lung adenocarcinoma and fried meat intake in this study. Chinese-style cooking produces low levels of HCAs (40,49–51). Previously, we have reported low to non-detectable urinary biomarker levels of HCAs in a Chinese population (52). These data were further supported by results from a case-control study of non-smoking Chinese women from Singapore that reported no association between dietary HCAs and lung cancer risk (53).

We reported that the statistically significant positive association for fried meat intake and lung adenocarcinoma risk was confined to cases with a shorter duration of follow-up. This finding suggests that the adverse effect of fried meat intake may be most evident in later stages of lung carcinogenesis, although the relevant experiments have yet to be conducted in order to test a late-stage hypothesis. There is experimental evidence supporting a role for cooking-fume constituents, for which there is reasonable overlap with fried meat constituents (19,44), as promoters of lung cancer development by inducing proteins that are involved in regulating apoptosis and tumor angiogenesis (54,55). If the results from future experimental studies support a late-stage model for the fried meat-lung cancer association, then our findings would carry important and encouraging prevention implications because a lower lung cancer risk could be realized within a relatively short time period following an individual’s reduction in fried meat intake.

After stratification by smoking status, we reported that the positive association between fried meat intake and lung adenocarcinoma was most apparent among never smokers. We do not interpret this finding to indicate that smokers are immune to the adverse effects of fried meat intake on lung adenocarcinoma risk. In fact, it is biologically plausible that tobacco-related and fried meats-related lung carcinogenesis share common etiologic pathways given that many of the probable causative carcinogenic agents detected in fried meats and accompanying cooking fumes (14,24,44) are also present in tobacco smoke (56,57). Under this common pathways model, we would expect that fried meat intake and smoking would have additive interacting effects on lung adenocarcinoma risk. In this study, current smoking exhibits a relative risk of 3.0 for lung adenocarcinoma (Table II), and high intake of fried meat exhibits a relative risk of 1.5 for lung adenocarcinoma in lifetime never smokers (Table III). Using these relative risks and assuming an additive interaction model, the joint effect of smoking and fried meats intake on lung adenocarcinoma risk would be 3.5 (=1.5 + 3.0 – 1.0). In other words, among current smokers, the relative risk of high versus low intake of fried meat would be 1.17 (=3.5/3.0). A sample size many times larger than this study would be required to detect such a small increase in risk with any statistical certainty. Therefore, it is not surprising that our finding for fried meat intake and lung adenocarcinoma risk was not statistically significant among smokers.

A notable strength of this study was the baseline collection of dietary history (e.g. prior to lung cancer diagnoses), thereby eliminating the opportunity for differential recall bias to adversely influence our findings. In addition, with the large percentage (69%) of lifetime never smokers in the cohort, an average of 11.8 years of follow-up per never smoking subject and 501 714 cumulative person-years of lifetime never smokers, this study had sufficient statistical power to provide unequivocal results on fried meat intake and lung cancer risk among never smokers. Limitations of our data were that we assessed fried meat intake only at the baseline interview. Thus, an alternative explanation for the positive association for fried meat intake and lung adenocarcinoma risk among cases with a shorter duration of follow-up is that prolonged follow-up without updating of interim exposure could lead to larger non-differential misclassification that would have a larger impact on the late versus early years of follow-up. In summary, the magnitude and statistical significance of our observed associations and their specificity for lung adenocarcinoma together provide confidence in the interpretation of the presented results.

Conclusion

Cigarette smoking is the primary cause of lung cancer (3), but lifetime never smokers comprise approximately 10–15% of all lung cancer diagnoses (6,7). Identification of etiological factors for non smoking-related lung cancer would help the development of a targeted cancer prevention strategy. We provide the first prospective evidence in support of the hypothesis that fried meat intake, as a surrogate for exposure to compounds on the meat surface that were generated during Chinese-style high-temperature cooking, increases risk of lung adenocarcinoma. Future prospective studies are warranted to confirm the findings of this study and to further investigate compounds in meat that were generated during high-temperature wok cooking as causes of lung adenocarcinoma.

Funding

National Institutes of Health’s National Cancer Institute (grant numbers R01CA55069;, R35CA53890;, R01CA80205; and R01CA144034).

Supplementary Material

Acknowledgements

We thank Ms Siew-Hong Low of the National University of Singapore for supervising the field work of the Singapore Chinese Health Study.

Glossary

Abbreviations:

References

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