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INTERNATIONAL JOURNAL OF ONCOLOGY 13: 0-00, 1998 Lifestyle factors and human lung cancer: An overview of recent advances (Review) YING-XIU DUt, BAO-SEN ZHOUZ and JOSEPH M. WUZ tDepartment of Preventive Medicine, Guangzhou Medical College, Guangzhou, China; ZDepartment of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA Abstract. This article presents a review on the association between certain lifestyle characteristics and the risk for lung cancer in humans, using information derived primarily from epidemiological studies. Emphasis will be placed on more recently identified risk factors such as exposure to indoor air pollutants, psychosocial and behavioral influences, diet preferences, and fat intake. More traditional lifestyle factors such as cigarette smoking, occupation, and exposure to outdoor air pollutants will not be reviewed since their association with an increased risk for human lung cancer has been relatively well characterized and extensively reported. Evidence to date suggests that the indoor"environment, life's events, and food choices may play a potentially important, albeit varying, role in the etiology of human lung cancer. Contents 1. Introduction 2. Nature of cancer and influence of low dose exposure to external agents on the incidence of cancer 3. Changing trends of histologic types of lung cancer 4. Emerging lifestyle characteristics as recently identified risk factors for lung cancer in humans 5. Conclusions 1. Introduction Epidemiology has been an important tool to provide leads and clues on the etiology of diseases. Data derived from a combination of ecological, case-control and cohort epidemiological studies have unequivocally demonstrated that the environment and lifestyle choices play a crucial role in disease development and manifestation. Some thirty years Correspondence to: Professor Joseph M. Wu, Department of Biochemistry and Molecular Biology, New York Melcal Collepae, Vplhalla, NY 10595, USA Key words: lifestyle factors, lung cancer ago a WHO report had forewarned of the possibility that as much as 70% of all human cancers would be caused by extrinsic factors. These refer to the entire range of environmental events encountered in living, including but not limited to exposure to mutagens and carcinogens (1). Because of tremendous strides made on various scientific fronts during the last several decades of 20th century, the science of environmental health appears to have reached a pinnacle in certain areas. As an example, illnesses due to some specific infections that were considered leading causes of morbidity and mortality in many countries including the United States at the beginning of the century are now virtually eradicated. Nevertheless, our ability to predict status of future health for the population in general has remained inadequate, probably in part due to insufficient consideration given to the role of lifestyle factors in health and disease. A growing view is that many form of lifestyle events predispose towards ill health, influence both the lifespan and the type of disease most of us suffer, and warrant more study than they have been accorded in the past. The subtleties of lifestyle factors, as is now beginning to be comprehended, have become virtually as encompassing as the dynamics of life itself. Cancer is a constellation of over 100 different diseases, all characterized by the uncontrolled growth and spread of abnormal cells. Common to all cancers is the characteristic multiple genetic changes, that include activation or over- expression of dominantly acting oncogenes, as well as loss of recessive growth regulatory genes (anti-oncogenes), that contribute to unrestrained cancerous cell growth, ultimately producing malignant tumor (3). As a malignant tumor develops, it compresses, invades, and/or destroys the surrounding normal tissue, and eventually spread to other parts of the body by a process referred to as metastasis. Cancer is one of the leading causes of death in the United States, accounting for approximately 370,000, or one out of five deaths each year. Of these, about 150,000 are due to lung cancer, which is the leading cause of cancer deaths in males (2). The tendency for lung cancer cells to metastasize is particularly great, and as a result the prognosis for lung cancer patients is bleak, with an approximately 92% mortality (2). Annual global deaths attributable to lung cancer have been rising steadily over the last three decades (4-6). It is

2 DU et af: LIFESTYLE FACTORS AND HUMAN LUNG CANCER be accounted for by the three risk factors, viz., cigarette smoking, occupational exposure to asbestos, arsenic and radon, and exposure to outdoor pollution, which are often considered most important in the etiology of lung cancer (5). Recent studies have suggested, however, that 'modern' lifestyles, such as exposure to substances generated indoors, psychosocial and behavioral factors, changing preferences in the diet, excessive intake of saturated fat, etc., may also play a significant role in the rising incidence of lung cancer in humans (4,5). The notion that lung and other cancers may correlate with 'modem' or 'urban' factors has received increasing attention and support in recent years, both in developed and developing countries (7-11). In a thirteen-population analysis of urban and rural cancer attributable mortalities, Doll suggested that lifestyle factors such as cigarette smoking, alcohol consumption, sexual promiscuity, exposure to ultraviolet light, type of diet and family size, may contribute to the observed urban excess in lung and several other forms of cancer (7). In this review we will summarize recent advances made of the association between lifestyle factors and the risk for lung cancer in humans, based on pYesentations at a symposium in which data obtained in China were compared and contrasted with those obtained in Western societies (12). 2. Nature of cancer and influence of low dose exposure to external agents on the incidence of cancer Cancer frequently affects the elderly and individuals in late middle age. The age-dependence is due to the fact that cancers usually have long latency periods. That is,-there is a delay of several decades or more between the initiation of exposure to a carcinogen and the development of the disease syndrome. For lung cancer the period of latency may be as long as 30 years or more, which makes it exceedingly difficult to conclusively identify a specific causal agent. For example, during this latency period an individual may experience a change in occupation, socioeconomic standing, place of residence, nutritional status, and personal habits, e.g., smoking. These commonly encountered changes tend to confound the epidemiological evaluation of purported risk factors, especially those related to low dose exposure to difficult-to-quantify single agents or complex mixtures, in the etiology of lung cancer. Another complication in interpreting data from low dose exposure studies comes from the realization that insult and damage to cellular DNA, potentially of relevance and consequence to carcinogenesis, are constant and ongoing events. Moreover, episodic genetic challenges not only occur due to exposure to external agents, but may also be generated endogenously, as part of normal metabolic turnover (13). Endogenous production of mutagens may be significant in at least two respects. First, by modifying DNA continuously, endogenous mutagens may contribute to the etiology of human cancer and other ge etic disease, although its generation may not be detected easily or be distinct from those generated exogenously. In a 'recent study thp levels of the major malondialdehyde-DNA adducts from disease-free human liver were found to be comparable, by~ mass spectrometric analysis, to the highest levels of adducts Second, in contrast to situations where humans are heavily exposed to known carcinogens, in which neither DNA damage by endogenous mutagens nor protection against damage should be relevant and of consequence, endogenous mutagen production and the consumption of foodstuffs that protect against DNA damage should be accorded due weight and consideration as contributing factors in evaluating cases involving only a low level of exposure to environmental mutagens. 3. Changing trends of histologic types of lung cancer Although there are as many as 13 cell types in lung cancer, the four most common ones are squamous cell carcinoma (SCC), adenocarcinoma (AC), small cell carcinoma and large cell carcinoma. SCC and AC constitute more than 80% of the total lung cancer cases. Recent advances in lung cancer research and diagnosis, however, have made it clear that, even within classically defined types of lung cancer, which by all standard criteria should be uniform, molecular and cytogenetic heterogeneity exist. Similarly, different clinical outcomes have been observed in treating seemingly identical types of lung cancer. Although it is not yet known whether the observed clinical differences are due to inherent stochastic nature of the cancer processes or to yet-to-be discovered molecular substratifications, the subtle diversity of both laboratory and clinical observations, in the pathogenesis of lung cancer is consistent with complex etiologies for the disease. SCC is the most common form of lung cancer in men. It originates centrally in the epithelial cells lining the large bronchial membrane near the hilus of the lung. By contrast, AC, the most common form of lung cancer in women, tends to arise in the peripheral airways and may possess distinctive intracellular mucin granules as part of their acinar/glandular differentiation. Many of the peripherally arising adeno- carcinomas have ultrastructural features and biochemical profiles characteristic of type Il pneumocytes (15). Also, many of the adenocarcinomas have reported papillary features, which are morphologically and biologically related to bronchio-alveolar carcinomas, suggesting that these adenocarcinoma subtypes may share a common histogenetic origin (16). Whereas cigarette smoking mainly induces SCC, AC is poorly or not at all correlated with smoking (12,15,16). Also, AC.is most prevalent in cases involving non-smoking females. Taken as a whole, these data suggest that factors other than smoking may be primarily involved in the etiology of AC. Another interesting development in lung carcinogenesis relates to the recently observed shift toward a higher incidence of adenocarcinoma, away from squamous cell carcinoma. Such a trend change has been reported both in developed (U.S.) and developing (China, Korea) countries and even within different regions of the same country (17-25). Li and coworkers compared the percentage of squamous cell carcinoma (SCC) versus adenocarcinoma (AC) in Guangzhou, China, for the periods 1978-1984, 1985-1989, 1990-1994, and reported that the rate of SCC decreased progressively whereas the incidence'of AC increased ~,,,r,7R..mll., .,,.,.. d.,. 1( ..-- .........1 /I 1 r ... ,d 1 ..,,,. (`.,.,-or

INTERNATIONAL JOURNAL OF ONCOLOGY [ 3: 0-00, 1998 14: abs. 5245, 1996). Thus, between 1978-1984, 68.7% of lung cancer cases was SCC, as compared to 38.8'fo in 1990- 1994. For the same sub-periods, there was almost a 3-fold increase in the proportion of AC (from 19.3% to 47.5). Choi et al (26) reported a similar progressive increase in the incidence of adenocarcinoma, especially in non-smokers by reviewing hospital records of lung cancer patients at Yonsei University Medical Center in South Korea. Wu et al (27) reported an increase in the frequency of adenocarcinoma in male lung cancer cases in Los Angeles County for the period 1972-1981, in the background of an essentially constant total lung cancer incidence. Similar trend changes in the histologic pattern of lung cancer have been reported for population in Midsouthern United States (covering Tennessee, Alabama, Mississippi, Arkansas, Missouri and Kentucky) between 1964 and 1985 (28), and in Connecticut (29). The changing distribution of lung cancer histologic types commonly observed in different countries and regions with diverse social and political systems and values makes a convincing argument for considering factors other than cigarette smoking, occupational exposure, and atmospheric pollution as being linked to risks for lung cancer in humans. 4. Emerging lifestyle characteristics as recently identified risk factors for lung cancer in humans Indoor air pollution and lung cancer. The problem of indoor air pollution is not new, as by-products of combustion have plagued mankind since fire was discovered. In recent years much attention has been given to the quality of the indoor environment and to measurement of indoor air'pollutants. This emphasis is in part based on the observation that modern people tend to spend up to 90% of their times indoors (30,31). Numerous scientific investigations have reported that air inside office buildings and residences is marred by numerous contaminants, some of which are apparently in sufficiently high concentrations to adversely affect the health of those exposed. Sporadic reported outbreaks of illness in office and other public access building, as well as homeowner complaints of building- related illness, lend support to the notion that indoor air pollution can cause serious health problems. In developed countries, concern with energy conservation in the seventies resulted in construction of building with airtight indoor environments and significant reduction in the air exchange rates. As a result, a new set of disease, commonly referred to as 'sick-building syndrome', has been described (32-34). Indoor air pollution as a suspected etiological factor for lung cancer in humans is best illustrated and supported by studies performed in China and the Pacific Rim region, especially those involving non-smoking females. It has been recognized for a number of years that Chinese women, few of whom are smokers, have much higher ratesof lung cancer than might be anticipated. In addition, they tend to be tliagnosed with lung cancer at a young age,,.y+ith adeno- carcinoma constituting a high percentage of lung tumars diagnosed. Numerous studies performed in Chinese cities, e.g., Harbin (35), Tianjin (Wang QS, et a(, Lung cancer 16: abs. S239, 1996), Shanghai (20,36), Shenyang (37; Zhou BS, 3 Table I. Comparison of air pollutants and urine B(a)P levels in housewives. Cooking with coal Cooking with propane gas CoaV propane SOz ([t/M') 279 58 4.81 No, (µ/M') 76 63 1.21 CO (p/M3) 9,424 2,340 0.03 TSP (µ/M3) 332 188 1.77 SD (g/M2/month) 12 5 2.40 B(a)P (µ/100 M') 11.9 2.2. 5.41 Radon (Bq/M3) 18.6 16.1 1.12 Thoron (BqlM3) 42.5 28.3 0 150 Urine-B(a)P (ng/I) 4.0 28 1.43 Guangzhou (4), Taiwan (21), and Hongkong (40) have consistently found a high incidence of lung cancer in non- smoking females. As pointed out before, the progressive shift in the rising incidence of adenocarcinoma is not limited to developing countries. For example, adenocarcinoma was found to be the predominant histologic type in both male non-smokers (70.8%) and female non-smokers (59.4%) in a 1995 published study published in the U.S. (41). In the case of studies performed in the Chinese cities mentioned above, although these cities have diverse and different cultural and economic backgrounds, they share, in common, significant and severe indoor air pollution, caused either by fumes generated during cooking or smoke derived from burning coal for purposes of heating or food preparation. Gao and co-workers reported that indoor air pollution and the use of rapeseed oil for cooking significantly increased the occurrence of female lung cancer in Shanghai (20,36). Dai and co-workers showed, after adjusting for smoking, that indoor coal stoves and fire pits used for heating increased risk of female lung cancer in Harbin (35). Shen et a1 (39) analyzed cancer risk factors in Nanjing in both squamous cell carcinoma and adenocarcinoma in the lung and reported that a primary risk factor is the exposure to kitchen cooking fumes. Women in Tianjin living in rundown one story houses in close proximity to low boiler chimneys and being exposed to burning coal smoke from workshops were reported to have higher risks of lung cancer (42). Domestic coal consumption was suggested to be a primary risk factor for female lung cancer in Guangzhou (43) by Du and coworkers who also reported higher benzo(a)pyrene [B(a)P] content in urine of individuals working in the coal-burning indoor environments, compared to those in propane-burning households. Differences in suspended dust, suspended dust-B(a)P, sedimentary dust, and sedimentary dust-B(a)P, were also noted in the two different indoor environments (Table q. In a 1:2 case-control study, Ger et al (21) reported that employment as a cook was a significant risk factor for adenocarcinoma of the lung, and proposed that the increased risk may be due to the extensive exposure of cooks to airborne mutagens and carcinogens (44).

4 DU er al: LIFESTYLE FACTORS AND HUMAN LUNG CANCER health in general, and to increasing the risk for lung cancer in particular, was summarized in a recent review (45). Taken as a whole, results of these studies support the notion that mutagens and/or carcinogens present in indoor air may have a significant direct or indirect impact on the health status of the exposed individuals. Although indoor air pollution appears to be a significant risk factor for lung cancer in females, a number of unresolved questions regarding its actual role in female lung carcino- genesis remain. For example, use of coal for cooking/heating or use of vegetable oil for food preparation have been practiced in China for many years, why then should the lung cancer rate in non-smoking females only begin to rise during the past 20 or 30 years? Moreover, what is responsible for the predominant incidence of adenocarcinoma in non-smoking females? Equally puzzling is the fact that the same rising trend of female lung cancers, predominantly adenocarcinomas, has been found both in developed and developing countries, that are known to have striking differences both with respect to the sources and characteristics of indoor air pollution (46-48). Clearly more research is needed before a definitive unifying theme can be developed with respect to the involvement of indoor air pollution as a risk factor for lung cancer in humans, especially in non-smoking females. Exposure to environmental tobacco smoke (ETS) and lung cancer. Another indoor air pollutant that has been widely researched and publicized is ETS, which refers to the combination of sidestream smoke (given off from the tip of the cigarette between puffs) and exhaled mainstream smoke. The relationship of exposure to ETS and risks for lung cancer is one of considerable controversy and debate, because inconsistent and equivocal data regarding its association with lung cancer risks have been reported, both, in developing and developed countries. The majority of studies addressing the contribution of exposure to ETS in increasing the incidence of lung cancer are based on non-smoking women whose husbands smoke. It should be realized that, more likely than not, data and conditions of the non-smokers' exposure, such as numbers of cigarettes smoked by the smokers, the extent of close contacts with the smokers, and the conditions of the shared living space, are expected to be variable. In China, studies from Harbin, Shanghai, Guangzhou and Xuanwei all reported no association between exposure to ETS and incidence of lung cancer in females (49,50). Studies from other countries have produced mixed results- Some found no relationship between the two; others, while finding ETS an important risk for lung cancer in females, disagree on the type of lung cancer induced by exposure to ETS. Some have found an association between exposure to ETS and an increased incidence of adenocarcinoma only, while a number of other studies reported exposure to ETS to significantly increase the risk for squamous cell carcinoma only. Several ,recent reviews provided detailed analysis for many of the recent epidemiological studies supporting oi refuting athe qssociation between exposure to ETS and risks for lung cancer in humans (51-55). Survey and review of the literature dealing with exposurc information on the uniformity of the definition for exposure to ETS and the levels to which populations are exposed. In quantifying an individual exposure it is desirable to have full information on past and present exposure to specific pollutants. Even in the best designed studies such information is not available. Because of the paucity of exposure data many epidemiological studies have used the residence with smoking family members (mostly spouses) as an index of exposure severity. The place of residence of an exposed population may, however, introduce a bias since it may be associated with ethnic and cultural traits, living standard, occupation and exposure to infectious agents. In addition, mobility, i.e., the duration of time that an individual has lived in the area may complicate the use of residence as an index of exposure severity (54). Moreover, many of the reported epidemiological studies failed to adequately consider confounding factors such as: misclassification, presence of existing disease, age of the affected person, activity/occupation pursued before death, individual sensitivity to different types of stress, documentation of diet and nutrition histories, personality and behavioral traits, meteorological conditions during exposure, control for exposure to atmospheric pollutants and occupational hazardous substances, interaction between pollutants, etc. (53,54). In an attempt to minimize these and other shortcomings, a recent US hospital case-control study asked detailed questions on all potentially important sources of ETS such as exposure in childhood and adulthood, exposure at work, in social situations, in car and other vehicle use (41). Data were also obtained on multiple spouses, room-mates, and other household members. Design and application of the questionnaire and strength of the study was checked and validated by showing excellent agreement between different items in the questionnaire relative to common exposure. Results of the study did not support an association between exposure to ETS with lung cancer in non-smokers. Given the mixed outcome of the reported findings, it is not likely that exposure to ETS possess a strong and significant risk for lung cancer. Its potential irritating properties and relatively minor health effects, whether perceived or real, should not be overlooked. Psychosocial/behavioralfactors and risk for lung cancer. Traditional methods for identifying risk factors in disease have involved evaluating single external factors of one kind or another. Using such an approach, it has been commonly observed that the impact and magnitude of a risk factor characterized in a given locale may differ significantly when examined in a different region, country, and culture. The explanation for such divergence in human response to a given factor, apart from the often-considered confounders of ethnicity, race and gender, may lie in the influence of psychosocial and behavioral traits. There is accumulating evidence that psychosocial factors can play a role in modulating response to a universally accepted risk, and may have an especially critical contribution in situations involving risks of marginal significance. In the case of cancer, there is ample documentation for individual risk factors showing relatively little itrfluence on cancer mnrralilv whrn cturtirrl nlnnn h„r nrnrlnrlno avnrrnicfir

INTERNATiONAL JOURNAL OF ONCOLOGY 13: 0-00. 1998 effects once combined with psychosocial considerations. Inability to express anger, emotional suppression, stressful life events, particularly in the period preceding the cancer diagnosis, have been variously correlated with risks for cancer. Grossarth-Maticek and coworkers provided evidence for the powerful effect personality and stress exerted on a person's likelihood of dying of cancer and coronary heart disease, and for their ability to interact strongly with more widely studied risk factors, such as smoking (56). Although little attention has been given to psychosocial factors in general, and to the social and psychological conditions of work and occupation in particular, in the context of occupation-related causes of lung cancer, there is now greater appreciation concerning the impact of loss events, including job losses, on cancer development. Recent stressful events, most often the loss of a close relative, spouse or friend, have been proposed to increase the risk for lung cancer (57-59). Such a theme is best illustrated by the report of Jahn and co-workers (57). The study involved 391 male case-control pairs, in which cases consisted of men of German nationality with a histologically- or cytologically- confirmed diagnosis of primary lung tancer, who were matched by age and region with population controls. The study considered life-event perspectives using the following criteria. First, the occupational history or the job-changing history was assumed to be an important domain of the male life. Second, the study considered loss or.negative events as well as gain- or positive events as independent factors in the analysis. The investigators also evaluated job changes and switches during the occupational measurement. Results of their analysis showed that men whose job-changing histories were described as involuntary had a 40-60% increased risk of developing lung cancer compared with men whose job- changing history was described as neutral. In another recently published study, Colby and co-workers (59) evaluated social stress and state-to-state differences in smoking and smoking related mortality in the United States by computing a 'state stress index' utilizing the criteria of stressful events such as divorce rate, business failures, natural disasters etc. it was reported that the 'state stress index' was significantly associated with increased lung cancer mortality and with more frequent chronic obstructive pulmonary disease. The influence of psychological factors and life events as possible risk factors for lung cancer were addressed in several Chinese epidemiological studies. Yu and co-workers reported that death of a family member, work conflicts and dissatisfaction, and difficulties with children, all significantly increased the risk for lung cancer (Yu ZF, et al, Lung Cancer 14: abs. 5241, 1996). Similar results were also reported by other Chinese investigators (60). In addition to directly increasing the risk for lung cancer, psychosocial/behavioral factors may also affect data interpretation in low-risk epidemiological srudies, as was I:ecently articulated in two published studies of Koo and coworkers (40,61). Behavioral factors which are proposedas hpving the most influence in the outcome of weak epidemiological studies include: design and questionnaire oversights, political perceptions and public attitudes 5 beliefs of the researchers, lay beliefs of causation among researched subjects, quality control deficiencies in studies with large sample size, circumstantial biases resulting in non- compliance with protocol specifications, and known and unknown confounders not adequately or appropriately controlled for by statistical adjustments. In terms of plausible mechanisms linking psychosociaU behavioral factors with cancer, one possibility is that heightened neural activity in an untimely manner may promote already initiated cancer cells through a stress- induced neuroendocrine mechanism, changing hormonal and immune status and hence functions (62,63). There is evidence that anger-suppressing personality type is associated with a specific antibody profile and that lymphocyte levels are depressed in subjects who have recently suffered the loss of a spouse. Based on these recent findings, it seems prudent that future research on risk factors for human lung cancer should take into account the involvement of psychosocial factors to a greater extent than is customary at present. It should however, be cautioned that if psychological factors are to be considered as having a more prominent role in future epidemiological studies, it will be essential that psychosocial instruments and questionnaires be standardized and that data on potential confounding variables be obtained and analyzed systematically. Diet and lung cancer. Laboratory studies conducted in the early 1930s using animals already gave the indication that diet can modulate the process of carcinogenesis. As early as 1942, Tannenbaum (64) showed an increased number of breast tumors in animals fed a high calorie or high fat diet as compared to the occurrence in animals maintained on normal diets. That diet could play a role in human cancer started to appear in the 1960s. As a result of the landmark report by Bjelke (65) that provitamin A-rich foods could afford protection for lung cancer, in recent years a large body of evidence has been accumulated on the ability of vegetables and possibly fruits for protecting against lung cancer, although there is still some uncertainly about the conclusion that can be draw from the extensive but at times conflicting data in the literature. Part of the difficulty in assessing the exact contribution of nutrition or a specific dietary component, insofar as risk for human lung cancer is concerned, lies in the inherent uncertainty in measuring and quantifying human diets. For example, the information on dietary habit used in virtually all published studies on diet and cancer covers only a limited period. In case-control studies, data on diet are usually available for a few years prior to diagnosis of cases and for an equivalent period for controls. In the few prospective cohort studies that have been done, information on diet was collected only once - at the time the subjects were enrolled - and no information was gathered on changes that may have occurred during the follow-up period. Moreover, diet comprises a very complex mixture of foods and beverages, which must be translated into terms of nutrient composition. Errors in measurements vary substantially for different nutrients and different methods. Dorgan (66) reported that in white females, a significant ,n.rr.r .,wnr cvinn rv,cirrl hrr,.rrn ,nt~4~ r.l' vrnrtahlrc

6 DU et al: LIFESTYLE FACTORS AND HUMAN LUNG CANCER fruit and carotenoids and the number of lung cancer cases, suggesting a protective effect of yellow/green vegetables and carotenoids for lung cancer. Black males, on the other hand, showed only a week inverse association of lung cancer with vegetables but not with carotenoids. In both groups increasing risk with decreasing intake was limited to smokers. Byers and co-workers reported an inverse associating between vitamin A intake and the risk for squamous cell carcinoma but not adenocarcinoma cancer of the lung (67). More recently, Candelora et a! (68) conducted a case-control study on lung cancer among non-smoking women. The results of analysis, adjusted for age, education, and total calories, indicated a strong protective effect associated with total vegetable consumption and intake of carotene. Foreman and co-workers (69) reported that vegetable intake protected against the adverse health effects of smoking and occupational exposure on lung cancer in miners. In an analysis stratified by histological type of lung cancer, Steinmetz and others (70) reported that a strong inverse associations existed between vegetables and fruit intake and the incidence of large cell carcinoma. Further, when analyzed by smoking status, the inverse association'for most vegetable and fruit groups with risk for lung cancer was found to be stronger for ex-smokers than current smokers. Gao and co- workers (71) also suggested that fruit and vegetables might play an important role in protecting smokers from lung cancer. Mayne and co-workers (72) proposed that consumption of green fresh fruits was associated with a significant dose-dependent reduction in risk for lung cancer. Wong and Foliar (73) suggested that nutritional factors could be associated with a modest increase in lung-cancer in Louisiana. Wu et al (74) found an increased risk of adenocarcinoma among women with low carotenoid intake. Pisani and others (72) found that the nutritional effects were only related to carrot consumption and not to green vegetable intake. Holst and co-workers (76) reported no effect of 6- carotene, but did find that low intake of vitamin C resulted in a significantly increased relative risk for lung cancer. Paganini and Willet (77,78) failed to find protective effects of fruit and vegetable consumption in their studies. Pierce and co-workers (79) reported that the dietary intake of foods containing retinol and 6-carotene was not significantly different between cases and controls. In a cohort study involving California men. Shibata (80) reported that the age- adjusted relative risk for lung cancer was reduced by yellow vegetable consumption and for higher relative to lower consumption of 13-carotene in all vegetable and fruit categories. LeMarchard and co-workers (81) reanalyzed a population-based case-control study of diet and lung cancer conducted in Hawaii in 1983-1985. The analysis suggested that no association be found for dietary lycopene or 6- cryptoxanthin intake and the risk for lung cancer. In a large Finnish primary prevention trial study involving male smokers, daily supplementation of diets with 4Stamin E and/ pr 8-carotene for up to eight years was not associated with reduction in risk for developing lung cancer (82)rtIigher intake qf carotene-rich vegetables was not protective against lung cancer in a study involving residents in Northeast China (83).. Block and co-workers (84) reviewed approximately 200 relation to cancer prevention. In general, the data are I consistent with the interpretation that the consumption of fruit and vegetables correlated with reduced cancer incidence. For lung cancer, a protective effect was observed in all but 2 of 32 studies, with the cancer risk in infrequent fruit/vegetable ~ consumers being, on average, 2.2-fold greater than in frequent consumers. In a number of studies, significant effects have been found even within strata of smokers or non-smokers. In the vast majority of studies, a dose-response relationship has been found in which those in the lower end of the distribution experience a cancer risk generally at least twice as high as those in the upper end. The demonstration of a strong and consistent association in the face of substantial variability in methodologies, exposure cut-off points, statistical analyses, and adjustments for confounding, in nations and populations (85-91) as different as the Netherlands, China, India, Turkey, and Upstate New York argues strongly for a protective effect of vegetable intake for lung cancer, and that the association is not a result of confounding by smoking, fat consumption, or of energy and fat intake, or socioeconomic status, or of publication bias. To date, few studies in China have addressed the relationship between diet and lung cancer. In one published study, the relationship between diet and lung cancer was studied in male miners in Yunan province (92). The results suggested that the cases consumed less protein-rich foods and vegetables than did the controls. Results from a population-based case-control study in Shanghai showed that the risk for lung cancer was lower among those with reduced consumption of carotene-rich foods. No effect on risk of lung cancer was found for consumption of retinol-rich foods (36). In Shenyang, a more frequent intake of retinol and carotene containing foods did not protect against lung cancer in smokers or non-smokers (35). It is important to point out that many of the populations in which protective effects have been observed do not have the same cluster of correlated i behaviors found in the developed countries. For example, in I many developing countries, the alternative to a high fruit/ . vegetable diet is not necessarily a diet high in fat or meat but . more likely one high in a starchy staple food such as rice. In ! Hong Kong, an association between vegetable intakes and a ; reduced risk for lung cancer was observed among non- . smoking women (40). In summary, a statistically significant protective effect of l, fruit and vegetables or their associated nutrients, for lung cancer was reported in most studies. Such a conclusion is '. consistent with our current understanding of the details of carcinogenesis For example, the central role of oxidative 1 events and free radical damage in cancer causation is well established, as is the fact that antioxidants can block or repair ' such damage. Since carotenoids are free radical scavengers, it is conceivable that they may react with a carcinogen in (n cigarette smoke. Such an effect would be consistent with the 0 lower blood B-carotene levels noted in smokers relative to non-smokers with comparable carotenoid intakes. N, Carotenoids may also influence cell differentiation. y.'. Because of the growing awareness in recent years that j.., dietary non-nutrient compounds can have extremely important effects on the consequences of exposure to ,{ ~ ~..n~t,~n, ..f ..thrr nNrnlinllv .- -. , ,rr mnnrnc rn,rc rnrl .,n n

INTERNATIONAL JOURNAL OF ONCOLOGY 13: 0-00, 1998 toxic materials, more studies need to be performed on the mechanism of action of non-nutrient dietary compounds such as tea tannin, flavonoids, terpenes, isothiocyanates, organo- sulfur compounds, protease inhibitors and inositols, in light of the recognition that such chemical could block the formation of carcinogens, induce detoxifying enzymes, and antagonize the effects of endogenous estrogens (93). Dietary fat and lung cancer. A specific dietary component deemed important in the pathogenesis of cancer, including lung cancer, is fat intake (94-100). Worth nothing is the fact that only total fat has been considered in most epidemiological studies, whereas in actuality dietary fat and fat incorporated in the human body comprise a large family of compounds. The per capita supply of animal fat was reported to be strongly associated with lung cancer mortality rates. In a cohort study of lung cancer cases, however, Chyou and co- workers (91) found that there was no association between lung cancer and the 24-h intake of total calories, protein, and fat. The results of this study may have limited significance since a 24-h dietary questionnaire was used. It is important to further investigate whether the association between fat intake and risk for lung cancer exists in different areas of the world because of different lifestyle and consumption habits among ethnic populations. For example, a level that is categorized as low intake in the United States may be considered relatively high intake in China. Although the exact mechanisms by which dietary fat promotes lung carcinogenesis are not known, a number of mechanisms may be proposed. Some of those possible mechanisms include: modulation of eicosanoid production, changes in membrane fluidity or microviscosity, alteration in energy consumption and metabolism, modulation of cell: cell interaction, alteration in gene expression. 5. Conclusions A disease such as lung cancer is most likely the outcome of multiple characteristics of the individual interacting with a number of interdependent factors in the individual's lifestyle context. In this review, evidence is presented that 'modern' lifestyles, such as exposure to substances generated indoors, psychosocial and behavioral factors, changing preferences in diet, excessive intake of dietary fat, etc. plays a potentially important, albeit varying role in the rising incidence of human lung cancers. The notion that lifestyle factors may be etiologically linked to lung cancer is significant in the context of what constitutes tumorigenesis. The major yardstick for the ability of tumor cells to grow indefinitely, as opposed to the limited life span that all normal cells have, both in vitro and in vivo, is considered to be controlled by multiple pathways. It is entirely possible that one or more of the eme.~ging lifestyle factors described in this review act at one or more of the pivotal steps in the multiple pathways leading to the tumorigenic phenotypes. Whetherthesc checkpoints are sktared in common with the three risk factors of cigarette smoking, occupational exposure to asbestos, arsenic aqd radon, and exposure to outdoor air pollution, traditionally 7 remains to be researched. However, should lifestyle factors prove to act on other sites than the three major risk factors for lung cancer, then focussing exclusively on a single risk factor, albeit a.major one may shortchange designing ways to eradicate risk factors for a disease such as lung cancer. 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